{ "count": 1408, "items": [ { "id": "u-phononic-crystal-3d-complete-band-gap", "title": "What is the minimum impedance contrast required for a complete 3D phononic band gap (forbidding sound in all directions and polarizations), and can such structures be fabricated at audible frequencies?", "status": "open", "domain": "acoustics", "systematic_gaps": [ "Complete 3D phononic band gap has only been demonstrated at ultrasonic frequencies in mercury/steel composites", "No theoretical lower bound on the impedance contrast for a complete 3D gap has been proven", "Manufacturing tolerances at audible frequency scales (centimeter unit cells) are unstudied" ], "suggested_hypotheses": [], "file": "unknowns-catalog/acoustics/u-phononic-crystal-3d-complete-band-gap.yaml" }, { "id": "u-phononic-crystal-active-tunable-band-gap", "title": "Can phononic crystal band gaps be dynamically tuned over a 2:1 frequency ratio in real time using active mechanisms (piezoelectric, fluidic, magnetic), and what are the fundamental limits on tuning speed and bandwidth?\n", "status": "open", "domain": "acoustics", "systematic_gaps": [ "Active tuning has been demonstrated over <30% frequency range in most systems", "Speed of band gap switching has not been characterised for any active phononic crystal", "Topological phase transition by active tuning has only been proposed, not demonstrated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/acoustics/u-phononic-crystal-active-tunable-band-gap.yaml" }, { "id": "u-neural-correlates-consciousness-anesthesia-mechanism", "title": "What are the specific neural circuit mechanisms by which general anesthetics suppress consciousness — is it primarily thalamo-cortical disconnection, loss of cortical complexity (integrated information), suppression of specific oscillatory modes, or some combination?\n", "status": "open", "domain": "anesthesia", "systematic_gaps": [ "Thalamo-cortical vs. cortico-cortical pathway contributions have not been dissociated pharmacologically (thalamus-specific vs. cortex-specific GABA-A subtypes are poorly characterized).", "IIT's predictions about Φ under anesthesia have not been tested with sufficient neural data resolution to estimate Φ in humans.", "The specific network connectivity changes (effective connectivity during anesthesia) have not been comprehensively mapped across anesthetic agents." ], "suggested_hypotheses": [], "file": "unknowns-catalog/anesthesia/u-neural-correlates-consciousness-anesthesia-mechanism.yaml" }, { "id": "u-antibiotic-resistance-evolution-rate-clinical-deployment", "title": "Can the rate of antibiotic resistance evolution to a novel antibiotic be predicted before clinical deployment ΓÇö and what antibiotic features (target essentiality, mechanism of action, penetration, efflux susceptibility) best predict resistance emergence timelines?\n", "status": "open", "domain": "antimicrobial-resistance", "systematic_gaps": [ "Pre-clinical resistance evolution rate (mutations per antibiotic type in serial passage) has not been systematically correlated with clinical resistance emergence timelines across antibiotic classes.", "The role of horizontal gene transfer (plasmid-borne resistance) vs. chromosomal mutation in determining resistance timeline is not predictable a priori for novel antibiotics.", "PK/PD target attainment (time above MIC, AUC/MIC) and its effect on resistance suppression vs. selection is not quantitatively modeled at the clinical population level for novel scaffold antibiotics." ], "suggested_hypotheses": [], "file": "unknowns-catalog/antimicrobial-resistance/u-antibiotic-resistance-evolution-rate-clinical-deployment.yaml" }, { "id": "u-threshold-selection-bias-in-evt-based-amr-early-warning", "title": "What validation boundary conditions determine when `b-extreme-value-theory-x-antimicrobial-resistance-surveillance` remains decision-useful?", "status": "open", "domain": "antimicrobial-resistance", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-peaks-over-threshold-models-improve-amr-outbreak-early-warning" ], "file": "unknowns-catalog/antimicrobial-resistance/u-threshold-selection-bias-in-evt-based-amr-early-warning.yaml" }, { "id": "u-aesthetic-preference-neural-basis", "title": "What neural circuits and computational principles underlie aesthetic preference, and are these circuits domain-general or art-form specific?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "fMRI studies of aesthetic response are largely underpowered and use convenience samples from art-naive Western populations.", "The computational role of the orbitofrontal cortex in aesthetic vs. other reward evaluation has not been disambiguated.", "Whether aesthetic preference is a single construct or a family of related but separable processes (formal beauty, emotional resonance, novelty appreciation) has not been tested with confirmatory factor analysis." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-aesthetic-preference-neural-basis.yaml" }, { "id": "u-architectural-emotional-impact", "title": "What physical properties of built environments causally affect psychological well-being, stress, and cognitive performance?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Randomized controlled trials of architectural modifications and their effects on wellbeing in real buildings are rare due to cost and logistical constraints.", "The relative contributions of lighting spectrum, spatial volume, visual complexity, and acoustic characteristics to psychological outcomes have not been independently varied in an adequately powered study.", "Cultural variation in architectural preference and its interaction with psychological effects has not been systematically mapped." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-architectural-emotional-impact.yaml" }, { "id": "u-collective-vs-individual-creativity", "title": "Under what conditions does group collaboration enhance vs. inhibit creative output compared to individuals working alone?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Studies comparing individual vs. group creativity almost universally use laboratory tasks (unusual uses, remote associates) that may not generalize to professional creative domains.", "The role of implicit knowledge sharing in face-to-face creative collaboration (vs. remote) has not been adequately controlled in productivity comparisons.", "Longitudinal studies of creative team formation and dissolution are rare; whether team creative chemistry develops or declines over time is mostly anecdotal." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-collective-vs-individual-creativity.yaml" }, { "id": "u-color-emotion-mapping", "title": "Is the mapping between colors and emotional valence universal or culturally constructed, and what are the physiological mechanisms?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Cross-cultural studies of color-emotion associations are rarely pre-registered and often use convenience samples from WEIRD populations.", "The physiological hypothesis (wavelength effects on melanopsin → arousal) has been tested in laboratory conditions but not connected to real-world color-emotion associations.", "Whether color-emotion associations are learned in childhood or develop through exposure to culturally specific color symbolism (flags, marketing, art) has not been tracked longitudinally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-color-emotion-mapping.yaml" }, { "id": "u-creativity-intelligence-correlation", "title": "What is the relationship between general intelligence (g) and creative ability, and does the threshold hypothesis hold above IQ 120?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Studies testing the threshold hypothesis use heterogeneous creativity measures (divergent thinking tests, real-world achievement, expert ratings) that may tap different constructs.", "The few samples with sufficient high-IQ subjects are not representative; longitudinal studies of exceptional intellectual talent (SMPY) use self-report creativity.", "Whether the threshold (if real) applies to domain-specific creativity (mathematical vs. artistic) or only general creativity is untested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-creativity-intelligence-correlation.yaml" }, { "id": "u-flow-state-neural-signature", "title": "What are the neural and physiological signatures of the \"flow state\" (optimal experience), and can flow be reliably induced and measured?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "No study has measured neural activity during naturalistic high-skill performance (not laboratory tasks) and confirmed flow via concurrent psychophysiological or behavioral measures.", "The skill-challenge balance hypothesis predicts a narrow optimal zone, but the exact shape of the skill-challenge-flow relationship has not been parameterized empirically.", "Whether flow improves performance quality (beyond engagement effects) has not been tested with objective performance metrics in high-skill domains." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-flow-state-neural-signature.yaml" }, { "id": "u-humor-cognitive-mechanism", "title": "What is the computational and neural mechanism of humor comprehension, and why does incongruity resolution trigger positive affect?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "The boundary between what is funny and what is merely surprising or clever is not computationally characterized beyond informal descriptions of \"benign violations.\"", "Individual differences in humor comprehension (which correlates with Theory of Mind, language ability, and working memory) have not been fully mapped neurally.", "Cross-cultural variation in humor content vs. humor structure (mechanism) has not been disentangled in a large pre-registered study." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-humor-cognitive-mechanism.yaml" }, { "id": "u-improvisation-neural-correlates", "title": "What neural mechanisms distinguish improvised from rehearsed musical performance, and does improvisation require deactivation of executive control?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "fMRI studies of improvisation face a fundamental problem: the motor demands of playing an instrument while lying in a scanner are not matched to the realistic improvisation context.", "Whether DMN activation during improvisation reflects self-referential processing, prospective memory, or semantic conceptual integration has not been dissociated.", "Cross-domain studies of improvisation (visual arts, dance, comedy) sufficient to identify domain-general neural signatures do not exist." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-improvisation-neural-correlates.yaml" }, { "id": "u-metaphor-abstract-thought", "title": "Is abstract thought fundamentally grounded in sensorimotor metaphor (conceptual metaphor theory), or can genuine amodal abstract representation exist?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "The sensorimotor activations reported in embodied cognition studies are small and may reflect processing of metaphorical language rather than abstract conceptual structure.", "The boundary between genuinely embodied and arbitrarily symbolic concepts has not been formally drawn; the theory makes no clear predictions about which concepts should be embodied.", "Cross-linguistic tests of conceptual metaphor theory using truly distinct metaphor systems (not translations of English metaphors) are rare." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-metaphor-abstract-thought.yaml" }, { "id": "u-mirror-neuron-aesthetic-cross-cultural", "title": "Is aesthetic pleasure mediated by mirror neuron motor resonance universal across cultures, or does it depend on culturally specific motor repertoires and embodied experience?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Neuroimaging studies comparing motor cortex activation during art viewing across cultures with different art traditions and motor repertoires do not exist at sufficient scale.", "Whether the aesthetic uncanny valley effect for robot motion is universal or shows cultural variation (e.g. Japan vs. Western cultures with different robot familiarity) has not been tested neuroimaging-based.", "The contribution of cultural familiarity versus biological motor universals to dance aesthetics has not been disentangled using controlled paradigms." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-mirror-neuron-aesthetic-cross-cultural.yaml" }, { "id": "u-music-universals", "title": "Are there universal features of music across human cultures, and what are the cognitive or evolutionary origins of these universals?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Cross-cultural music psychology studies are methodologically heterogeneous; direct comparison of findings across populations is difficult.", "The corpus of analyzed musical traditions is biased toward written, Western, and recorded music; oral traditions of small-scale societies are underrepresented.", "Whether the universality of musical features reflects universal perceptual constraints or common social functions (that could be met by different musical structures) has not been disentangled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-music-universals.yaml" }, { "id": "u-narrative-comprehension-brain", "title": "What brain regions and computational processes support the construction of narrative mental models during story comprehension?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Event segmentation theory predicts DMN activity at narrative event boundaries, but the content of DMN representations (what is being computed) is not established.", "Cross-linguistic and cross-cultural neuroimaging of narrative comprehension has not been conducted at sufficient scale to identify universal vs. language-specific circuits.", "The developmental trajectory of narrative comprehension abilities and their neural substrates has not been mapped from early childhood to adulthood with longitudinal imaging." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-narrative-comprehension-brain.yaml" }, { "id": "u-rhythm-synchronization-social", "title": "What is the social function of rhythmic synchronization in music and collective movement, and does entrainment causally increase prosocial behavior?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Many synchrony-prosociality studies used demand characteristics (participants know they are synchronizing); pre-registered blind replication studies are rare.", "The physiological mechanism linking motor synchrony to prosocial behavior (oxytocin? mirror neuron activation? shared arousal state?) has not been established.", "Longitudinal studies of rhythmic training effects on social behavior in children are few and have not found consistent effects outside musical contexts." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-rhythm-synchronization-social.yaml" }, { "id": "u-synaesthesia-mechanism", "title": "What neural mechanisms produce synesthesia, and why does cross-activation of perceptual modalities occur in approximately 4% of the population?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "Direct structural connectivity between grapheme-color synesthetes' V4 and VWFA regions has not been consistently demonstrated by diffusion tractography.", "Whether synesthetic color percepts are truly perceptual (early visual cortex) or conceptual (higher-order color representations) cannot currently be resolved by existing methodology.", "The developmental critical period for establishing synesthetic associations, and why they persist immutably across adulthood, has not been characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-synaesthesia-mechanism.yaml" }, { "id": "u-visual-art-emotional-response", "title": "What visual features of artworks reliably evoke specific emotional responses, and does the \"aesthetic emotion\" differ from ordinary emotion?", "status": "open", "domain": "art-and-cognition", "systematic_gaps": [ "The aesthetic distance between art-evoked and real-world emotion has not been quantified physiologically (autonomic signatures, hormonal markers).", "Computational models of emotional response to visual art do not generalize across art styles and cultural contexts.", "The experience of \"being moved\" (Kama Muta) overlaps with aesthetic chills but the two have not been clearly dissociated in neuroimaging experiments." ], "suggested_hypotheses": [], "file": "unknowns-catalog/art-and-cognition/u-visual-art-emotional-response.yaml" }, { "id": "u-astronomical-source-matching-structured-outlier-robustness", "title": "How robust are RANSAC-family geometric source-matching methods when astronomical outliers are spatially clustered, quality-ranked, and caused by blends or survey artifacts rather than uniform random contamination?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Public benchmark with injected blends, cosmic rays, proper-motion shifts, and spatially clustered artifacts.", "Comparison of uniform RANSAC, PROSAC-style ranked sampling, and survey-specific Bayesian matchers." ], "suggested_hypotheses": [ "h-quality-ranked-ransac-improves-astrometric-crossmatch-precision" ], "file": "unknowns-catalog/astronomy/u-astronomical-source-matching-structured-outlier-robustness.yaml" }, { "id": "u-baryon-asymmetry-origin", "title": "What is the mechanism of baryogenesis that produced the observed matter-antimatter asymmetry?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Sakharov conditions require B violation, CP violation, and departure from equilibrium", "Standard Model CP violation is insufficient by many orders of magnitude" ], "suggested_hypotheses": [ "Leptogenesis from heavy Majorana neutrino decay in the early universe generates sufficient baryon asymmetry via sphaleron processes" ], "file": "unknowns-catalog/astronomy/u-baryon-asymmetry-origin.yaml" }, { "id": "u-black-hole-information-paradox", "title": "Is information destroyed by black hole evaporation, and if not, how is it encoded in Hawking radiation?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Page curve requires information to escape before page time", "Island formula and replica wormholes provide calculation but physical mechanism unclear" ], "suggested_hypotheses": [ "Gravitational replica wormholes encode quantum information in Hawking radiation correlations that only become detectable after the Page time" ], "file": "unknowns-catalog/astronomy/u-black-hole-information-paradox.yaml" }, { "id": "u-cgm-enrichment", "title": "How is the circumgalactic medium enriched with metals and what is its role in the baryon cycle?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Quasar absorption spectroscopy reveals CGM metallicity ~0.1 solar", "Mechanism of metal transport from galactic disk to CGM poorly constrained" ], "suggested_hypotheses": [ "Supernova-driven galactic winds efficiently transport metals to the CGM at z>2, and the CGM acts as a reservoir for future star formation" ], "file": "unknowns-catalog/astronomy/u-cgm-enrichment.yaml" }, { "id": "u-cluster-cooling-flows", "title": "Why do galaxy cluster cooling flows not form stars at the rates predicted by their X-ray luminosities?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Soft X-ray cooling should deposit hundreds solar masses per year", "Observed star formation rates are 10-100× lower" ], "suggested_hypotheses": [ "AGN jet feedback deposits energy at the sound speed in the intracluster medium, maintaining thermal balance and suppressing cooling flows" ], "file": "unknowns-catalog/astronomy/u-cluster-cooling-flows.yaml" }, { "id": "u-cosmic-string-networks", "title": "Do cosmic string networks exist and what are their observational signatures in the CMB and gravitational wave background?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "CMB non-Gaussianity limits string tension Gμ < 10^-7", "PTA gravitational wave background could include string signal" ], "suggested_hypotheses": [ "Cosmic string networks with tension Gμ ~10^-10 contribute a distinctive spectral feature to the nanohertz gravitational wave background" ], "file": "unknowns-catalog/astronomy/u-cosmic-string-networks.yaml" }, { "id": "u-cosmological-constant-small-value-explanation", "title": "Why is the cosmological constant Λ ~ 10⁻⁵² m⁻² (small but non-zero), and what physical mechanism causes the ~120-order-of-magnitude cancellation between UV quantum vacuum contributions and the observed dark energy density?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "No quantum gravity theory makes a first-principles calculation of Λ that matches observation.", "The anthropic argument requires a populated multiverse with a specific measure; no such measure is derived from first principles.", "Precision measurements of dark energy equation of state are insufficient to distinguish Λ from quintessence at current sensitivity." ], "suggested_hypotheses": [], "file": "unknowns-catalog/astronomy/u-cosmological-constant-small-value-explanation.yaml" }, { "id": "u-dark-energy-equation-of-state", "title": "Is dark energy a cosmological constant or a dynamical field, and what is its equation of state w(z)?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "CMB and supernovae are consistent with w=-1 but uncertainties allow evolution", "DESI 2026 results suggest potential w≠-1 tension" ], "suggested_hypotheses": [ "Dark energy is a slowly rolling scalar field with w crossing -1 at z~0.3, distinguishable with next-generation surveys" ], "file": "unknowns-catalog/astronomy/u-dark-energy-equation-of-state.yaml" }, { "id": "u-dark-matter-particle-identity", "title": "What particle or particles constitute cosmological dark matter?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "WIMPs have not been detected despite decades of searches", "Axion and sterile neutrino parameter space largely unexplored" ], "suggested_hypotheses": [ "Ultralight axion dark matter with mass ~10^-22 eV forms a Bose-Einstein condensate explaining galactic core-cusp discrepancies" ], "file": "unknowns-catalog/astronomy/u-dark-matter-particle-identity.yaml" }, { "id": "u-early-galaxy-formation-jwst", "title": "Why do JWST observations reveal massive, evolved galaxies at z>10 that are absent in ΛCDM predictions?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "JWST finds candidate massive galaxies at z~12-16 inconsistent with standard models", "Photometric redshifts and mass estimates carry large uncertainties" ], "suggested_hypotheses": [ "Enhanced star formation efficiency in minihaloes at z>10 driven by metal-free Population III enrichment explains the excess massive galaxy population" ], "file": "unknowns-catalog/astronomy/u-early-galaxy-formation-jwst.yaml" }, { "id": "u-exoplanet-biosignature-false-positives", "title": "What abiotic processes can mimic biosignature gases in exoplanet atmospheres?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Photochemical O2 and O3 production identified around M dwarfs", "False positive probability as a function of host star type unpredictified" ], "suggested_hypotheses": [ "Volcanic hydrogen outgassing on water-rich rocky planets produces abiotic CH4 and CO2 ratios indistinguishable from biogenic signatures" ], "file": "unknowns-catalog/astronomy/u-exoplanet-biosignature-false-positives.yaml" }, { "id": "u-exoplanet-spectral-retrieval", "title": "How do cloud/haze model degeneracies in atmospheric retrieval limit detection of biosignature gases, and what spectral features most robustly distinguish biogenic from abiotic gas sources?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "No retrieval code fully couples cloud microphysics, photochemistry, and thermal emission in a single Bayesian framework.", "The prior distributions over cloud properties (particle size, optical depth, scale height) are physically unmotivated and dominate posterior uncertainty.", "Biosignature context — whether coexisting gases are consistent with biological production — is not incorporated into standard retrieval statistical tests." ], "suggested_hypotheses": [], "file": "unknowns-catalog/astronomy/u-exoplanet-spectral-retrieval.yaml" }, { "id": "u-fast-radio-burst-origin", "title": "What are the dominant progenitor mechanisms for cosmological fast radio bursts?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Magnetars confirmed as one source class from SGR 1935+2154", "Volumetric rate and diversity suggest multiple progenitors" ], "suggested_hypotheses": [ "Magnetar flares account for the majority of repeating FRBs while compact binary mergers produce the non-repeating population" ], "file": "unknowns-catalog/astronomy/u-fast-radio-burst-origin.yaml" }, { "id": "u-galaxy-angular-momentum", "title": "How is angular momentum transported during galaxy formation to produce the observed diversity of disk sizes?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Angular momentum is acquired from tidal torques during collapse", "Angular momentum loss to dark matter halo and mergers poorly quantified" ], "suggested_hypotheses": [ "Feedback-regulated disk formation preserves angular momentum by preventing early gaseous collapse before virialization" ], "file": "unknowns-catalog/astronomy/u-galaxy-angular-momentum.yaml" }, { "id": "u-globular-cluster-formation", "title": "How do globular clusters form and why do they show multiple stellar populations?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Multiple populations require multiple star formation episodes within GCs", "Self-enrichment mechanism and required gas retention disputed" ], "suggested_hypotheses": [ "Massive proto-GC clumps in high-redshift disk galaxies undergo multiple fragmentation episodes, each producing a distinct chemical population" ], "file": "unknowns-catalog/astronomy/u-globular-cluster-formation.yaml" }, { "id": "u-gravothermal-catastrophe-globular-cluster-timescale", "title": "What determines the core-collapse timescale of globular clusters undergoing the gravothermal catastrophe, and can post-collapse gravothermal oscillations be confirmed observationally to test the statistical mechanics of negative- heat-capacity systems?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Direct observation of core radius evolution over timescales > 10⁷ years is impossible; only ensemble statistics across the Milky Way GC population are available", "N-body simulations with N > 10⁵ remain computationally expensive; most published simulations use N ~ 10⁴-10⁵, below realistic GC sizes", "The role of stellar mass spectrum (not modelled in Lynden-Bell's original isothermal sphere) in modifying the collapse timescale is not fully characterised" ], "suggested_hypotheses": [ "h-negative-heat-capacity-stellar-stability-criterion" ], "file": "unknowns-catalog/astronomy/u-gravothermal-catastrophe-globular-cluster-timescale.yaml" }, { "id": "u-gwb-spectrum", "title": "What is the origin of the nanohertz gravitational wave background detected by pulsar timing arrays?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "NANOGrav 15-year data shows a stochastic background", "Supermassive black hole binary vs exotic origins unresolved" ], "suggested_hypotheses": [ "Supermassive black hole binary coalescences at z<1 produce the majority of the observed GWB signal with environmental hardening timescales <100 Myr" ], "file": "unknowns-catalog/astronomy/u-gwb-spectrum.yaml" }, { "id": "u-halo-merger-tree-nbody-clustering-analogy", "title": "Which algorithmic choices in halo merger-tree construction dominate uncertainties in inferred substructure statistics compared with cosmological parameters — and how should tree-builder ambiguity be propagated into galaxy–dark-matter connection constraints?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Ensemble tree-builder protocols applied to identical particle dumps with community-agreed merger-event definitions.", "Downstream sensitivity analyses linking tree-choice variance to stellar-halo matching scatter." ], "suggested_hypotheses": [ "h-merger-tree-branching-matches-subhalo-statistics-scaling" ], "file": "unknowns-catalog/astronomy/u-halo-merger-tree-nbody-clustering-analogy.yaml" }, { "id": "u-hubble-tension-origin", "title": "What physical mechanism resolves the 5σ tension between local and CMB-inferred Hubble constants?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Cepheid and TRGB distance ladders agree with each other", "No single systematic error identified that explains the discrepancy" ], "suggested_hypotheses": [ "Early dark energy that decays before recombination reduces the sound horizon and reconciles CMB-inferred H0 with local measurements" ], "file": "unknowns-catalog/astronomy/u-hubble-tension-origin.yaml" }, { "id": "u-magnetar-formation-mechanism", "title": "What fraction of neutron stars form as magnetars and what determines the extreme magnetic field strength?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Galactic magnetar population constrains birth rate to ~10% of neutron stars", "Dynamo mechanism during proto-NS convection is uncertain" ], "suggested_hypotheses": [ "Rapid proto-neutron star rotation during convective dynamo amplification generates fields >10^15 G when spin period < 5 ms at birth" ], "file": "unknowns-catalog/astronomy/u-magnetar-formation-mechanism.yaml" }, { "id": "u-magnetic-field-origin-galaxies", "title": "What generates and maintains large-scale magnetic fields in galaxies over Hubble time?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Galactic dynamo theory predicts exponential amplification from weak seed fields", "Seed field origin and coherence length are uncertain" ], "suggested_hypotheses": [ "A small-scale turbulent dynamo operating at z>10 generates sufficient coherent field to seed the large-scale galactic dynamo by cosmic noon" ], "file": "unknowns-catalog/astronomy/u-magnetic-field-origin-galaxies.yaml" }, { "id": "u-neural-operator-space-weather-extreme-event-calibration", "title": "How reliably do neural-operator surrogates calibrate extreme geomagnetic event risk under assimilation updates?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-neural-operator-assimilation-improves-space-weather-lead-time" ], "file": "unknowns-catalog/astronomy/u-neural-operator-space-weather-extreme-event-calibration.yaml" }, { "id": "u-neutron-star-equation-of-state", "title": "What is the equation of state of dense nuclear matter above 2× nuclear saturation density?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "GW170817 tidal deformability constrains radius to 11-13 km", "Phase transition to quark matter is unconstrained above 3ρ_0" ], "suggested_hypotheses": [ "A first-order phase transition to deconfined quark matter occurs at ~3 nuclear saturation densities, creating a mass gap at 2.5-2.8 solar masses" ], "file": "unknowns-catalog/astronomy/u-neutron-star-equation-of-state.yaml" }, { "id": "u-population-iii-stars", "title": "When and where can Population III stars first be detected, and what is their characteristic mass function?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "21-cm observations may probe the cosmic dawn", "No direct observation of Pop III star confirmed" ], "suggested_hypotheses": [ "JWST can detect gravitationally lensed Pop III stars in magnification events during the epoch of reionisation at z~10-15" ], "file": "unknowns-catalog/astronomy/u-population-iii-stars.yaml" }, { "id": "u-primordial-gravitational-waves", "title": "What is the tensor-to-scalar ratio r and what does it imply for inflationary models?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Planck and BICEP/Keck place upper limit r < 0.036", "CMB-S4 and LiteBIRD will probe r ~ 0.001" ], "suggested_hypotheses": [ "Plateau inflation models predict r ~0.004, detectable by next-generation CMB polarisation experiments" ], "file": "unknowns-catalog/astronomy/u-primordial-gravitational-waves.yaml" }, { "id": "u-quasar-feedback-mechanism", "title": "How does quasar feedback quench star formation in massive galaxies across cosmic time?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "AGN-driven outflows observed reaching kpc scales", "Whether outflows prevent star formation or merely redistribute gas is unresolved" ], "suggested_hypotheses": [ "Quasar-driven outflows heat circumgalactic gas to prevent future infall rather than expelling ISM directly, quenching star formation on Gyr timescales" ], "file": "unknowns-catalog/astronomy/u-quasar-feedback-mechanism.yaml" }, { "id": "u-red-sequence-quenching-unified-timescales", "title": "What fraction of red sequence scatter at fixed stellar mass is driven by progenitor diversity versus ongoing environmental perturbations rather than measurement error?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Consistent dust modeling across redshifts changes inferred quenching times.", "Selection effects in cluster vs field samples complicate scatter comparisons." ], "suggested_hypotheses": [ "h-red-sequence-age-spreads-constrain-quenching-models" ], "file": "unknowns-catalog/astronomy/u-red-sequence-quenching-unified-timescales.yaml" }, { "id": "u-reionization-topology", "title": "What is the spatial topology of cosmic reionization and which sources dominate the ionizing photon budget?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "21-cm observations will probe reionization morphology", "Faint galaxy vs AGN contribution at z>6 unresolved" ], "suggested_hypotheses": [ "Low-luminosity star-forming galaxies provide the dominant ionizing photon budget while rare AGN drive topology in overdense regions" ], "file": "unknowns-catalog/astronomy/u-reionization-topology.yaml" }, { "id": "u-saturn-ring-viscosity-radial-transport", "title": "What is the dominant angular-momentum transport mechanism in Saturn's dense B ring, and does collisional viscosity alone explain the observed density structure, or are self-gravity wakes and non-local transport required?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Non-local gravitational viscosity in dense self-gravitating rings is not constrained by Cassini observations independently of surface density", "B ring surface density profiles are degenerate with particle size distribution", "Long-timescale viscous evolution models disagree on whether rings are primordial or recent" ], "suggested_hypotheses": [], "file": "unknowns-catalog/astronomy/u-saturn-ring-viscosity-radial-transport.yaml" }, { "id": "u-solar-system-stability-billion-year-timescale", "title": "Is the solar system dynamically stable over its remaining ~5 Gyr lifetime, and what is the probability that Mercury or Mars undergoes a close encounter or collision with another planet?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Monte Carlo uncertainty in the 1% Mercury collision probability arises from truncation errors in numerical integrations over 5 Gyr; symplectic integrators with adaptive step-size are needed.", "The effect of general relativistic corrections on Mercury's secular dynamics is only partially included in most long-term simulations.", "Observational improvement in current planetary ephemerides (from Gaia and VLBI) has not yet propagated into updated stability estimates." ], "suggested_hypotheses": [], "file": "unknowns-catalog/astronomy/u-solar-system-stability-billion-year-timescale.yaml" }, { "id": "u-stellar-bh-spin-distribution", "title": "What process sets the spin magnitude distribution of stellar-mass black holes in binary systems?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "LIGO measurements show a bimodal spin distribution", "Natal kick, accretion, and tidal synchronisation contributions poorly separated" ], "suggested_hypotheses": [ "Natal kick direction relative to pre-collapse spin determines post-collapse misalignment, producing the observed bimodal effective spin distribution" ], "file": "unknowns-catalog/astronomy/u-stellar-bh-spin-distribution.yaml" }, { "id": "u-stellar-forcing-climate-sensitivity-scale", "title": "What is the quantitative climate sensitivity to solar irradiance variations across timescales from the 11-year cycle to Milankovitch orbital forcing, and how does it scale with background climate state?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Climate sensitivity to TSI changes is poorly constrained: instrumental era TSI variability too small for clean signal separation from internal variability", "The amplification mechanisms for small TSI changes (UV-ozone stratospheric pathway, cosmic ray-cloud hypothesis) are contested", "Milankovitch forcing is too small to explain glacial terminations without nonlinear ice-sheet amplification — the amplifier mechanism is not fully understood", "Faint young Sun paradox: stellar evolution models require 30% dimmer early Sun, yet Archaean sediments indicate liquid water — the compensating mechanism is unknown" ], "suggested_hypotheses": [ "Climate sensitivity to solar forcing is state-dependent: near glacial maximum, the ice-albedo feedback amplifies solar sensitivity by a factor of 3-5 compared to modern interglacial, explaining the 100 kyr power without invoking internal oscillators", "The cosmic ray-cloud nucleation mechanism (Svensmark) is real but operates primarily in clean marine air masses; its global radiative effect is 0.1-0.3 W/m2, too small to dominate but sufficient to modulate decadal climate" ], "file": "unknowns-catalog/astronomy/u-stellar-forcing-climate-sensitivity-scale.yaml" }, { "id": "u-stellar-initial-mass-function", "title": "Is the stellar initial mass function universal, and what physics drives variations in extreme environments?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "IMF appears top-heavy in some starburst systems", "Radiation pressure and magnetic field effects on fragmentation poorly modelled" ], "suggested_hypotheses": [ "The characteristic Jeans mass set by dust cooling temperature drives IMF variations, producing top-heavy IMFs in high-pressure starbursts" ], "file": "unknowns-catalog/astronomy/u-stellar-initial-mass-function.yaml" }, { "id": "u-type-ia-supernova-progenitor", "title": "What stellar system produces the majority of Type Ia supernovae: single-degenerate or double-degenerate?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Both channels produce Chandrasekhar and sub-Chandrasekhar explosions", "No surviving companion detected in nearby remnants" ], "suggested_hypotheses": [ "The double-degenerate merger channel dominates at low metallicity while single-degenerate systems account for the bright-end luminosity function" ], "file": "unknowns-catalog/astronomy/u-type-ia-supernova-progenitor.yaml" }, { "id": "u-uhecr-origin", "title": "What are the sources of ultra-high-energy cosmic rays above the GZK cutoff and what accelerates them?", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Pierre Auger Observatory shows anisotropy toward star-forming galaxies", "Composition measurements are inconsistent between experiments" ], "suggested_hypotheses": [ "Starburst galaxy jets accelerate heavy nuclei via shear acceleration, explaining UHECR composition and directional correlations" ], "file": "unknowns-catalog/astronomy/u-uhecr-origin.yaml" }, { "id": "u-virial-cloud-cluster-multicomponent-bias", "title": "How large are systematic mass biases when joint virial-style estimators ignore turbulence, magnetic pressure, cosmic rays, or merger-induced departures from equilibrium across molecular clouds versus galaxy clusters?\n", "status": "open", "domain": "astronomy", "systematic_gaps": [ "Simulation suites with identical virial estimators applied across GMC and cluster mocks with matched diagnostic pipelines.", "Observation programs pairing independent mass probes (lensing, SZ, stellar dynamics) on overlapping cluster samples with documented systematic covariance." ], "suggested_hypotheses": [ "h-virial-multicomponent-consistency-reduces-cluster-mass-bias" ], "file": "unknowns-catalog/astronomy/u-virial-cloud-cluster-multicomponent-bias.yaml" }, { "id": "u-accretion-disk-mri-saturation", "title": "What determines the saturation amplitude of MRI-driven MHD turbulence in accretion disks, and why does the effective α parameter depend on magnetic Prandtl number?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "The functional dependence of α on magnetic Prandtl number Pm lacks a theoretical derivation from first principles.", "The parasitic instability mechanism controlling MRI channel mode saturation is not fully characterized.", "Whether MRI turbulence in the Pm >> 1 regime is in the same universality class as Pm << 1 is unknown.", "The role of large-scale magnetic field geometry (toroidal vs. poloidal) in setting α is debated." ], "suggested_hypotheses": [ "α ~ Pm^{1/2} scaling arises from the Alfvén velocity matching the turbulent velocity at the resistive dissipation scale." ], "file": "unknowns-catalog/astrophysics/u-accretion-disk-mri-saturation.yaml" }, { "id": "u-black-hole-information-paradox", "title": "Is information that falls into a black hole preserved (as implied by quantum unitarity and AdS/CFT) or destroyed (as implied by Hawking's original calculation) — and what is the precise physical mechanism by which information escapes in Hawking radiation?\n", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "Microscopic mechanism for information escape from black hole Hawking radiation", "Resolution of AMPS firewall paradox (equivalence principle vs. unitarity)", "Non-perturbative derivation of the island formula from first principles", "Connection between bulk (gravitational) and boundary (CFT) entanglement structure" ], "suggested_hypotheses": [ "h-spacetime-emerges-from-entanglement" ], "file": "unknowns-catalog/astrophysics/u-black-hole-information-paradox.yaml" }, { "id": "u-gravitational-lensing-caustic-topology", "title": "What is the complete topological classification of caustic networks produced by realistic large-scale structure lens distributions, and how do higher-order catastrophe singularities (swallowtail, butterfly) affect the statistical properties of extreme-magnification events observable by next-generation lensing surveys?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "Full 3D lens-reconstruction codes that compute caustic topology in all six catastrophe types are computationally prohibitive for survey-scale datasets", "Wave-optics corrections require full diffraction integral computation, orders of magnitude more expensive than geometric optics ray tracing", "Observational identification of butterfly/swallowtail caustics in real arc systems has not been achieved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/astrophysics/u-gravitational-lensing-caustic-topology.yaml" }, { "id": "u-gravitational-wave-astrophysics-population", "title": "What is the mass distribution and formation channel of compact binary mergers detected by LIGO-Virgo, and what does it imply for stellar evolution?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "The low-mass gap (3-5 solar masses, between heaviest neutron stars and lightest black holes) has only 2 candidate detections; its reality is statistically uncertain.", "Population synthesis models differ by factors of 10-100 in predicted merger rates for different formation channels, making channel inference ambiguous." ], "suggested_hypotheses": [], "file": "unknowns-catalog/astrophysics/u-gravitational-wave-astrophysics-population.yaml" }, { "id": "u-grb-jet-breakout-shock-microphysics", "title": "Which afterglow features uniquely identify jet structure (structured jets, late energy injection) versus observer-angle effects within a single RHD model class?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "Magnetic field dominance in some jets complicates pure hydrodynamic blast-wave fits.", "Early-time prompt emission engine remains uncertain, limiting self-consistent initial conditions." ], "suggested_hypotheses": [ "h-jet-break-timescale-scales-with-entropy-and-opening-angle" ], "file": "unknowns-catalog/astrophysics/u-grb-jet-breakout-shock-microphysics.yaml" }, { "id": "u-helioseismic-inversion-uniqueness-depth", "title": "Under realistic observational frequency errors and mode sets, how tight are uniqueness guarantees for solar sound-speed profiles versus degenerate interior models sharing overlapping eigenfrequency windows?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "Simulation studies injecting realistic realization noise into synthetic stellar models across inverse pipelines used operationally by asteroseismic consortia", "Open benchmarks releasing Jacobian kernels alongside synthetic spectra for inverse-problem algorithm competitions" ], "suggested_hypotheses": [ "h-helioseismology-x-inverse-eigenvalue-problems" ], "file": "unknowns-catalog/astrophysics/u-helioseismic-inversion-uniqueness-depth.yaml" }, { "id": "u-neutron-star-eos-dense-matter-phase-transition", "title": "Does the dense matter in neutron star cores undergo a first-order phase transition to quark matter, hyperon matter, or a condensate, and if so at what density?", "status": "open", "domain": "astrophysics", "systematic_gaps": [ "NICER radius measurements have ~1 km uncertainty; distinguishing EOS families requires < 0.5 km precision", "Phase transition signatures in gravitational waveforms from NS mergers have not been observed", "Heavy-ion experiments probe nuclear matter up to 3*rho_0 but cannot reach 5-6*rho_0 conditions in neutron stars" ], "suggested_hypotheses": [], "file": "unknowns-catalog/astrophysics/u-neutron-star-eos-dense-matter-phase-transition.yaml" }, { "id": "u-solar-wind-alfven-wave-dissipation-scale", "title": "At what spatial scale and through what kinetic mechanism does the solar wind Alfvénic turbulence cascade ultimately dissipate, heating the solar wind ions and electrons?\n", "status": "open", "domain": "astrophysics", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/astrophysics/u-solar-wind-alfven-wave-dissipation-scale.yaml" }, { "id": "u-bargaining-power-measurement-real-world-negotiations", "title": "How can bargaining power be empirically measured in real-world negotiations where the disagreement point, the feasible set, and outside options are unobservable, and do observed outcomes match Nash or Rubinstein equilibrium predictions?\n", "status": "open", "domain": "bargaining", "systematic_gaps": [ "Large-scale empirical tests of Nash vs. Rubinstein bargaining predictions in real negotiations are rare; most evidence is from lab experiments with stakes unrepresentative of field negotiations.", "The role of fairness norms and social preferences (inequity aversion) in determining bargaining outcomes above and beyond game-theoretic predictions has not been systematically decomposed.", "International climate negotiation outcomes (Paris Agreement, Kyoto Protocol) have not been formally analyzed as Nash bargaining solutions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/bargaining/u-bargaining-power-measurement-real-world-negotiations.yaml" }, { "id": "u-marcus-tunneling-reaction-coordinate-biochemistry", "title": "How tightly do Marcus parameters (λ, V_DA, ΔG°) inferred from driving-force sweeps on enzymes predict tunneling-corrected kinetic isotope effects measured independently?", "status": "open", "domain": "biochemistry", "systematic_gaps": [ "Coupled multi-mode tunneling not reducible to a single effective reaction coordinate", "Limited datasets matching Marcus fits to sub-picosecond vibrational spectroscopy on the same enzyme series" ], "suggested_hypotheses": [ "h-marcus-tunneling-x-enzyme-reaction-coordinate" ], "file": "unknowns-catalog/biochemistry/u-marcus-tunneling-reaction-coordinate-biochemistry.yaml" }, { "id": "u-active-brownian-motion-x-cell-migration", "title": "Do migrating cancer cells in 3D tissue environments follow active Brownian particle statistics, and how does confinement geometry and matrix stiffness modify the effective persistence time and diffusivity?", "status": "open", "domain": "biology", "systematic_gaps": [ "3D single-cell tracking in dense ECM is technically challenging; most ABP parameterizations are from 2D assays", "Cell heterogeneity (different phenotypic states) produces mixed ABP populations; population-level statistics mask individual-cell differences", "Active Brownian particle theory assumes constant self-propulsion speed; migrating cells show speed-persistence correlations not captured by basic ABP" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-active-brownian-motion-x-cell-migration.yaml" }, { "id": "u-adaptive-therapy-evolutionary-trap-clinical-validation", "title": "Does adaptive therapy based on Pontryagin optimal control and evolutionary game theory outperform maximum tolerated dose chemotherapy in randomized clinical trials for solid tumors?", "status": "open", "domain": "biology", "systematic_gaps": [ "No randomized phase III trial of adaptive therapy vs. MTD exists for any solid tumor type.", "Real-time measurement of tumor subclone frequencies by liquid biopsy is not yet accurate enough for closed-loop optimal control in most solid tumors.", "The evolutionary game payoff matrix between drug-sensitive and drug-resistant clones has not been measured experimentally in vivo for any human tumor type." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-adaptive-therapy-evolutionary-trap-clinical-validation.yaml" }, { "id": "u-aging-hallmarks-causal-hierarchy", "title": "Among the 12 hallmarks of aging (telomere attrition, epigenetic drift, proteostasis loss, etc.), which are causes and which are consequences — is there a causal hierarchy?", "status": "open", "domain": "biology", "systematic_gaps": [ "No experiment has established the causal hierarchy among all 12 hallmarks", "Whether partial reprogramming reverses damage or only epigenetic marks is unknown", "The quantitative contribution of each hallmark to lifespan variance across species is not established" ], "suggested_hypotheses": [ "Epigenetic drift is causally upstream of at least 6 other hallmarks (senescence, proteostasis, stem cell exhaustion, mitochondrial dysfunction, intercellular communication, inflammation), testable by partial reprogramming experiments that restore the epigenome while measuring other hallmark markers" ], "file": "unknowns-catalog/biology/u-aging-hallmarks-causal-hierarchy.yaml" }, { "id": "u-allometric-scaling-metabolic-universality", "title": "Do quarter-power allometric scaling laws reflect a universal mathematical property of resource-distribution networks, or are they approximate empirical relationships with taxon-specific deviations that challenge the WBE fractal geometry model?", "status": "open", "domain": "biology", "systematic_gaps": [ "Metabolic rate measurements for extremely small (~1mg) and extremely large (~100,000kg) organisms are sparse and methodologically heterogeneous", "WBE model assumes laminar flow and rigid branching rules; turbulence and elastic branching modify the exponent in unknown ways", "The origin of quarter-power scaling in unicellular organisms lacking vascular networks challenges the network geometry explanation" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-allometric-scaling-metabolic-universality.yaml" }, { "id": "u-allometry-fractal-networks-deviations", "title": "Do organisms without hierarchical vascular networks (sponges, fungi, prokaryotes) deviate predictably from the WBE 3/4-power metabolic scaling, and what alternative exponent does the geometry predict?", "status": "open", "domain": "biology", "systematic_gaps": [ "No quantitative WBE-derived prediction for metabolic scaling in organisms with non-hierarchical distribution networks", "Empirical metabolic scaling exponents for fungi and sponges have large uncertainties (0.6-0.8 range)", "Whether mycelial network topology satisfies any of the three WBE assumptions has not been tested quantitatively" ], "suggested_hypotheses": [ "Organisms with fractal but non-hierarchical distribution networks (fungi) follow M^{(d-1)/d} scaling where d is the measured fractal dimension of the mycelial network, predicting d ≈ 2.5-2.8 to yield observed exponents of 0.60-0.70" ], "file": "unknowns-catalog/biology/u-allometry-fractal-networks-deviations.yaml" }, { "id": "u-allosteric-regulation-x-conformational-dynamics", "title": "Can the allosteric coupling constant between two binding sites be quantitatively predicted from protein structure and molecular dynamics simulations without measuring it experimentally?", "status": "open", "domain": "biology", "systematic_gaps": [ "MD force fields are not accurate enough for quantitative free energy perturbation of conformational equilibria in large proteins", "Allosteric coupling involves correlated motions on ms timescales inaccessible to standard MD; enhanced sampling methods introduce errors", "No benchmark dataset of quantitatively measured allosteric coupling constants for a diverse set of protein families" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-allosteric-regulation-x-conformational-dynamics.yaml" }, { "id": "u-alzheimer-network-attractor-dynamics", "title": "Does Alzheimer's disease progression trace a deterministic trajectory through a low-dimensional attractor landscape in functional brain network space, and can this predict individual prognosis?", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether individual AD trajectories follow deterministic attractor dynamics or are stochastic diffusion in high-dimensional space has not been tested with longitudinal imaging data.", "The number of dimensions required to describe AD progression dynamics (d_effective) has not been estimated from PET time series data.", "Whether bifurcation points in the network model correspond to clinically recognizable transition events (MCI to AD, rapid to slow progressors) has not been validated." ], "suggested_hypotheses": [ "Alzheimer's disease trajectories collapse onto a 2-3 dimensional attractor manifold in functional connectivity space, with stable attractors corresponding to MCI, mild, moderate, and severe AD stages." ], "file": "unknowns-catalog/biology/u-alzheimer-network-attractor-dynamics.yaml" }, { "id": "u-ant-colony-optimization-convergence-rate", "title": "What is the time complexity of ant colony optimization convergence to the optimal TSP tour, and under what parameter conditions does ACO outperform other metaheuristics?", "status": "open", "domain": "biology", "systematic_gaps": [ "Convergence rate proofs for ACO on TSP with > 100 cities do not exist", "Parameter sensitivity analysis has not been connected to problem structure features", "The relationship between biological foraging parameters and ACO algorithm parameters is qualitative" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-ant-colony-optimization-convergence-rate.yaml" }, { "id": "u-bacterial-chemotaxis-x-gradient-descent", "title": "How does E. coli chemotaxis achieve near-optimal gradient detection at the Cramer-Rao bound, and can the methylation memory system be replicated in artificial optimizers?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether the specific methylation kinetics of E. coli chemoreceptors represent an evolutionary optimum for temporal gradient computation under noise has not been quantitatively verified", "The information-theoretic capacity of the chemotaxis signaling network (bits per gradient step) has not been measured experimentally and compared to the Cramer-Rao bound", "Translation of the receptor methylation circuit to a continuous-time optimization algorithm with formal convergence guarantees for non-convex objectives has not been demonstrated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-bacterial-chemotaxis-x-gradient-descent.yaml" }, { "id": "u-biofilm-x-active-nematic", "title": "Do topological defects in bacterial biofilms (+1/2 disclinations) causally determine sites of biofilm expansion, cell extrusion, or matrix secretion, or are they merely epiphenomenal signatures of mechanical stress?", "status": "open", "domain": "biology", "systematic_gaps": [ "No direct manipulation experiment has perturbed defect positions independently of bacterial growth rate", "The relationship between +1/2 defect velocity and actual extensile stress in biofilm matrix has not been measured", "Active nematic theory assumes rodlike particles, but cocci and other shapes violate this assumption" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-biofilm-x-active-nematic.yaml" }, { "id": "u-biomechanics-x-soft-robotics", "title": "What is the minimum tendon compliance (spring stiffness k) relative to muscle force (F_max) that achieves the metabolic cost reduction predicted by the spring-mass model, and can this ratio be systematically optimized across body mass scales for soft robotic design?", "status": "open", "domain": "biology", "systematic_gaps": [ "No analytical prediction for the optimal tendon compliance ratio k·L/F_max as a function of body mass and stride frequency", "Soft actuator fatigue life (number of compression cycles before failure) degrades with compliance; the compliance-durability trade-off is not characterized for dielectric elastomers", "Proprioceptive feedback in soft robotic systems cannot replicate muscle spindle sensitivity; the effect of proprioceptive noise on compliant locomotion stability is unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-biomechanics-x-soft-robotics.yaml" }, { "id": "u-blood-coagulation-cascade", "title": "What triggers the threshold crossing from hemostasis (localized clot) to disseminated intravascular coagulation (systemic activation), and can this transition be predicted from routine plasma biomarkers?", "status": "open", "domain": "biology", "systematic_gaps": [ "Reaction-diffusion models of coagulation (including spatial thrombin transport and inhibitor gradients) have been developed but not validated against clinical data.", "The critical TF expression level or spatial extent needed to trigger systemic vs. localized coagulation has not been determined in vivo.", "Early DIC prediction scores (ISTH, JAAM) have AUC ~0.75 in sepsis; machine learning models using time-series biomarkers have not been systematically evaluated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-blood-coagulation-cascade.yaml" }, { "id": "u-boolean-attractor-cell-fate-mapping", "title": "Can the complete attractor landscape of a Boolean gene regulatory network model be mapped onto the full repertoire of cell types in a multicellular organism, and does attractor number predict cell type count?", "status": "open", "domain": "biology", "systematic_gaps": [ "No genome-scale Boolean attractor computation has been validated against scRNA-seq cell types", "Critical K=2 assumption needs empirical validation from regulatory network data", "The role of epigenetic state (methylation, chromatin) in attractor definition is unresolved" ], "suggested_hypotheses": [ "Boolean network attractors for K=2 critical networks match cell type diversity across organisms" ], "file": "unknowns-catalog/biology/u-boolean-attractor-cell-fate-mapping.yaml" }, { "id": "u-boolean-network-cancer-attractors", "title": "Can Boolean network attractor analysis identify reliable therapeutic targets by mapping oncogenic mutations to epigenetic attractor transitions?", "status": "open", "domain": "biology", "systematic_gaps": [ "Boolean network models use deterministic update rules; the role of stochastic gene expression noise in attractor transitions is not captured.", "The attractor landscape inferred from bulk RNA-seq may not reflect single-cell heterogeneity within tumors where multiple attractors coexist." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-boolean-network-cancer-attractors.yaml" }, { "id": "u-bp-convergence-loopy-genetic-linkage-graphs", "title": "When do undamped versus damped belief-propagation schedules remain reliable for genotype phasing on graphs with long-range linkage disequilibrium and irregular marker density?", "status": "open", "domain": "biology", "systematic_gaps": [ "Limited public synthetic benchmarks reproducing long-range LD weirdness with ground-truth phase.", "Under-reported sensitivity of phasing accuracy to graph-construction rules across arrays.", "Sparse head-to-head comparisons of BP damping schedules under identical haplotype reference panels." ], "suggested_hypotheses": [ "h-damped-bp-calibration-improves-phasing-accuracy" ], "file": "unknowns-catalog/biology/u-bp-convergence-loopy-genetic-linkage-graphs.yaml" }, { "id": "u-braess-paradox-biological-foraging", "title": "Does Braess's paradox appear systematically in biological foraging and transport networks, and what evolutionary mechanism prevents networks from getting trapped in the paradox regime?", "status": "open", "domain": "biology", "systematic_gaps": [ "The prevalence of Braess-paradox-inducing connections across biological network types (vascular, mycelial, neural, ant trails) has not been surveyed.", "Whether individual foragers have learned heuristics that avoid Nash-equilibrium traps (equivalent to Braess-paradox avoidance) is unknown.", "The evolutionary game theory analysis predicting when Braess's paradox is eliminated by natural selection (social vs. individual optimality) has not been formalized." ], "suggested_hypotheses": [ "Biological foraging networks avoid Braess paradox via pheromone-based self-organization that implements a distributed Wardrop social optimum, rather than Nash equilibrium routing." ], "file": "unknowns-catalog/biology/u-braess-paradox-biological-foraging.yaml" }, { "id": "u-calcium-signaling-x-stochastic-resonance", "title": "Does intracellular calcium stochastic resonance operate at the optimal noise level in living cells, and if so, what homeostatic mechanism tunes IP3 receptor cluster density to the SR optimal point for the cell's specific signaling context?", "status": "open", "domain": "biology", "systematic_gaps": [ "No measurement of IP3R cluster density as a function of signaling demand has been performed in primary (non-immortalized) cells", "The mutual information between IP3 input and calcium wave output has not been measured as a function of IP3R expression level", "Whether SR is a design principle or an epiphenomenon of calcium dynamics cannot be distinguished without genetic control of IP3R cluster density" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-calcium-signaling-x-stochastic-resonance.yaml" }, { "id": "u-cell-division-x-branching-process", "title": "What is the effective division/death probability ratio for early pre-cancerous clones in normal tissue, and does it cross the critical threshold m = 1 before or after acquiring the first driver mutation?", "status": "open", "domain": "biology", "systematic_gaps": [ "In situ division and death rate measurements for individual pre-cancerous clones in human tissue are unavailable", "Whether neutral drift (m = 1) or selection (m > 1) dominates early clonal expansion in normal tissue is debated", "Branching process models assume independent cells but ignore stem cell niche spatial constraints" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-cell-division-x-branching-process.yaml" }, { "id": "u-cell-jamming-tissue-development", "title": "Does the jamming transition control tissue fluidity during embryonic morphogenesis and cancer invasion, and what determines the critical shape index in vivo?", "status": "open", "domain": "biology", "systematic_gaps": [ "In vivo measurement of shape index q* and its correlation with tissue rheology (viscoelastic moduli measured by laser ablation) in developing Drosophila, zebrafish, or mouse embryos is incomplete.", "Whether cell division and active forces shift the critical shape index from the passive vertex model prediction is untested.", "The relationship between q* and epithelial-to-mesenchymal transition (EMT) markers in cancer cells has been measured in 2D culture but not validated in 3D tumour organoids or primary tissue." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-cell-jamming-tissue-development.yaml" }, { "id": "u-chromatin-loop-extrusion-processivity", "title": "What determines the processivity (loop-extrusion run length) of cohesin in vivo, and how does nucleosome density, transcription, and supercoiling modulate it?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Single-molecule in vitro cohesin loop extrusion rates do not match in vivo TAD sizes; the discrepancy source is unknown.", "How RNA polymerase II collision events reset or bypass cohesin rings is not mechanistically characterised.", "The role of DNA supercoiling gradients in directing cohesin directionality has not been tested in mammalian cells." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-chromatin-loop-extrusion-processivity.yaml" }, { "id": "u-chromatin-loop-extrusion-speed-processivity-in-vivo", "title": "What is the in vivo speed, processivity, and stall force of cohesin-mediated chromatin loop extrusion in mammalian cells, and how do CTCF, WAPL, and transcription machinery pause or terminate extrusion to establish TAD boundaries?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Live-cell single-molecule imaging of cohesin loop extrusion in mammalian nuclei (requires bright, photostable fluorescent tags on cohesin + fast enough tracking to resolve ~1 kb/s movement).", "Optical tweezers measurement of cohesin stall force at CTCF in chromatin context (nucleosome-containing template).", "Single-cell Hi-C at higher resolution to measure cell-to-cell variability in loop positions and sizes.", "Quantitative relationship between NIPBL/cohesin dosage and TAD insulation strength (allele series experiments)." ], "suggested_hypotheses": [ "In vivo cohesin extrusion speed is 2-5× slower than in vitro (~0.1-0.3 kb/s) due to nucleosome barrier resistance, and the in vivo processivity is limited to ~50 kb (much less than the 150+ kb measured on naked DNA) — explaining why observed TADs cluster at 100-200 kb despite models predicting larger loops from unconstrained extrusion.\n" ], "file": "unknowns-catalog/biology/u-chromatin-loop-extrusion-speed-processivity-in-vivo.yaml" }, { "id": "u-circadian-clock-x-feedback-oscillator", "title": "What molecular mechanism ensures temperature compensation of the circadian period (Q₁₀ ≈ 1.0) despite temperature sensitivity of all biochemical rate constants (Q₁₀ ≈ 2-3)?", "status": "open", "domain": "biology", "systematic_gaps": [ "No single molecular mechanism has been confirmed to explain temperature compensation across phylogenetic diversity", "Mathematical models predict temperature compensation requires precise parameter tuning that seems evolutionarily fragile", "Whether temperature compensation is an evolved property or a generic feature of delayed negative feedback oscillators is unresolved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-circadian-clock-x-feedback-oscillator.yaml" }, { "id": "u-circadian-kuramoto-jet-lag-dynamics", "title": "Does the speed of jet-lag recovery follow Kuramoto re-entrainment dynamics, and can phase-response curves (PRCs) quantitatively predict optimal light-exposure protocols?", "status": "open", "domain": "biology", "systematic_gaps": [ "Quantitative test of whether jet-lag recovery rate scales with K*PRC_amplitude as Kuramoto model predicts", "Whether PRC measured in vitro (dissociated SCN neurons) matches the effective PRC of the intact SCN network", "Optimal light pulse timing for eastward vs westward travel computed from Kuramoto PRC theory vs empirical trial" ], "suggested_hypotheses": [ "Jet-lag recovery time (days) equals delta_phi / (K * PRC_max * omega_0) where delta_phi is the phase shift, K is VIP coupling strength, and PRC_max is the maximum advance/delay" ], "file": "unknowns-catalog/biology/u-circadian-kuramoto-jet-lag-dynamics.yaml" }, { "id": "u-circadian-metabolism-coupling", "title": "Is circadian clock disruption (shift work, jet lag) a direct cause of metabolic disease, or merely correlated via confounding lifestyle factors?", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether circadian disruption causes metabolic disease independent of sleep restriction has not been established in humans with full confounder control", "The reversibility of circadian disruption-induced metabolic damage after schedule normalization is not characterized", "Which clock gene targets mediate metabolic disruption (vs. other BMAL1 targets) has not been established" ], "suggested_hypotheses": [ "Circadian misalignment independently increases insulin resistance by >30% above sleep-restriction-only controls, demonstrable in a 4-arm RCT (circadian aligned vs. misaligned x sleep sufficient vs. restricted) over 2 weeks" ], "file": "unknowns-catalog/biology/u-circadian-metabolism-coupling.yaml" }, { "id": "u-circadian-temperature-compensation-mechanism", "title": "What molecular mechanism allows the circadian clock period to remain approximately constant (~24 hours) across a 10-20 degree Celsius temperature range (Q10 approximately 1), when all biochemical reaction rates typically double with each 10-degree increase?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "No quantitative mechanistic model correctly predicts Q10~1 from measured reaction rate temperature sensitivities.", "Whether temperature compensation requires evolved rate matching or an intrinsic thermodynamic property of the oscillator is unresolved.", "Temperature compensation differs between cyanobacteria (KaiABC), Drosophila (PER/TIM), and mammals (CLOCK/BMAL1) without clear mechanistic theme." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-circadian-temperature-compensation-mechanism.yaml" }, { "id": "u-confluent-tissue-brownian-universality", "title": "What universality class governs persistent random motion (anomalous diffusion) in dense confluent cell sheets?", "status": "open", "domain": "biology", "systematic_gaps": [ "The exponent alpha in MSD(t) ~ t^alpha for dense cell monolayers has been measured in scattered systems but not systematically compared across cell types to test universality", "No connection has been drawn between the anomalous diffusion exponent in confluent tissues and the exponents of known universality classes (KPZ, Edwards-Wilkinson, voter model)", "The crossover from ballistic to diffusive motion in cell sheets has no consensus mechanistic model" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-confluent-tissue-brownian-universality.yaml" }, { "id": "u-contact-graph-hessian-rank-native-basin-surrogate", "title": "Does the effective numerical rank of coarse-grained Hessians near predicted native basins correlate with simple graph statistics (spectral gap of contact Laplacian, foldon modularity) independent of protein length?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Force-field dependence may swamp graph-only predictions — controlled benchmarks needed.", "Intrinsically disordered segments violate stable contact maps yet fold upon binding." ], "suggested_hypotheses": [ "h-low-rank-hessian-surrogate-predicts-two-state-phi-profile-class" ], "file": "unknowns-catalog/biology/u-contact-graph-hessian-rank-native-basin-surrogate.yaml" }, { "id": "u-cortical-folding-topology", "title": "Does cortical gyrification (brain folding) obey the same topological transition rules as physical membrane buckling, and can topological defect theory predict sulcal pattern variability across individuals?", "status": "open", "domain": "biology", "systematic_gaps": [ "It is unknown whether the sulcal pattern satisfies topological conservation laws (Euler characteristic, total Gaussian curvature) that are fixed by the initial neuroepithelial configuration.", "The connection between topological defects in the neuroepithelial actomyosin field (during neural tube closure) and the final sulcal pattern has not been tested experimentally.", "Fine-scale sulcal variability between individuals has not been quantified using topological distance metrics (Wasserstein distance between sulcal persistence diagrams) rather than geometric landmark distances.", "Neurodevelopmental conditions associated with altered gyrification (lissencephaly, polymicrogyria, autism) have not been characterised as topological-defect-count anomalies." ], "suggested_hypotheses": [ "The total topological charge of the neuroepithelial defect field at neural tube closure predicts the number and coarse positions of primary sulci in the adult cortex.", "Individual differences in fine-scale sulcal pattern are metrically captured by the Wasserstein distance between the topological persistence diagrams of the cortical surface — which correlates with functional connectivity variability." ], "file": "unknowns-catalog/biology/u-cortical-folding-topology.yaml" }, { "id": "u-crispr-base-editing-x-error-correction", "title": "Can information-theoretic principles (guide RNA design as error-correcting code) predict and minimize off-target base editing rates across the human genome?", "status": "open", "domain": "biology", "systematic_gaps": [ "Off-target editing rates are measured by NGS but vary by cell type, editor version, and delivery method; no unified model", "Guide RNA design algorithms use empirical scoring functions; first-principles error probability models have not been developed", "The information capacity of the CRISPR targeting code (20-nt guide vs 3-billion-base genome) implies a fundamental off-target floor that has not been computed" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-crispr-base-editing-x-error-correction.yaml" }, { "id": "u-crispr-multiplex-error-floor-vs-code-distance", "title": "What quantitative separation margins (effective Hamming-like distances among barcode sequences) are required for multiplexed CRISPR pooled screens to achieve targeted decoding error floors under realistic PCR and sequencing noise models?", "status": "open", "domain": "biology", "systematic_gaps": [ "Empirical noise channels aggregated across sequencing platforms for barcode reads tied to CRISPR pools", "Benchmark suites linking primer-distance spacing to observed misassignment rates in negative controls" ], "suggested_hypotheses": [ "h-barcode-spacing-heuristic-lowers-decoding-error-measured-in-negative-controls" ], "file": "unknowns-catalog/biology/u-crispr-multiplex-error-floor-vs-code-distance.yaml" }, { "id": "u-crispr-x-search-and-replace", "title": "What is the theoretical minimum off-target cleavage rate achievable by any CRISPR system given the genome size and guide RNA length, and can this bound be achieved by engineered Cas variants?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Information-theoretic minimum off-target rate has not been calculated for realistic mismatch tolerance models", "Off-target sites in heterochromatin are systematically undersampled by current detection methods (GUIDE-seq, CIRCLE-seq)", "Effect of guide RNA secondary structure on PAM search kinetics is not incorporated in off-target prediction models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-crispr-x-search-and-replace.yaml" }, { "id": "u-cryoem-laplacian-eigenmode-physical-interpretability", "title": "When do cryo-EM Laplacian eigenmodes correspond to physically meaningful conformational motions?", "status": "open", "domain": "biology", "systematic_gaps": [ "Few benchmark systems include independent experimental labels for latent conformational axes.", "Sensitivity of eigenmodes to graph-construction choices remains under-reported." ], "suggested_hypotheses": [ "h-laplacian-eigenmodes-improve-cryoem-conformation-clustering" ], "file": "unknowns-catalog/biology/u-cryoem-laplacian-eigenmode-physical-interpretability.yaml" }, { "id": "u-cryptochrome-radical-pair-quantum-nav", "title": "Is avian magnetic compass navigation via cryptochrome radical pairs a coherent quantum process that persists at physiological temperatures, and what decoherence timescale is critical?", "status": "open", "domain": "biology", "systematic_gaps": [ "The decoherence time of the FAD•- / Trp•+ radical pair in cryptochrome has not been measured directly in living avian retinal cells.", "Whether the singlet-triplet interconversion rate in vivo matches the RPM prediction (not just in vitro) is unknown.", "Behavioral magnetoreception experiments with controlled RF disruption have not been combined with in vivo EPR measurements." ], "suggested_hypotheses": [ "Cryptochrome radical pairs maintain quantum coherence > 1 microsecond at 40°C in avian retinal cells due to spin-selective protein confinement that suppresses hyperfine-induced dephasing." ], "file": "unknowns-catalog/biology/u-cryptochrome-radical-pair-quantum-nav.yaml" }, { "id": "u-developmental-gradient-x-pde", "title": "How do embryos robustly maintain morphogen gradient precision despite noise in gene expression, cell number variability, and tissue growth during development?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Quantitative measurement of morphogen diffusion coefficients in vivo remains difficult due to limited temporal resolution of imaging", "Mechanisms that scale pattern wavelength with organism size (embryo scaling) are not fully understood", "Role of mechanical feedback (tissue tension, cell rearrangement) in pattern robustness is uncharacterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-developmental-gradient-x-pde.yaml" }, { "id": "u-dna-origami-compiler-analogy-yield-prediction-limits", "title": "Do software-style dependency and staged-compilation metrics predict DNA origami assembly yield beyond existing thermodynamic and geometric design rules, or is the compiler analogy only pedagogical?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Open benchmark linking origami designs, routing graphs, annealing schedules, and measured yields.", "Separation of graph-constraint effects from staple sequence and ionic-condition effects." ], "suggested_hypotheses": [ "h-scaffold-routing-constraint-metrics-predict-origami-yield" ], "file": "unknowns-catalog/biology/u-dna-origami-compiler-analogy-yield-prediction-limits.yaml" }, { "id": "u-dna-replication-x-error-correction", "title": "Is there an information-theoretic optimal mutation rate for evolution, and does DNA replication fidelity operate near this optimum?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The information-theoretic optimum mutation rate as a function of genome size, fitness landscape ruggedness, and population size has not been derived in closed form", "Whether organisms with elevated stress-induced mutation rates (SOS response in bacteria) are implementing an optimal strategy of varying mutation rate with environment has not been tested information-theoretically", "The Shannon channel capacity of the DNA replication channel (with biological error correction) has not been computed and compared to the theoretical limit" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-dna-replication-x-error-correction.yaml" }, { "id": "u-ecology-resilience-spatial-indicator", "title": "Do spatial geometric properties of vegetation patterns (separatrix distance, fractal dimension) provide earlier and more reliable early-warning indicators of ecosystem collapse than temporal variance or autocorrelation?", "status": "open", "domain": "biology", "systematic_gaps": [ "The lead time of geometric/separatrix-based EWIs relative to temporal EWIs has not been measured in empirical dryland vegetation datasets.", "Whether the separatrix distance can be estimated from satellite imagery without ground-truth observations is unknown.", "The false-positive rate of spatial EWIs (triggering without actual tipping) has not been quantified across ecosystem types." ], "suggested_hypotheses": [ "Geometric EWIs derived from spatial vegetation patterns detect desertification tipping 6-18 months earlier than temporal AR(1) EWIs computed from the same data, across at least 5 distinct dryland ecosystems." ], "file": "unknowns-catalog/biology/u-ecology-resilience-spatial-indicator.yaml" }, { "id": "u-epigenetic-escape-loci-mechanisms-transgenerational-scope", "title": "Which genomic loci consistently escape epigenetic reprogramming at fertilisation in mammals, what molecular features protect them from erasure, and how many generations can environmentally-induced epigenetic marks persist through the germline in humans?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Genome-wide single-cell methylation profiling of human sperm and oocytes has not identified all escapee loci; current data is from bulk sequencing.", "The mechanistic basis for IAP vs. non-IAP retrotransposon differential erasure resistance is not understood at the DNMT/TET enzyme level.", "Human transgenerational epigenetic inheritance beyond F2 (grandchildren) has not been demonstrated with methylation data; most data is F1 offspring.", "Cross-fostering studies equivalent to Meaney's rat experiments have not been performed in non-human primates to test the relative contribution of direct epigenetic vs. behavioural transmission." ], "suggested_hypotheses": [ "h-sperm-small-rna-mediates-paternal-trauma-epigenetic-inheritance" ], "file": "unknowns-catalog/biology/u-epigenetic-escape-loci-mechanisms-transgenerational-scope.yaml" }, { "id": "u-epigenetic-inheritance-transgenerational", "title": "How far does transgenerational epigenetic inheritance extend in mammals, and what molecular mechanisms survive reprogramming at fertilization?", "status": "open", "domain": "biology", "systematic_gaps": [ "Which methylated loci survive germline reprogramming and are transmitted to F1 and F2 in mammals", "Whether sperm miRNA changes are causal for paternal TEI or mere correlates", "The evolutionary significance of TEI vs. DNA sequence variation for adaptation speed" ], "suggested_hypotheses": [ "Sperm miRNA pools encode 10-20 bits of paternal environmental experience, transmitted to F1 metabolism with >70% penetrance, detectable by deep miRNA sequencing of sperm from fathers exposed to defined diets" ], "file": "unknowns-catalog/biology/u-epigenetic-inheritance-transgenerational.yaml" }, { "id": "u-epigenetic-landscape-x-attractor", "title": "Can the Waddington epigenetic landscape be quantitatively reconstructed from single-cell RNA-seq data, and do predicted attractor barriers match reprogramming efficiency?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "RNA velocity methods (scVelo, dynamo) infer vector fields from splicing ratios but the connection to protein-level GRN dynamics and the Waddington potential has not been rigorously established", "Predicted attractor barriers from RNA velocity landscapes have not been quantitatively correlated with measured iPSC reprogramming efficiency across 100+ cell types", "The role of non-gradient (rotational) components of the GRN vector field in maintaining cell identity has not been separated from potential-derived (gradient) components in real data" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-epigenetic-landscape-x-attractor.yaml" }, { "id": "u-error-threshold-genome-size", "title": "Does the Shannon channel capacity of biological replication channels quantitatively predict the maximum viable genome size as a function of per-base mutation rate across all domains of life — RNA viruses, DNA viruses, bacteria, and eukaryotes?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The Shannon capacity bound C = 1-H(mu) has not been fitted to the full (mu, L) distribution across domains of life", "The selective advantage sigma has not been estimated independently and compared to the value required for Shannon-bound consistency", "The coronavirus proofreading exonuclease genome-size increase (~3x) has not been quantitatively analysed as a Shannon capacity expansion", "Finite-length coding theory corrections (analogous to finite genome length) have not been applied to predict genome size variance around the Shannon limit" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-error-threshold-genome-size.yaml" }, { "id": "u-evolution-undecidability-open-ended", "title": "Is open-ended biological evolution undecidable in principle - analogous to the halting problem - and does this explain why no finite model can predict evolutionary trajectories indefinitely?", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether the evolutionary dynamics of real organisms produce Kolmogorov-incompressible complexity growth (true open-endedness) or bounded-novelty pseudo-evolution has not been tested empirically.", "The connection between biological undecidability mechanisms (HGT, recombination) and the Chaitin incompleteness framework has not been formalized.", "No measure of \"degree of open-endedness\" calibrated against undecidability has been applied to empirical phylogenetic data." ], "suggested_hypotheses": [ "Sexual recombination is an algorithmic randomness injection mechanism that allows biological evolution to exceed the complexity bounds of any deterministic Turing machine of equivalent size." ], "file": "unknowns-catalog/biology/u-evolution-undecidability-open-ended.yaml" }, { "id": "u-evolutionary-graph-amplifier-natural-populations", "title": "Do real biological population structures (tissue architectures, social networks, geographic ranges) act as amplifiers or suppressors of natural selection, and can this be quantified from empirical connectivity data?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The effective fixation probability in real population graphs with both spatial structure and demographic stochasticity has not been computed for any empirical population.", "Whether crypt-villus intestinal architecture suppresses oncogenic mutation fixation (as theorised) has not been tested with single-cell sequencing at sufficient resolution.", "The dynamic nature of real population graphs (individuals join/leave, edges change) invalidates static graph results but dynamic graph evolution theory is underdeveloped." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-evolutionary-graph-amplifier-natural-populations.yaml" }, { "id": "u-fermentation-thermodynamic-efficiency-limit", "title": "What is the thermodynamic upper bound on ATP yield per mole of substrate in anaerobic fermentation, and how close do naturally evolved microbes operate to this limit?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The thermodynamic efficiency of individual fermentation steps (phosphofructokinase, pyruvate kinase) under physiological conditions has not been measured with sufficient precision.", "The trade-off between ATP yield and growth rate (Pareto frontier) in fermentation has not been derived from thermodynamic principles.", "Whether any microbe operates near the thermodynamic ATP yield limit in any fermentation pathway is not known." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-fermentation-thermodynamic-efficiency-limit.yaml" }, { "id": "u-fisher-natural-gradient-evolution", "title": "Does natural selection implement natural gradient ascent on the fitness landscape in the Fisher information metric, and does the evolutionary speed limit (dW_bar/dt <= V_A = I_pop) match empirical selection responses across taxa?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The Fisher-information speed limit V_A has not been compared to empirical selection response in artificial selection experiments across multiple taxa", "The G-matrix (genetic covariance matrix) has not been analysed as a Fisher information matrix and compared to the theoretical optimum for the measured fitness landscape", "Multi-trait selection responses have not been tested for correspondence with natural gradient ascent direction vs steepest gradient ascent direction", "The machine learning natural gradient convergence guarantees have not been applied to predict evolutionary convergence time in adaptive landscapes" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-fisher-natural-gradient-evolution.yaml" }, { "id": "u-fitness-landscape-overlapping-genes", "title": "How does overlapping gene structure constrain the ruggedness of the fitness landscape and the accessibility of evolutionary paths in dense genomes?", "status": "open", "domain": "biology", "systematic_gaps": [ "The ruggedness (correlation length) of the fitness landscape as a function of gene overlap fraction has not been systematically measured across diverse organisms.", "Whether overlapping genes create topological barriers to adaptive evolution (local optima that non-overlapping homologues can escape) has not been tested.", "The information-theoretic constraint imposed by gene overlap (mutual information between reading frames) has not been correlated with substitution rates across viral evolution." ], "suggested_hypotheses": [ "The substitution rate in overlapping gene regions scales inversely with the mutual information between the two reading frames, providing a quantitative information-theoretic explanation for conserved viral proteins." ], "file": "unknowns-catalog/biology/u-fitness-landscape-overlapping-genes.yaml" }, { "id": "u-flagellar-motor-x-rotary-engine", "title": "How does the bacterial flagellar motor achieve near-100% energy conversion efficiency at stall, and what is the mechanochemical coupling mechanism at atomic resolution?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Atomic-resolution cryo-EM of the complete BFM in multiple states (resting, torque-generating, switching) has not been achieved for the full 50+ protein complex", "The number of protons required per complete flagellar revolution (currently estimated 1200 H+/revolution) has not been measured directly with single-proton counting accuracy", "The mechanochemical coupling mechanism (how proton transit drives conformational changes in MotA/MotB) has not been captured in a molecular dynamics simulation that reproduces experimental torque-speed curves" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-flagellar-motor-x-rotary-engine.yaml" }, { "id": "u-flocking-topological-interaction-mechanism", "title": "What is the sensory and computational mechanism by which individual birds in a murmuration identify and track their k ~ 7 topological neighbours in a dense, rapidly moving flock, and how is this number evolutionarily constrained?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Mechanism of topological neighbour identification is not known", "Whether k varies dynamically with flock density has not been measured", "Cross-species comparison of topological interaction number is absent", "No neuroscience experiment has tested visual processing capacity for topological vs. metric neighbour tracking" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-flocking-topological-interaction-mechanism.yaml" }, { "id": "u-funnel-ruggedness-docking-false-minima", "title": "How does landscape ruggedness quantifiably drive false-minimum trapping in protein-ligand docking pipelines?", "status": "open", "domain": "biology", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-funnel-aware-search-reduces-docking-decoy-traps" ], "file": "unknowns-catalog/biology/u-funnel-ruggedness-docking-false-minima.yaml" }, { "id": "u-game-theory-x-antibiotic-resistance", "title": "Can evolutionary game theory predict optimal antibiotic dosing regimens that exploit producer-cheater dynamics to prevent resistance evolution in clinical infections?", "status": "open", "domain": "biology", "systematic_gaps": [ "In vitro game dynamics may not translate to in vivo conditions (immune clearance, spatial heterogeneity, multiple species)", "Clinical antibiotic dosing is constrained by pharmacokinetics/pharmacodynamics (PK/PD), not just evolutionary game theory", "Multi-species communities (e.g. hospital-acquired polymicrobial infections) create multi-player games that are not analytically tractable" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-game-theory-x-antibiotic-resistance.yaml" }, { "id": "u-gene-expression-noise-x-information-theory", "title": "Do gene regulatory networks in living cells operate near their Shannon channel capacity limit, and what evolutionary pressures drive them toward or away from this optimum?", "status": "open", "domain": "biology", "systematic_gaps": [ "Single-cell RNA-seq noise estimates conflate technical noise with biological noise; deconvolution methods are imperfect", "Capacity calculations assume simple one-input one-output channels; real networks have correlated inputs and feedback", "No direct test of whether capacity-near-optimal networks have higher fitness than sub-optimal ones" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-gene-expression-noise-x-information-theory.yaml" }, { "id": "u-gene-regulatory-network-x-boolean-circuit", "title": "Are endogenous developmental gene regulatory networks in vertebrates operating at or near the Boolean criticality threshold K = 2, and if so, does this determine the evolvability of body plan morphology?", "status": "open", "domain": "biology", "systematic_gaps": [ "The effective Boolean connectivity K has not been estimated for any vertebrate GRN from single-cell transcriptomic data", "Boolean binarisation of continuous gene expression introduces artefacts whose effect on criticality estimates is unknown", "Whether GRN criticality is a product of evolution (selection for evolvability) or a neutral structural constraint is debated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-gene-regulatory-network-x-boolean-circuit.yaml" }, { "id": "u-grb-mass-extinction-link", "title": "Is there a statistically significant causal relationship between gamma-ray burst events within the Milky Way or Local Group and major mass extinction events in the terrestrial fossil record?", "status": "open", "domain": "biology", "systematic_gaps": [ "GRB rate in the Milky Way is uncertain by an order of magnitude; host galaxy characteristics and local GRB rate extrapolation are poorly constrained", "Ozone depletion by GRBs depends on burst fluence, latitude, and atmospheric state — all poorly reconstructed for ancient events", "The fossil record resolution (~1 Myr) is insufficient to temporally co-register with individual GRB events, which are instantaneous", "Cosmogenic isotope spikes (^10Be, ^26Al) in geological strata could constrain past energetic radiation events but are rarely compared with extinction boundaries" ], "suggested_hypotheses": [ "The Late Ordovician mass extinction (443 Mya) was initiated by a long GRB within 2 kpc that removed >50% of Earth's ozone column, causing an ultraviolet-driven kill curve preferentially affecting surface and shallow-water taxa", "The 26 Myr periodicity in mass extinction intensity (Raup-Sepkoski) reflects the solar system's galactic plane oscillation period modulating GRB exposure, but the signal is marginally significant and may be a statistical artifact" ], "file": "unknowns-catalog/biology/u-grb-mass-extinction-link.yaml" }, { "id": "u-great-ape-false-belief-implicit-explicit", "title": "Do great apes possess an explicit, flexible theory of mind capable of tracking false beliefs, or only an implicit, inflexible agent model, and does the dissociation reflect a difference in degree or in kind from human mentalizing?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Systematic comparison of implicit ToM tasks across great ape species with matched stimulus difficulty", "Neural imaging (fMRI) of ape mentalizing network during false-belief paradigms", "Disambiguation of associative learning vs. mental state attribution using fully counter-conditioned stimuli", "Whether ape implicit ToM transfers flexibly to novel agents and novel action sequences" ], "suggested_hypotheses": [ "h-tom-implicit-explicit-dissociation" ], "file": "unknowns-catalog/biology/u-great-ape-false-belief-implicit-explicit.yaml" }, { "id": "u-grn-gnn-perturbation-identifiability", "title": "Are GNN-informed gene regulatory perturbation models identifiable under sparse intervention data?", "status": "open", "domain": "biology", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-grn-gnn-priors-improve-perturbation-response-prediction" ], "file": "unknowns-catalog/biology/u-grn-gnn-perturbation-identifiability.yaml" }, { "id": "u-gut-microbiome-x-lotka-volterra", "title": "Are the interaction parameters of the gut microbiome generalized Lotka-Volterra model sufficiently stable across individuals and perturbations to enable personalized microbiome therapy prediction, and what ecological principles determine the basin of attraction for healthy microbiome states?", "status": "open", "domain": "biology", "systematic_gaps": [ "gLV interaction matrices estimated from different time periods of the same individual differ by ~50%; model is not identifiable from typical clinical data", "No experimental validation of predicted bifurcation points in human microbiome dysbiosis", "The relationship between microbial metabolic networks (which determine true interactions) and phenomenological gLV parameters is unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-gut-microbiome-x-lotka-volterra.yaml" }, { "id": "u-habitat-fragmentation-threshold", "title": "Do species extinction thresholds in fragmented landscapes obey 2D percolation finite-size scaling with exponent nu=4/3, and can early-warning indicators of approaching percolation criticality be detected in satellite habitat data?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The FSS exponent nu=4/3 for 2D percolation has not been measured from empirical species-persistence vs habitat-coverage data", "Percolation cluster-size power-law exponent (tau=187/91) has not been rigorously tested against satellite habitat patch-size distributions", "Early-warning indicators of approaching percolation criticality (rising correlation length, power-law cluster size distribution) have not been computed from time-series satellite land-cover data", "The appropriate percolation universality class (2D random vs structured landscape) for real fragmented habitats has not been determined empirically" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-habitat-fragmentation-threshold.yaml" }, { "id": "u-homeostasis-integral-feedback-synthetic-design", "title": "Can integral feedback control theory guide de novo design of synthetic gene circuits that achieve perfect homeostasis of arbitrary metabolite concentrations in living cells?", "status": "open", "domain": "biology", "systematic_gaps": [ "The antithetic integral feedback circuit has been demonstrated in principle but not optimized for robustness to molecular noise.", "Methods for systematic identification of the PID parameters of natural homeostatic circuits from time-course data are lacking.", "A design-rule framework mapping from desired steady-state error and settling time to gene circuit architecture does not yet exist." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-homeostasis-integral-feedback-synthetic-design.yaml" }, { "id": "u-immune-memory-x-long-term-potentiation", "title": "Do immune memory formation (germinal center affinity maturation) and neural long-term potentiation share a common molecular mechanism for memory consolidation — specifically, does both systems use protein synthesis-dependent structural changes governed by analogous signaling cascades?", "status": "open", "domain": "biology", "systematic_gaps": [ "No systematic comparison of kinase cascade architectures in GC B cells vs. hippocampal CA1 neurons has been published", "The role of local protein synthesis (dendritic mRNA translation in neurons; somatic mRNA in B cells) in memory maintenance is not characterized for both systems", "Whether the critical period for memory consolidation (time window for disruption) follows the same temporal dynamics in both systems is unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-immune-memory-x-long-term-potentiation.yaml" }, { "id": "u-intestinal-crypt-stem-cell-moran-selection", "title": "What is the selection coefficient of the earliest oncogenic mutations (APC, KRAS, TP53) in intestinal stem cells, and does the Moran process with positive selection quantitatively predict the observed age-dependent clonal expansion in normal human colon?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Selection coefficient estimates from human colon somatic sequencing have wide uncertainty ranges", "Crypt fission (population expansion) is not captured by fixed-N Moran model", "Multi-driver clone dynamics (two mutations in same cell) are not modelled" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-intestinal-crypt-stem-cell-moran-selection.yaml" }, { "id": "u-jamming-exponent-universality-epithelium-versus-colloid", "title": "Do epithelial jamming transitions near confluence share quantitative scaling exponents (e.g., velocity correlations, susceptibility divergences) with laboratory colloidal glasses at comparable effective packing fractions?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Harmonized imaging pipelines comparing particle-image velocimetry statistics on cells versus tracer beads in rheometers", "Controls separating thermal versus active noise contributions near the transition" ], "suggested_hypotheses": [ "h-shared-shape-index-scaling-near-jamming-across-donors" ], "file": "unknowns-catalog/biology/u-jamming-exponent-universality-epithelium-versus-colloid.yaml" }, { "id": "u-lateral-gene-transfer-rate-limits", "title": "What determines the maximum rate of lateral gene transfer (LGT) before it overwhelms vertical inheritance and destroys phylogenetic signal in prokaryotes?", "status": "open", "domain": "biology", "systematic_gaps": [ "The critical LGT rate for phylogenetic information loss has not been derived from information theory", "Whether selection acts to maintain low LGT in housekeeping genes (natural selection against LGT) is debated", "The timescale for integration of LGT genes into core regulatory networks is not quantified" ], "suggested_hypotheses": [ "The maximum tolerable LGT rate per gene per generation is 1/L where L is the gene length in codons, because longer genes experience proportionally more disruptive recombination — testable by comparing LGT rates per codon for genes of different lengths in metagenomes" ], "file": "unknowns-catalog/biology/u-lateral-gene-transfer-rate-limits.yaml" }, { "id": "u-lipid-raft-protein-sorting-mechanism", "title": "What is the physical mechanism by which lipid rafts sort integral membrane proteins, and what are the quantitative rules governing protein partitioning between ordered (raft) and disordered phases in living cell membranes?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Live-cell imaging at spatial resolution below raft domain size (~10-100 nm)", "Quantitative measurement of Lo/Ld partition coefficients for diverse proteins", "Theoretical prediction of protein-induced defect energy in the LC order field", "Understanding raft dynamics in the presence of active cytoskeleton remodeling" ], "suggested_hypotheses": [ "h-membrane-defects-protein-clustering" ], "file": "unknowns-catalog/biology/u-lipid-raft-protein-sorting-mechanism.yaml" }, { "id": "u-loss-aversion-cross-cultural-evolutionary-universality", "title": "Is the loss aversion coefficient λ ≈ 2.25 a universal human constant with an evolutionary fixed point, or does it vary systematically with ecological subsistence mode, cultural context, and individual genetic variation in dopaminergic/serotonergic systems?", "status": "open", "domain": "biology", "systematic_gaps": [ "Systematic measurement of λ using identical methods across populations with different subsistence modes (forager, pastoralist, agriculturalist, industrial) has not been conducted at scale; existing cross-cultural comparisons use different elicitation methods making direct comparison invalid.", "The genetic architecture of loss aversion (GWAS of λ estimated from incentivised choices) has not been conducted in any large cohort; heritability of λ is estimated from twin studies at h² ≈ 0.3–0.5 but specific variants are unknown.", "Whether loss aversion is calibrated to the statistical distribution of gains and losses in the local environment (Bayesian adaptation) has not been tested; this would predict λ decreasing in environments with symmetric gain/loss distributions." ], "suggested_hypotheses": [ "Loss aversion coefficient λ is positively correlated with subsistence variance (coefficient of variation in daily caloric intake) across populations, with forager populations showing λ ≈ 3–4 and post-industrial urban populations showing λ ≈ 1.5–2, consistent with Bayesian ecological calibration." ], "file": "unknowns-catalog/biology/u-loss-aversion-cross-cultural-evolutionary-universality.yaml" }, { "id": "u-maxent-ecology-failure-modes", "title": "Under what ecological conditions does the Maximum Entropy Theory of Ecology (METE) fail, and do systematic deviations from METE predictions identify specific ecological mechanisms beyond information-theoretic constraints?", "status": "open", "domain": "biology", "systematic_gaps": [ "Criteria for determining when a community has reached MaxEnt \"equilibrium\" are not defined; METE provides no dynamic model of approach to equilibrium.", "The role of spatial heterogeneity as an additional constraint not captured by S, N, E is unquantified.", "Invaded communities deviate strongly from METE; it is unknown whether the invasion signal decays on timescales predictable from relaxation dynamics.", "METE has been tested primarily in plant communities; systematic tests in animal communities, freshwater ecosystems, and microbial communities are sparse." ], "suggested_hypotheses": [ "h-mete-non-equilibrium-deviations" ], "file": "unknowns-catalog/biology/u-maxent-ecology-failure-modes.yaml" }, { "id": "u-mechanical-bifurcation-morphogenesis", "title": "Do mechanical bifurcations in epithelial sheets set universal constraints on body plan diversity across multicellular life, and can this predict which body plans are physically forbidden?", "status": "open", "domain": "biology", "systematic_gaps": [ "The complete bifurcation diagram of elastic sheet mechanics at the scale of whole-organism morphogenesis has not been mapped.", "No systematic comparison exists between the predicted \"mechanically forbidden\" morphologies and observed gaps in the fossil record or comparative anatomy.", "Whether the mechanical bifurcation framework applies beyond Volvocaceae (e.g., to gastrulation mechanics across metazoa) is unknown." ], "suggested_hypotheses": [ "The number of distinct folding morphologies accessible to a spherical epithelial sheet scales as log(N_cells), following the number of bifurcations in the elastic shell model as size increases." ], "file": "unknowns-catalog/biology/u-mechanical-bifurcation-morphogenesis.yaml" }, { "id": "u-mechanosensing-x-force-transduction", "title": "What is the molecular-scale mechanism by which focal adhesions convert substrate stiffness (Young's modulus) into intracellular biochemical signals — and can it be described by a single Hookean spring model?", "status": "open", "domain": "biology", "systematic_gaps": [ "Single-molecule measurements of talin unfolding under physiological load ranges are incomplete", "Non-linear viscoelastic effects of the cytoskeleton confound simple Hookean interpretations", "Whether durotaxis requires active probing (myosin-II pulling) or passive stiffness sensing is debated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-mechanosensing-x-force-transduction.yaml" }, { "id": "u-membrane-tension-x-laplace-pressure", "title": "How do cells coordinate cortical tension anisotropy during mitosis to ensure symmetric division, and what is the quantitative relationship between cortical tension gradients and cleavage furrow positioning?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Quantitative measurement of cortical tension spatial distribution during mitosis is limited by resolution of current probes", "Feedback loop between spindle orientation and cortical tension asymmetry is not fully characterized", "Effect of cell substrate geometry and confinement on division plane selection is not fully predicted by Laplace pressure theory" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-membrane-tension-x-laplace-pressure.yaml" }, { "id": "u-metabolic-flux-control-redistribution-disease", "title": "How does metabolic flux control redistribution in human disease (cancer, diabetes, heart failure) differ from healthy tissue, and can MCA-derived flux control coefficients identify new therapeutic targets?", "status": "open", "domain": "biology", "systematic_gaps": [ "No genome-scale human metabolic model has validated kinetic parameters for FCC computation", "Disease-specific FCC redistribution has only been computed for toy networks (< 20 enzymes)", "The relationship between FCC redistribution and drug target optimality is not formalised" ], "suggested_hypotheses": [ "In cancer glycolysis, PKM2 has a flux control coefficient > 0.5 (violating the summation theorem expectation) due to its allosteric regulation being uniquely sensitive to oncometabolite concentrations in the tumour microenvironment" ], "file": "unknowns-catalog/biology/u-metabolic-flux-control-redistribution-disease.yaml" }, { "id": "u-metabolic-flux-entropy-production-cancer-cells", "title": "Is the entropy production rate (σ̇) of cancer cells systematically higher than normal cells of the same tissue, and does σ̇ predict cancer aggressiveness and drug response beyond conventional metabolic biomarkers?", "status": "open", "domain": "biology", "systematic_gaps": [ "Simultaneous measurement of entropy production rate (microcalorimetry) and metabolic flux map (¹³C-MFA) in isogenic cancer cell lines varying in aggressiveness has not been performed; the expected quantitative relationship σ̇ ≈ Σ_i v_i ΔG_i/T (where v_i is flux and ΔG_i is reaction free energy) has not been validated experimentally.", "Whether cancer cell σ̇ exceeds normal cell σ̇ beyond what is explained by proliferation rate alone (i.e., whether Warburg fermentation contributes excess entropy production over oxidative phosphorylation) has not been definitively established.", "Clinical correlation between tumour microcalorimetry measurements and patient outcomes (survival, treatment response) has not been tested in a prospective cohort study with adequate statistical power." ], "suggested_hypotheses": [ "Cancer cells have σ̇ > normal cells by a factor of 2–5× even at matched growth rates, because Warburg fermentation generates ATP less efficiently than oxidative phosphorylation (Onsager coupling coefficient P/O ≈ 1 vs. 2.5), requiring higher metabolic flux and thus higher entropy production per unit biosynthetic output; σ̇ measured by microcalorimetry predicts cancer metastatic potential independently of Ki-67 proliferation index.\n" ], "file": "unknowns-catalog/biology/u-metabolic-flux-entropy-production-cancer-cells.yaml" }, { "id": "u-metabolic-flux-x-linear-programming", "title": "Does the assumption of growth-rate maximization in flux balance analysis hold across environmental conditions and organisms, or does the objective function change with nutritional stress and evolutionary history?", "status": "open", "domain": "biology", "systematic_gaps": [ "Biomass composition varies with growth rate and environment, making the objective function itself a variable", "13C metabolic flux analysis measures actual fluxes but is limited to ~100 reactions; genome-scale FBA has ~2000 reactions with no direct validation", "Multi-objective FBA (MOMA, ROOM) requires choosing trade-off weights that are not determined by first principles" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-metabolic-flux-x-linear-programming.yaml" }, { "id": "u-metabolic-scaling-deviations-non-mammalian", "title": "Why do metabolic scaling exponents deviate from 3/4 in insects, unicellular organisms, and plants, and do these deviations reflect differences in vascular network geometry or violations of the WBE model assumptions?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Systematic comparison of measured vascular/tracheal network fractal dimensions against WBE predictions across phyla has not been performed.", "Whether insect tracheal systems satisfy the volume-filling constraint of WBE is not quantified.", "The dependence of the measured scaling exponent on phylogenetic correction and dataset composition is not adequately controlled in existing meta-analyses." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-metabolic-scaling-deviations-non-mammalian.yaml" }, { "id": "u-metabolic-scaling-fractal-transport-unification", "title": "How much of cross-species variation in metabolic scaling exponents is explained by measurable deviations from fractal-like branching in real vascular and respiratory networks?", "status": "open", "domain": "biology", "systematic_gaps": [ "High-throughput 3D vascular reconstruction across species is rare.", "Models rarely integrate cardiac pulsatility and nonlinear rheology into scaling exponents." ], "suggested_hypotheses": [ "h-kleiber-exponent-from-fractal-like-transport-networks" ], "file": "unknowns-catalog/biology/u-metabolic-scaling-fractal-transport-unification.yaml" }, { "id": "u-microbiome-brain-axis-mechanism", "title": "What are the primary mechanistic pathways (vagus nerve, immune signaling, metabolite diffusion) by which gut microbiome composition influences brain function and behavior?", "status": "open", "domain": "biology", "systematic_gaps": [ "The relative contribution of vagal, immune, and metabolite pathways has not been quantified under controlled conditions", "Which specific bacterial taxa and metabolites are causal (not merely correlated) for behavioral effects", "How to translate mouse germ-free findings to human microbiome interventions" ], "suggested_hypotheses": [ "SCFA-mediated modulation of microglial activation is the dominant gut-brain pathway for depression risk, accounting for >50% of the variance in human depression scores explained by gut microbiome composition, testable by SCFA supplementation in prospective RCTs" ], "file": "unknowns-catalog/biology/u-microbiome-brain-axis-mechanism.yaml" }, { "id": "u-microbiome-diversity-stability-causality", "title": "Does gut microbiome species diversity causally protect against pathogen invasion and antibiotic-associated dysbiosis, or is it merely correlated with host factors that drive both diversity and resilience?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Mendelian randomisation approaches for microbiome diversity are not well validated due to the absence of SNPs with large microbiome effects that do not also affect immunity.", "Germ-free mouse colonisation experiments using defined microbial communities of varying diversity cannot fully recapitulate human microbiome ecology.", "The minimum diversity required for colonisation resistance (the key functional outcome) has not been determined for any specific pathogen." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-microbiome-diversity-stability-causality.yaml" }, { "id": "u-microplate-inverse-beer-lambert-conditioning", "title": "How ill-conditioned is practical inverse concentration retrieval from multi-well absorbance when spectra overlap, scattering rises, and plate-edge artifacts distort calibration curves — and what regularized inversion beats ordinary linear regression in routine assays?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Open benchmark plates with ground-truth concentrations and multiplex dyes across vendors for inversion-method comparisons.", "Uncertainty propagation standards tying posterior concentration widths to pipetting and reader repeatability." ], "suggested_hypotheses": [ "h-multi-wavelength-beer-lambert-inverse-improves-plate-precision" ], "file": "unknowns-catalog/biology/u-microplate-inverse-beer-lambert-conditioning.yaml" }, { "id": "u-modularity-robustness-evolvability-tradeoff", "title": "Is there a quantitative, universal trade-off between robustness and evolvability in biological regulatory networks, and does modularity reliably occupy the Pareto front of this trade-off across scales from protein domains to body plans?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "No consensus metric for biological modularity that predicts evolvability across scales (molecular, cellular, organismal).", "The robustness-evolvability trade-off has been demonstrated in artificial life systems; empirical tests in real organisms are limited to a few model systems (yeast, E. coli, Drosophila).", "The engineering near-decomposability metric (Simon 1962) has not been systematically applied to gene regulatory networks using high-throughput epistasis data.", "Whether developmental constraints (limits on phenotypic variation) are robustness features or evolutionary accidents is unresolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-modularity-robustness-evolvability-tradeoff.yaml" }, { "id": "u-morphogenesis-x-mechanical-instability", "title": "Are mechanical instabilities sufficient to explain species-specific brain gyrification patterns, or do molecular pre-patterning signals (Wnt, PDGF) constrain fold positions independently of mechanical forces?", "status": "open", "domain": "biology", "systematic_gaps": [ "Fold position conservation across individuals is inconsistent with a purely mechanical (degenerate instability) model", "Molecular pre-patterning signals (Wnt, PDGF) have established topographic patterns in cortex but causal proof is lacking", "No experiment has ablated both mechanical and molecular inputs independently to test their relative contributions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-morphogenesis-x-mechanical-instability.yaml" }, { "id": "u-multilevel-selection-kin-equivalence", "title": "Are kin selection and multilevel selection genuinely equivalent (Price equation unification) or do they make different empirical predictions, and which level of selection dominates in human social evolution?", "status": "open", "domain": "biology", "systematic_gaps": [ "Empirical tests that would distinguish kin selection from group selection as causal mechanisms (not just equivalent descriptions) have not been designed or agreed upon.", "The role of cultural group selection in human prosociality (Henrich 2004) versus genetic kin selection is not quantified for any large-scale human cooperation phenomenon.", "Nowak et al. (2010) inclusive fitness challenge to eusociality has not been resolved — subsequent mathematical analysis shows the paper contained errors, but the conceptual debate continues." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-multilevel-selection-kin-equivalence.yaml" }, { "id": "u-muscle-mechanics-x-crossbridge-theory", "title": "How many distinct biochemical states does the myosin crossbridge cycle require to quantitatively reproduce all mechanical transients in skeletal muscle, and what are the structural correlates of these states?", "status": "open", "domain": "biology", "systematic_gaps": [ "Cryo-EM of myosin in situ is limited to ~10 angstrom resolution; intermediate states are not structurally resolved", "Mechanical transient data (T1 curve, recovery phases) constrain only a few rate constants; remaining parameters are underdetermined", "Cardiac myosin has different isoforms and regulatory proteins (troponin, titin) that make direct comparison to skeletal difficult" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-muscle-mechanics-x-crossbridge-theory.yaml" }, { "id": "u-myosin-motor-x-brownian-ratchet", "title": "What is the complete energy transduction mechanism of myosin II at the single-molecule level, and how does the Brownian ratchet efficiency scale with temperature?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The free energy landscape of the myosin power stroke at atomic resolution during each ATP hydrolysis sub-step has not been fully mapped", "Temperature dependence of myosin step efficiency has not been systematically measured from 4°C to 42°C to test Brownian ratchet predictions", "Jarzynski equality-based measurement of myosin free energy transduction from non-equilibrium single-molecule trajectories has not been performed" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-myosin-motor-x-brownian-ratchet.yaml" }, { "id": "u-neutral-theory-x-stochastic-sampling", "title": "Does the observed species abundance distribution of tropical tree communities follow the Poisson-Dirichlet prediction of neutral theory, or do deterministic niche effects create significant deviations detectable with modern tree census data?", "status": "open", "domain": "biology", "systematic_gaps": [ "Full Poisson-Dirichlet likelihood fitting to BCI census data with immigration correction has not been performed", "Neutral theory goodness-of-fit tests do not adequately account for phylogenetic signal in abundance distributions", "Distinguishing pure neutral drift from nearly-neutral models with small fitness differences is statistically very difficult" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-neutral-theory-x-stochastic-sampling.yaml" }, { "id": "u-optimal-transport-angiogenesis", "title": "Does tumour angiogenesis deviate from Murray's optimal transport law in a measurable, drug-targetable way?", "status": "open", "domain": "biology", "systematic_gaps": [ "Murray's law has been verified in normal vasculature but not systematically measured in tumour microvessels using modern 3D imaging", "The deviation from the optimal branching exponent gamma=3 in tumour vessels has not been quantified as a function of tumour type or stage", "No therapeutic intervention has been designed based on restoring Murray branching geometry to normalise tumour vasculature" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-optimal-transport-angiogenesis.yaml" }, { "id": "u-pathogen-coevolution-network-percolation", "title": "Does pathogen diversity coevolve with host contact network topology through a percolation-like process, with a diversity threshold above which epidemic control becomes impossible?", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether a percolation-like threshold exists in pathogen strain co-circulation as a function of host network degree distribution has not been derived theoretically.", "The critical strain diversity above which WHO-recommended vaccination strategies are predicted to fail has not been computed for any pathogen family.", "Whether historical influenza strain diversity has been tracking the percolation threshold is unknown." ], "suggested_hypotheses": [ "The number of co-circulating influenza strains that can be controlled by seasonal vaccination scales with the square root of the host network degree, following percolation theory predictions." ], "file": "unknowns-catalog/biology/u-pathogen-coevolution-network-percolation.yaml" }, { "id": "u-percolation-epidemic-fss", "title": "Do finite-size scaling corrections from percolation theory quantitatively improve epidemic risk estimates in populations of 10,000-100,000?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "FSS corrections to epidemic threshold have not been validated against real outbreak data in populations of N < 100,000", "The appropriate universality class (random-graph vs 2D spatial) for institutional contact networks (hospitals, schools) has not been empirically determined", "No public health tool currently reports R_0 with finite-size uncertainty bands derived from percolation FSS", "Retrospective COVID-19 nursing home / hospital outbreak data has not been analysed with FSS methods" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-percolation-epidemic-fss.yaml" }, { "id": "u-photoreceptor-quantum-efficiency-x-photon-statistics", "title": "What limits the signal-to-noise ratio of single-photon detection in retinal rods - thermal rhodopsin isomerization (dark noise) vs gain variability in the cGMP cascade - and can the cascade be engineered to approach the quantum efficiency limit?", "status": "open", "domain": "biology", "systematic_gaps": [ "Single-molecule measurements of the cascade in intact rod outer segments are not possible; only ensemble averages are measured", "The thermal isomerization rate of rhodopsin is measured but its relationship to quantum efficiency limit is not derived from first principles", "Comparative studies of different vertebrate rhodopsins (gecko vs frog vs human) have not been done with matched electrophysiology" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-photoreceptor-quantum-efficiency-x-photon-statistics.yaml" }, { "id": "u-phylogenetics-x-coalescent-theory", "title": "How do ancestral recombination graphs (ARGs) scale computationally to whole-genome biobank data, and what population history features are identifiable from ARGs but not from summary statistics?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "ARG inference algorithms (ARG-Weaver, Relate, tsinfer) scale poorly beyond 10^4 individuals", "Statistical tests for distinguishing selective sweeps from neutral demographic events using ARG topology are not established", "Minimum description length of ARG for given sequence data is not known, limiting compression and inference efficiency" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-phylogenetics-x-coalescent-theory.yaml" }, { "id": "u-prion-nucleation-spontaneous-rate-physiological", "title": "What is the spontaneous de novo nucleation rate of PrPSc from PrPC in healthy mammalian brain tissue, and does it account for the observed sporadic prion disease incidence of ~1 per million per year?", "status": "open", "domain": "biology", "systematic_gaps": [ "No in vitro system replicates the spontaneous nucleation rate observed in vivo", "PRNP M129V polymorphism affects sCJD risk but its effect on nucleation kinetics is not measured", "The role of chaperones and the proteostasis network in suppressing spontaneous PrPSc nucleation is unexplored" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-prion-nucleation-spontaneous-rate-physiological.yaml" }, { "id": "u-protein-aggregation-x-nucleation-growth", "title": "Does secondary nucleation (fibril-surface catalysed) or primary nucleation dominate the early seeding events in Alzheimer's disease in vivo, and can the Knowles-Michaels rate equations predict in vivo amyloid-β aggregation kinetics from in vitro parameters?", "status": "open", "domain": "biology", "systematic_gaps": [ "In vivo primary vs. secondary nucleation rate constants for Aβ42 have not been measured", "Whether lipid membrane surfaces act as heterogeneous nucleation templates in neuronal synapses is unresolved", "The Knowles-Michaels equations have not been validated against in vivo plaque spreading kinetics from PET imaging data" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-protein-aggregation-x-nucleation-growth.yaml" }, { "id": "u-protein-crystal-packing-predictability", "title": "Can the space group and unit-cell parameters of a protein crystal be predicted de novo from the protein sequence or structure, and what determines the observed non-uniform space-group frequency distribution in the PDB?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The relative contributions of protein surface properties vs. crystallisation conditions to space-group selection are not quantified.", "No validated computational tool can reliably predict space group from sequence alone (success rate <15% for best current methods).", "The relationship between space-group frequency and protein evolutionary pressures (e.g., symmetry selection in oligomers) is not explored." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-protein-crystal-packing-predictability.yaml" }, { "id": "u-protein-folding-alphafold2-de-novo-design-limits", "title": "What are the fundamental limits of AlphaFold2-based de novo protein design, and can designed proteins achieve the functional diversity of naturally evolved proteins without evolutionary history in their training data?", "status": "open", "domain": "biology", "systematic_gaps": [ "The fraction of AF2 structure predictions that represent the functional ground-state conformation (vs. a low-energy local minimum or domain-swapped alternative) has not been systematically quantified; for allosteric proteins and IDPs, this fraction may be <50%.", "De novo designed proteins with novel binding functions (enzymes, receptors) achieve catalytic efficiencies 10-100x lower than natural proteins even with computational optimization — the mechanistic source of this gap (active site preorganization? loop dynamics? allosteric communication?) is unidentified.", "The boundary of AlphaFold2's \"distribution\" — the set of protein sequences for which AF2 prediction is reliable vs. extrapolation failure — has not been mapped; there is no uncertainty quantification that distinguishes confident predictions from hallucinations." ], "suggested_hypotheses": [ "AF2-based designed proteins show a bimodal success distribution — designs with >70% sequence identity to natural proteins in the PDB succeed experimentally at >80% rate, while designs with <40% identity succeed at <20% rate — establishing the evolutionary coverage threshold for reliable computational design.\n" ], "file": "unknowns-catalog/biology/u-protein-folding-alphafold2-de-novo-design-limits.yaml" }, { "id": "u-protein-folding-pl-constant-coarse-grained-surrogate", "title": "Can coarse-grained order parameters for protein folding (native contact fraction, radius of gyration channels) admit empirically measurable Polyak–Łojasiewicz-like constants that predict folding timescale ordering across homologs?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Dimension reduction destroys guarantees; rigorous PL constants do not automatically survive arbitrary projections.", "Path ensembles for multi-domain proteins violate simple funnel pictures even when native states are unique." ], "suggested_hypotheses": [ "h-two-state-folders-admit-pl-like-surrogate-on-contact-order-parameter" ], "file": "unknowns-catalog/biology/u-protein-folding-pl-constant-coarse-grained-surrogate.yaml" }, { "id": "u-protein-folding-x-energy-landscape", "title": "What determines the folding funnel depth-to-width ratio for a given amino acid sequence, and can frustrated landscapes predict aggregation propensity?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "No method reliably predicts folding rates (log kf) from sequence alone without prior structural knowledge", "The relationship between local frustration index (Ferreiro et al. frustratometer) and aggregation propensity in amyloid-forming sequences is not quantitatively established", "Whether metamorphic proteins (fold-switching on function) can be rationally designed by engineering competing landscape minima has not been demonstrated de novo" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-protein-folding-x-energy-landscape.yaml" }, { "id": "u-protein-misfolding-disease-mechanism", "title": "What is the detailed molecular mechanism by which protein misfolding drives neurodegenerative disease, and can energy landscape theory predict which sequences are misfolding-prone?", "status": "open", "domain": "biology", "systematic_gaps": [ "No quantitative mapping between energy landscape frustration metrics and disease-associated misfolding rates in vivo.", "AlphaFold2 structure prediction does not include misfolded state ensembles or aggregation-prone regions.", "The toxic species (monomer, oligomer, or fibril) responsible for neurodegeneration in each disease is disputed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-protein-misfolding-disease-mechanism.yaml" }, { "id": "u-quantum-coherence-physiological-role", "title": "Does quantum coherence in biological light-harvesting complexes play a functional role in energy transfer efficiency at physiological temperatures, or are the observed spectroscopic oscillations artefacts of vibronic coupling with no fitness consequence?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "In vivo 2DES at physiological temperature for intact thylakoid membranes remains technically challenging; most data is on isolated complexes in buffer at 77K or 277K", "Theoretical models disagree on the bath spectral density (Drude-Lorentz vs Brownian oscillator vs underdamped vibrational peaks)", "Transfer efficiency measurements that isolate the coherence contribution (vs. structural topology) have not been performed with sufficient precision" ], "suggested_hypotheses": [ "h-fmo-enaqt-efficiency" ], "file": "unknowns-catalog/biology/u-quantum-coherence-physiological-role.yaml" }, { "id": "u-quantum-tunneling-enzyme-room-temperature-scope", "title": "What fraction of enzymatic reactions in biology involve quantum tunneling as a quantitatively significant rate enhancement, and is quantum tunneling a universal feature of enzyme catalysis or limited to specific oxidoreductase classes with extreme KIE signatures?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Systematic KIE measurement across diverse enzyme families (not just oxidoreductases)", "Path integral molecular dynamics for proton transfer in diverse enzyme active sites", "Protein evolutionary analysis of \"promoting vibration\" residues across phylogeny", "Room-temperature quantum coherence timescale in biological environments" ], "suggested_hypotheses": [ "h-protein-dynamics-optimize-quantum-tunneling" ], "file": "unknowns-catalog/biology/u-quantum-tunneling-enzyme-room-temperature-scope.yaml" }, { "id": "u-quorum-signaling-as-multiplayer-game", "title": "Under what spatial structures do quorum-sensing strategies form evolutionarily stable polymorphisms between producers, responders, and cheaters?", "status": "open", "domain": "biology", "systematic_gaps": [ "In vivo measurement of effective signal fields at single-cell resolution is hard.", "Clinical isolates show diverse QS systems; payoff inference needs high-throughput assays." ], "suggested_hypotheses": [ "h-quorum-thresholds-are-ess-under-stochastic-demography" ], "file": "unknowns-catalog/biology/u-quorum-signaling-as-multiplayer-game.yaml" }, { "id": "u-random-matrix-eigenvalue-cleaning-single-cell-batch-effects", "title": "When does random-matrix covariance cleaning preserve biological signal while suppressing single-cell batch artifacts?", "status": "open", "domain": "biology", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-rmt-covariance-cleaning-improves-single-cell-state-clustering" ], "file": "unknowns-catalog/biology/u-random-matrix-eigenvalue-cleaning-single-cell-batch-effects.yaml" }, { "id": "u-redfield-ratio-evolution-optimality", "title": "Is the Redfield ratio C:N:P=106:16:1 an evolutionary optimum, a dynamical attractor, or a geochemical accident — and can we distinguish these mechanisms experimentally?", "status": "open", "domain": "biology", "systematic_gaps": [ "No long-term evolution experiment has tested whether phytoplankton evolve toward the Redfield ratio from perturbed stoichiometries", "The degree to which ocean N:P ratios are set by geological vs biological fluxes is unresolved", "Whether organisms with non-standard Redfield ratios (diatoms, N2-fixers) are evolutionarily stable or transient deviants" ], "suggested_hypotheses": [ "Under competitive evolution in N:P-imbalanced chemostats, phytoplankton communities converge toward the Redfield ratio as an evolutionary attractor within 100-500 generations" ], "file": "unknowns-catalog/biology/u-redfield-ratio-evolution-optimality.yaml" }, { "id": "u-regulatory-network-attractor-enumeration", "title": "How many stable attractors (cell states) do mammalian gene regulatory networks support, and can the attractor landscape be systematically mapped from transcriptomic data alone?", "status": "open", "domain": "biology", "systematic_gaps": [ "Attractor enumeration in Boolean networks with N > 100 nodes is computationally intractable without approximations", "Empirical identification of attractors from scRNA-seq data conflates technical noise with biological cell states", "The relationship between network topology (number of feedback loops) and attractor number is not established for real networks" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-regulatory-network-attractor-enumeration.yaml" }, { "id": "u-renormalization-allometric", "title": "Are biological allometric scaling exponents RG fixed points, and what do the correction-to-scaling terms predict about small-organism deviations from Kleiber's Law?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "The WBE vascular branching recursion has not been cast as an explicit RG transformation with a fixed-point equation", "Correction-to-scaling exponents from the RG calculation have not been derived and compared to the observed sub-1g deviations in Savage et al. (2004)", "It is unknown whether non-vascular organisms (fungi, tunicates, siphonophores) fall in the same RG universality class or a distinct one", "The relationship between the pulsatile-wave mechanism (u-kleiber-pulsatile-waves) and the area-preserving branching constraint (RG fixed-point condition) has not been formalised" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-renormalization-allometric.yaml" }, { "id": "u-replication-fork-tasep-parameter-identifiability-from-seq-stalling-assays", "title": "Can genome-wide replication stalling assays paired with polymerase occupancy sequencing identify measurable ASEP-like parameters (effective hopping asymmetry, defect densities) without overfitting sparse kinetic toy models?", "status": "open", "domain": "biology", "systematic_gaps": [ "Synthetic lethality screens perturbing helicase–polymerase stoichiometry interpreted via lattice shocks with falsifiable shock-speed predictions", "Uncertainty bands on inferred hopping asymmetry given sequencing depth and cell-cycle heterogeneity" ], "suggested_hypotheses": [ "h-stalling-density-wave-speed-correlates-with-seq-measured-pause-density-peaks" ], "file": "unknowns-catalog/biology/u-replication-fork-tasep-parameter-identifiability-from-seq-stalling-assays.yaml" }, { "id": "u-replicator-dynamics-llm-training", "title": "Does LLM self-play fine-tuning (RLHF, constitutional AI) converge to the same Nash equilibria as biological replicator dynamics?", "status": "open", "domain": "biology", "systematic_gaps": [ "The convergence rate of self-play LLM fine-tuning has not been compared to the convergence rate of replicator dynamics on equivalent payoff matrices", "Whether RLHF reward model fixed points are Nash equilibria in the game-theoretic sense has not been formally verified for large language models", "The Price equation decomposition of gradient descent has been proposed but not empirically validated on real training runs" ], "suggested_hypotheses": [ "h-gan-training-redqueen-dynamics" ], "file": "unknowns-catalog/biology/u-replicator-dynamics-llm-training.yaml" }, { "id": "u-replicator-dynamics-prebiotic-origin", "title": "Can replicator dynamics on chemical reaction networks explain the origin of hereditary information, and what is the minimum complexity required for self-sustaining replication?", "status": "open", "domain": "biology", "systematic_gaps": [ "The minimum chemical complexity required for the emergence of heritable variation (not just autocatalytic amplification) from non-living chemistry is not established theoretically or experimentally.", "Whether the replicator equation can emerge continuously from mass-action kinetics of a CRN without a discontinuous phase transition to discrete replicators is an open mathematical question.", "The role of spatial structure and non-equilibrium conditions in stabilising replicator networks against parasitic sequences has been modelled but not experimentally validated in prebiotic chemistry scenarios." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-replicator-dynamics-prebiotic-origin.yaml" }, { "id": "u-rna-folding-pseudoknot-partition-function", "title": "Can the RNA partition function be extended to include pseudoknots in polynomial time, and what fraction of biologically functional RNA structures require pseudoknot thermodynamics for accurate prediction?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "No polynomial-time exact algorithm exists for the general pseudoknot partition function.", "The fraction of PDB RNA structures where the MFE pseudoknot-free prediction differs from the crystal structure by >50% base pairs has not been computed systematically.", "Efficient approximations to the pseudoknot partition function (variational, stochastic) have not been benchmarked on a curated pseudoknot-containing RNA structure database." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-rna-folding-pseudoknot-partition-function.yaml" }, { "id": "u-scale-free-network-x-metabolic", "title": "Do all metabolic networks across life exhibit the same scale-free exponent gamma, and does preferential attachment explain the evolutionary origin of metabolic hubs?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "Modern metabolic network reconstructions (BIGG database, 8000+ organisms) have not been systematically analyzed for scale-free topology vs. alternative distributions (log-normal, exponential cutoff)", "The preferential attachment hypothesis has not been tested against the fossil record of metabolism (phylogenetically dated first appearances of metabolites)", "The relationship between metabolic hub degree and evolutionary conservation (phylogenetic breadth) has not been quantified across all domains of life" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-scale-free-network-x-metabolic.yaml" }, { "id": "u-self-organized-criticality-consciousness", "title": "Is self-organized criticality (SOC) through brain-body resonance a necessary and sufficient mechanism for conscious integration, or merely correlative?", "status": "open", "domain": "biology", "systematic_gaps": [ "Whether artificially perturbing neural SOC (e.g., via transcranial magnetic stimulation) produces measurable changes in conscious integration measures (IIT Phi, perturbational complexity index) has not been tested.", "The mechanism by which peripheral physiological rhythms maintain central neural criticality has not been established causally.", "Whether SOC during dreaming (when bodily coupling is reduced) differs measurably from waking SOC is unknown." ], "suggested_hypotheses": [ "Anesthesia abolishes neural avalanche power laws (departing from criticality) before electroencephalographic signatures of unconsciousness appear, with a measurable lag predictable from the coupling model." ], "file": "unknowns-catalog/biology/u-self-organized-criticality-consciousness.yaml" }, { "id": "u-senescence-sasp-cancer-promotion-threshold", "title": "At what senescent cell burden does the SASP switch from tumor-suppressive (immune recruitment) to tumor-promoting (chronic inflammation), and can this threshold be measured as a clinical biomarker?", "status": "open", "domain": "biology", "systematic_gaps": [ "No animal model has systematically measured cancer incidence as a function of senescent cell burden at defined levels", "p16 expression in blood is a systemic proxy but not tissue-specific", "SASP composition changes with time after senescence induction and is not uniform" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-senescence-sasp-cancer-promotion-threshold.yaml" }, { "id": "u-sir-model-x-compartmental-ode", "title": "Do the topological properties of contact networks (degree distribution, clustering, community structure) systematically alter the epidemic threshold R₀ in ways not captured by mean-field SIR models, and can a unified network-kinetics framework predict epidemic outcomes on arbitrary network topologies?", "status": "open", "domain": "biology", "systematic_gaps": [ "No closed-form epidemic threshold for general degree-correlated networks with overlapping communities", "Stochastic extinction probability on finite heterogeneous networks has no analytic solution beyond mean-field", "Time-varying contact networks (temporal networks) break Markovian assumptions; non-Markovian SIR theory is incomplete" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-sir-model-x-compartmental-ode.yaml" }, { "id": "u-stochastic-gene-expression-bet-hedging-quantitative", "title": "What are the quantitative design principles linking promoter noise parameters (burst size b, burst frequency k_on) to optimal bet-hedging fitness in fluctuating environments — and do measured Fano factors in bacterial genomes match the Kelly-criterion prediction for their ecological volatility?\n", "status": "open", "domain": "biology", "systematic_gaps": [ "No systematic measurement of F values across all promoters in any organism combined with ecological volatility data for the same species' natural habitat.", "The Kelly-criterion optimality condition for bet-hedging (maximise geometric mean fitness) has been stated qualitatively but not translated into a quantitative prediction for F given environmental power spectrum.", "The timescale matching condition (promoter switching rate k_on + k_off must match the environmental fluctuation frequency) has not been experimentally tested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-stochastic-gene-expression-bet-hedging-quantitative.yaml" }, { "id": "u-stochastic-resonance-neural-tuning", "title": "Has evolution tuned internal physiological noise levels in sensory neurons to the stochastic resonance optimum, and if so, what molecular and developmental mechanisms enforce this tuning?", "status": "open", "domain": "biology", "systematic_gaps": [ "Quantitative comparison of measured physiological noise levels against SR-predicted D_opt is lacking for most sensory modalities.", "The evolutionary hypothesis (noise optimized for SR) has not been tested with comparative genomics across species with different sensory environments.", "Molecular identity of the noise sources contributing to the SR optimum in hair cells (spontaneous otoacoustic emissions) is incomplete.", "SR-based therapeutic protocols for neuropathy and hearing loss lack controlled trials comparing SR-optimized vs. conventional noise." ], "suggested_hypotheses": [ "h-sensory-noise-sr-optimality" ], "file": "unknowns-catalog/biology/u-stochastic-resonance-neural-tuning.yaml" }, { "id": "u-synthetic-biology-x-circuit-design", "title": "Can formal CAD methods from electronic engineering (logic synthesis, formal verification, timing analysis) be systematically applied to synthetic gene circuit design to achieve predictable, composable biological logic?", "status": "open", "domain": "biology", "systematic_gaps": [ "No formal composability theorem for genetic parts analogous to logical isolation in CMOS", "Resource competition (ribosomes, polymerases) creates hidden coupling between nominally independent modules", "Evolutionary instability causes circuit degradation over generations, absent in silicon" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-synthetic-biology-x-circuit-design.yaml" }, { "id": "u-synthetic-lichen-biofabrication", "title": "Whether engineered autotrophic-heterotrophic microbial consortia can achieve stable, self-sustaining biogeochemical cycles on non-Earth mineral substrates without continuous external inputs", "status": "open", "domain": "biology", "systematic_gaps": [ "Existing demonstrations of lichen-inspired consortia on regolith simulants rely on controlled lab conditions; robustness to radiation, temperature cycles, low pressure, and nutrient starvation in situ is untested.", "Metabolic coupling between autotrophic (cyanobacterial) and heterotrophic (fungal) partners in mineral-limited systems is not well characterized at the molecular level — especially the nitrogen and carbon exchange stoichiometry.", "It is unknown whether biomineral consolidation of regolith particles can generate structurally load-bearing materials at relevant scales, or whether this is limited to surface crusting effects.", "Evolutionary stability of the consortium over many generations is unknown; competitive exclusion or loss of mutualism under selection pressure may dissolve the partnership." ], "suggested_hypotheses": [ "h-lichen-consortium-metabolic-coupling" ], "file": "unknowns-catalog/biology/u-synthetic-lichen-biofabrication.yaml" }, { "id": "u-temporal-biosignature-information", "title": "Can temporal information retention in molecular systems serve as a universal biosignature to distinguish living from abiotic chemistry, and what is the minimum retention timescale?", "status": "open", "domain": "biology", "systematic_gaps": [ "A quantitative threshold for \"temporal information retention\" that distinguishes known life from known abiotic chemistry has not been established.", "Whether this biosignature is detectable remotely (e.g., from atmospheric time series on exoplanets) has not been analyzed.", "The minimum molecular system complexity required to exhibit supra-abiotic temporal information retention is unknown." ], "suggested_hypotheses": [ "Living systems maintain mutual information between present and past states above I_min = k_B*T per degree of freedom over timescales > 1 cell cycle, while abiotic systems decay below this threshold within one chemical relaxation time." ], "file": "unknowns-catalog/biology/u-temporal-biosignature-information.yaml" }, { "id": "u-topoisomerase-knot-selection", "title": "Do topoisomerases actively select against specific DNA knot types, and how does the equilibrium knot distribution in cells depend on chromosome topology?", "status": "open", "domain": "biology", "systematic_gaps": [ "The molecular mechanism by which Type II topoisomerase achieves below-equilibrium knot frequencies (topological discrimination) is not established.", "The equilibrium knot distribution of chromosomal DNA in living cells under different supercoiling conditions has not been measured directly.", "Whether specific knot types (beyond trefoil and figure-eight) occur in vivo at biologically significant frequencies is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-topoisomerase-knot-selection.yaml" }, { "id": "u-topological-morphogenesis", "title": "How do topological defects in cell-packing geometry direct the physical forces that shape organs during development?", "status": "open", "domain": "biology", "systematic_gaps": [ "Topological defect mapping has been demonstrated in 2D epithelial sheets; whether 3D organ morphogenesis uses the same organising principle is unknown.", "No predictive model exists that uses topological defect positions and charges to forecast morphogenetic failure modes (i.e. congenital defects).", "The connection between topological defects in tissue and the biochemical signalling gradients (Wnt, Hedgehog, BMP) is entirely unexplored — it is not known whether biochemical gradients create defects or defects create gradients.", "Mathematical tools from topological field theory (homotopy groups, topological invariants) have not been applied to 3D developmental biology at the whole-organ scale." ], "suggested_hypotheses": [ "Topological defect charge is conserved during organ morphogenesis; conservation law violations predict and precede developmental malformations.", "The positions and charges of topological defects in the early embryonic epithelium can predict the axes of future organ curvature (gut looping, heart spiralling) with greater accuracy than current biochemical-gradient models alone." ], "file": "unknowns-catalog/biology/u-topological-morphogenesis.yaml" }, { "id": "u-tumor-containment-percolation", "title": "Whether tumor progression can be reliably halted through network connectivity disruption rather than cell elimination, and what structural thresholds govern the transition from contained to invasive growth", "status": "open", "domain": "biology", "systematic_gaps": [ "The percolation-theoretic framing of tumor spread predicts a connectivity threshold below which spatial invasion is suppressed, but this threshold has not been experimentally validated across tumor types and microenvironments.", "Containment strategies (adaptive therapy, ecological control) show promise in vitro and in some clinical trials but the mechanistic link to network topology vs direct cytotoxicity is not isolated.", "Most tumor evolution models treat cell fitness independently; spatial interaction networks and how they encode metastatic potential are undercharacterized.", "It is unclear whether sub-percolation containment states are dynamically stable or prone to escape via rare long-range dispersal events." ], "suggested_hypotheses": [ "h-adaptive-therapy-percolation-threshold" ], "file": "unknowns-catalog/biology/u-tumor-containment-percolation.yaml" }, { "id": "u-turing-digit-wavelength-scaling", "title": "Does vertebrate digit number scale with limb-bud width as predicted by the Turing wavelength ratio Lambda*/W?", "status": "open", "domain": "biology", "systematic_gaps": [ "No cross-species dataset of limb-bud width at the time of digit condensation vs final digit count", "Wnt and BMP diffusivities have only been measured in mouse and zebrafish — not in tetrapods spanning the full digit-number range", "The nonlinear saturation term (stripe vs spot bifurcation) has not been measured experimentally" ], "suggested_hypotheses": [ "h-turing-zebrafish-diffusivity-ratio" ], "file": "unknowns-catalog/biology/u-turing-digit-wavelength-scaling.yaml" }, { "id": "u-turing-ms-demyelination-pattern", "title": "Are multiple sclerosis demyelination lesions spatially patterned by a Turing reaction-diffusion instability?", "status": "open", "domain": "biology", "systematic_gaps": [ "No systematic spatial-frequency analysis of MS lesion distributions across patients to test for a characteristic wavelength", "The activator-inhibitor pair driving oligodendrocyte-myelin dynamics has not been parameterised for a Turing instability test", "Weakly nonlinear analysis (Turing near-threshold behaviour) exists for toy RD models but not for validated CNS-specific kinetics" ], "suggested_hypotheses": [ "h-turing-zebrafish-diffusivity-ratio" ], "file": "unknowns-catalog/biology/u-turing-ms-demyelination-pattern.yaml" }, { "id": "u-vicsek-transition-order-finite-systems", "title": "Is the Vicsek model phase transition first-order or continuous in the thermodynamic limit, and how does finite-size scaling affect collective behavior in biological groups of 10-10^4 individuals?", "status": "open", "domain": "biology", "systematic_gaps": [ "Finite-size scaling analysis of the Vicsek transition is computationally expensive; results up to N ~ 10^5 are available but extrapolation to thermodynamic limit is uncertain", "Empirical data on alignment strength in different species are not systematically compared to Vicsek predictions", "The role of heterogeneity (different speeds, sizes) in biological collectives is not captured by the basic Vicsek model" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-vicsek-transition-order-finite-systems.yaml" }, { "id": "u-whale-song-information-content-localization", "title": "What is the information content and function of whale song — mate attraction, individual identification, group coordination, or SOFAR-channel navigation — and can passive acoustic methods resolve whale positions at basin scale?", "status": "open", "domain": "biology", "systematic_gaps": [ "No information-theoretic analysis has quantified the Shannon entropy of humpback whale song and compared it to other communication systems.", "The spatial resolution of passive TDOA triangulation for blue whale calls in the SOFAR channel has not been empirically characterized using simultaneous satellite tracking.", "Whether humpbacks actively adjust call frequency for SOFAR channel propagation optimization (analogous to bat Doppler compensation) has not been tested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-whale-song-information-content-localization.yaml" }, { "id": "u-xylem-cavitation-repair-mechanism", "title": "How do plants repair embolised xylem conduits under positive or negative pressure, and is hydraulic recovery after drought a universal mechanism or species-specific with distinct biochemical substrates?", "status": "open", "domain": "biology", "systematic_gaps": [ "The thermodynamic mechanism of xylem refilling under tension has not been conclusively demonstrated — the energetics do not balance with known sugar concentrations and cell osmotic potentials.", "Whether observed xylem refilling in X-ray CT studies is real recovery or an artifact of altered water potential during imaging remains contested in the literature.", "Species-level variation in refilling capacity has not been mapped onto phylogeny or anatomy at sufficient resolution to identify the anatomical or biochemical determinants." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology/u-xylem-cavitation-repair-mechanism.yaml" }, { "id": "u-lipid-raft-functional-role-signaling", "title": "Do lipid rafts exist as stable, nanoscale liquid-ordered domains in living cell membranes, and if so, what is their functional role in receptor clustering and signal transduction?", "status": "open", "domain": "biology-chemistry", "systematic_gaps": [ "Single-molecule tracking in live cells has not definitively resolved raft size distribution and lifetime at physiological temperature.", "Causal manipulation of raft composition (beyond cholesterol depletion with methyl-β-cyclodextrin, which has pleiotropic effects) to test signaling function is lacking.", "Quantitative connection between 2D phase separation physics (Cahn-Hilliard theory) and the nanoscale raft dynamics observed in live cells is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology-chemistry/u-lipid-raft-functional-role-signaling.yaml" }, { "id": "u-protein-fitness-landscape-epistasis-ruggedness", "title": "How rugged are protein fitness landscapes — what fraction of beneficial mutations are epistatic (context-dependent), and can the landscape topology be predicted from protein structure well enough to guide directed evolution without exhaustive experimental measurement?\n", "status": "open", "domain": "biology-chemistry", "systematic_gaps": [ "Pairwise DMS (measuring all ~(20L)² double mutants) has been performed for only a handful of small proteins (GB1, Protein G, GFP) — insufficient to characterize the full epistasis distribution across protein space.", "Structure-based predictions of epistasis (Rosetta, EVcouplings, AlphaFold2) have been benchmarked only against limited DMS data — their accuracy for predicting sign epistasis is not well-characterized.", "The relationship between protein evolutionary history (phylogenetic depth, ancestral fitness landscape) and present-day epistasis patterns has not been systematically studied." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology-chemistry/u-protein-fitness-landscape-epistasis-ruggedness.yaml" }, { "id": "u-rna-world-nonenzymatic-replication-fidelity", "title": "What minimum replication fidelity is required for non-enzymatic RNA replication to sustain a functional RNA world — and can plausible prebiotic chemistry achieve this fidelity threshold under realistic environmental conditions?\n", "status": "open", "domain": "biology-chemistry", "systematic_gaps": [ "The minimum functional ribozyme length has not been determined for all catalytic classes relevant to early replication (RNA ligase, RNA polymerase, RNA recombinase).", "Systematic measurement of non-enzymatic error rates across all 4 canonical and modified nucleotide pairs under varied temperature, pH, and mineral surface conditions has not been performed.", "The Eigen error threshold has not been rigorously computed for realistic rugged fitness landscapes where the quasispecies structure may sustain function above the flat-landscape threshold." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology-chemistry/u-rna-world-nonenzymatic-replication-fidelity.yaml" }, { "id": "u-silent-bgc-activation-novel-antibiotics", "title": "What fraction of silent biosynthetic gene clusters in soil actinobacteria encode genuinely novel antibiotic scaffolds with activity against multidrug-resistant pathogens — and what are the minimal conditions (growth signals, co-culture, epigenetic modification) needed to reliably activate silent clusters in situ?\n", "status": "open", "domain": "biology-chemistry", "systematic_gaps": [ "The true distribution of novel vs. redundant scaffolds in silent BGC space has not been determined because expression of the vast majority of clusters has not been achieved.", "Natural ecological induction signals for most silent clusters are unknown; high-throughput co-culture screening is in its infancy.", "The regulatory hierarchy controlling cluster silencing — H-NS, HDACs, Wbl proteins, γ-butyrolactones — is known for only a small number of clusters." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biology-chemistry/u-silent-bgc-activation-novel-antibiotics.yaml" }, { "id": "u-oxyluciferin-excited-state-mechanism-enol-vs-keto", "title": "Which tautomeric form of oxyluciferin — enolate, keto, or phenolate — is the actual light emitter in firefly bioluminescence, and how do active-site electrostatics and protonation state tune emission from 540 nm (green) to 620 nm (red) without changing the luciferin substrate?\n", "status": "open", "domain": "bioluminescence", "systematic_gaps": [ "High-resolution crystal structures of luciferase with transition-state analogues for the emitting species (oxyluciferin tautomers) have not been obtained for the full colour range of luciferase species.", "Gas-phase spectroscopy of isolated oxyluciferin tautomers (avoiding solvent effects) compared to computational predictions has not been done with sufficient resolution to identify the emitting form.", "Time-resolved emission spectroscopy of the bioluminescence reaction with ps-ns resolution has not resolved whether multiple emitting species contribute sequentially or simultaneously to the emission spectrum." ], "suggested_hypotheses": [ "The enolate tautomer of oxyluciferin is the primary light emitter in wild-type Photinus pyralis luciferase at pH 7.0, but active-site mutations (Y255F, H245N) that eliminate key H-bonding interactions shift emission to the keto tautomer at 580 nm — testable by time-resolved fluorescence and resonance Raman spectroscopy of the bioluminescence reaction.\n" ], "file": "unknowns-catalog/bioluminescence/u-oxyluciferin-excited-state-mechanism-enol-vs-keto.yaml" }, { "id": "u-anomalous-diffusion-cytoplasm", "title": "What molecular mechanisms drive anomalous (non-Brownian) diffusion in the cytoplasm, and how do they change under cellular stress?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Most single-molecule tracking studies lack the temporal resolution to distinguish viscoelastic subdiffusion from transient binding at short timescales.", "The relationship between cytoplasmic glass-transition temperature and organismal thermal tolerance has not been systematically measured.", "Active (motor-driven) anomalous diffusion and passive viscoelastic subdiffusion are not cleanly separable with current experimental methods." ], "suggested_hypotheses": [ "h-cytoplasm-glass-transition" ], "file": "unknowns-catalog/biophysics/u-anomalous-diffusion-cytoplasm.yaml" }, { "id": "u-antifreeze-protein-ice-binding", "title": "What is the molecular mechanism by which antifreeze proteins distinguish ice from liquid water and adsorb irreversibly to specific crystal planes, and can this selectivity be computationally designed into synthetic polymers for cryopreservation applications?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Cryo-EM and AFM studies of AFP-ice interfaces have limited resolution at the atomic scale due to radiation damage and thermal motion", "Force-field accuracy for protein-ice interfaces is limited; specialized water models are needed but not validated for ice-protein systems", "Rational design of synthetic polymers with AFP-like activity remains empirical due to incomplete understanding of the mechanism" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-antifreeze-protein-ice-binding.yaml" }, { "id": "u-aqp-gating-osmosensing-mechanism", "title": "What is the molecular gating mechanism of aquaporin water channels, and how do cells sense osmotic stress to trigger AQP2 vesicle trafficking and membrane insertion within minutes of vasopressin stimulation?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Molecular identity of the primary osmosensor in renal collecting duct principal cells", "Structural mechanism of AQP2 vesicle docking and fusion (SNARE identity, fusion kinetics)", "Whether constitutive AQPs (AQP1, AQP4) undergo functional gating on biologically relevant timescales", "Quantitative relationship between AQP2 surface density and collecting duct water permeability in vivo" ], "suggested_hypotheses": [ "h-aqp2-trafficking-as-osmotic-valve" ], "file": "unknowns-catalog/biophysics/u-aqp-gating-osmosensing-mechanism.yaml" }, { "id": "u-atp-synthase-torque-slip-mechanism", "title": "What is the molecular mechanism of torque generation and \"slip\" in the F₀ c-ring of ATP synthase, and how does the rotor stoichiometry (8–15 c-subunits across species) determine the H⁺/ATP ratio and hence the thermodynamic efficiency of oxidative phosphorylation?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Cryo-EM structures of F₀F₁ in lipid nanodisc at sub-2 Å resolution are available for bovine mitochondria but not for plant chloroplast ATP synthase (different c-ring stoichiometry and regulatory mechanisms).", "Single-molecule experiments (Noji 1997, Yasuda 1998) measured γ-subunit rotation but have not directly resolved individual c-subunit steps (<36° per step) to determine whether rotation is stepwise or continuous at physiological ATP/ADP ratios.", "The thermodynamic efficiency near the H⁺/ATP ratio transition (marginal PMF conditions) has not been measured for isolated mitochondria with controlled pmf and ATP/ADP ratios." ], "suggested_hypotheses": [ "The c-ring stoichiometry is set by the minimum PMF required to drive ATP synthesis against physiological ΔGATP: species living at lower PMF require larger c-rings (more H⁺ per ATP) to achieve ΔG_H+ × n_H > ΔGATP. This predicts a linear correlation between c-ring size and the PMF measured in natural habitat across organisms from alkaliphiles (smallest c-ring) to acidophilic chloroplasts (largest c-ring).\n" ], "file": "unknowns-catalog/biophysics/u-atp-synthase-torque-slip-mechanism.yaml" }, { "id": "u-capsid-assembly-kinetic-intermediates", "title": "What are the structures and stabilities of transient oligomeric intermediates during viral capsid nucleation, and can they be targeted for antiviral intervention?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Cryo-EM structures of pre-nucleation oligomers below pentamer size do not exist for any major human pathogen.", "The relationship between critical nucleus size, subunit concentration dependence of the lag phase, and the effective CAC has not been measured for HIV or influenza capsids.", "Whether the nucleation pathway is unique or whether multiple parallel assembly pathways coexist remains unresolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-capsid-assembly-kinetic-intermediates.yaml" }, { "id": "u-cochlear-amplifier-molecular-mechanism-prestin", "title": "What is the complete molecular mechanism by which prestin (SLC26A5) converts membrane potential changes to outer hair cell length changes at acoustic frequencies up to 70 kHz, and how does the nanoscale conformational change couple to the macroscale basilar membrane resonance?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "No complete molecular dynamics simulation of prestin conformational change at physiological speed.", "The coupling between individual prestin molecules in the OHC lateral membrane is poorly understood.", "The energy source for electromotility (electrochemical gradient vs elastic energy) is debated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-cochlear-amplifier-molecular-mechanism-prestin.yaml" }, { "id": "u-cochlear-hopf-bifurcation-active-hair-bundle-vs-somatic-motility", "title": "What is the relative contribution of active hair bundle motility (myosin- based, present in all hair cells) versus outer hair cell somatic electromotility via prestin (mammal-specific) to the cochlear amplifier, and which mechanism is the primary driver of the Hopf bifurcation dynamics and associated otoacoustic emissions?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Direct measurement of the relative force contributions of electromotility vs. hair bundle motility at a single frequency location in an intact cochlea has not been achieved.", "Conditional knockout of MYO1C in OHCs (while preserving prestin) has not been reported to test the hair bundle contribution in isolation.", "Whether the Hopf bifurcation parameters (μ, ω₀, nonlinear coefficient) can be independently fitted to prestin-knockout vs. wild-type BM displacement data has not been done.", "High-frequency OHCs (>10 kHz, basal cochlea) may rely more on electromotility (higher membrane RC time constant bandwidth) while apical OHCs rely more on hair bundle — this frequency-dependent mechanism switch has not been systematically tested." ], "suggested_hypotheses": [ "h-prestin-somatic-motility-primary-cochlear-amplification-mechanism-mammals" ], "file": "unknowns-catalog/biophysics/u-cochlear-hopf-bifurcation-active-hair-bundle-vs-somatic-motility.yaml" }, { "id": "u-cytoskeletal-active-matter-defect-dynamics", "title": "Do topological defects in cytoskeletal active matter (actin-myosin networks) control cell division plane orientation, and can active matter defect theory predict mitotic spindle positioning errors?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "No systematic mapping of cytoskeletal defect density to spindle positioning errors in dividing cells", "Active matter defect theory not applied to 3D cytoskeletal networks in confined geometries", "Relationship between actin/myosin stoichiometry perturbations and defect creation rate not quantified" ], "suggested_hypotheses": [ "h-cytoskeletal-active-matter-defect-dynamics" ], "file": "unknowns-catalog/biophysics/u-cytoskeletal-active-matter-defect-dynamics.yaml" }, { "id": "u-debye-length-ion-specificity-membrane-binding", "title": "How much of apparent Debye-length scaling of peripheral protein binding to membranes is actually ion-specific chemistry (Hofmeister, chelation) versus mean-field electrostatic screening?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Limited systematic datasets pairing binding curves with molecular dynamics of ion distributions at realistic membrane compositions.", "Membrane heterogeneity (rafts, charged lipids) breaks 1D Gouy–Chapman cartoons." ], "suggested_hypotheses": [ "h-ion-specific-double-layer-competition-modulates-permeation" ], "file": "unknowns-catalog/biophysics/u-debye-length-ion-specificity-membrane-binding.yaml" }, { "id": "u-eis-channel-gating-mechanistic-link", "title": "Can electrochemical impedance spectroscopy non-invasively extract Hodgkin-Huxley channel gating parameters (activation/inactivation time constants, channel density) from intact excitable cell layers?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Multi-frequency EIS at sub-millisecond time resolution needed to capture fast Na channel gating has not been demonstrated on intact mammalian excitable cell layers.", "The mapping from HH parameters to EIS Nyquist plot features is known analytically only for linearized (small-signal) channel models around a fixed operating point.", "Drug-induced channel block creates characteristic EIS signatures that have not been systematically catalogued for ion channel pharmacology screening." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-eis-channel-gating-mechanistic-link.yaml" }, { "id": "u-eis-membrane-hodgkin-huxley-identification", "title": "To what extent can broadband membrane impedance spectra uniquely identify multi-state gating schemes without single-channel resolution?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Nonlinear rectification breaks small-signal impedance interpretation at strong drives.", "Cell geometry and folds create distributed RC networks complicating equivalent-circuit uniqueness." ], "suggested_hypotheses": [ "h-eis-spectra-constrain-gating-substates" ], "file": "unknowns-catalog/biophysics/u-eis-membrane-hodgkin-huxley-identification.yaml" }, { "id": "u-hertz-adhesion-crossover-biological-tissues", "title": "At what length scales does pure Hertz elastic contact fail for compliant tissues versus AFM tips — and how should indentation pipelines blend JKR/DMT adhesion corrections with poroelastic relaxation kernels?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Benchmark curves coupling AFM ramp-rate sweeps with concurrent microscopic hydration imaging across collagen-dense versus lipid-rich regions", "Open datasets labeling adhesion crossover regimes alongside reduced-modulus estimates from competing models on identical pixels" ], "suggested_hypotheses": [ "h-hertz-contact-x-spherical-indentation" ], "file": "unknowns-catalog/biophysics/u-hertz-adhesion-crossover-biological-tissues.yaml" }, { "id": "u-intrinsically-disordered-proteins", "title": "Do intrinsically disordered protein condensates obey Flory-Huggins phase diagrams, and can the critical concentration for phase separation be predicted from amino acid sequence alone?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Quantitative comparison of sequence-based χ parameter estimates to measured c* values from LLPS assays (turbidity, fluorescence) for >20 IDPs is absent.", "Concentration of IDPs in specific cell compartments (nucleus vs. cytoplasm) relative to their c* is not known for most condensate-forming proteins.", "The multi-component nature of condensates (many IDPs co-condensing) makes single-component FH theory a simplification whose validity range is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-intrinsically-disordered-proteins.yaml" }, { "id": "u-kinesin-thermal-noise-efficiency", "title": "How do molecular motors achieve near-optimal thermodynamic efficiency while operating in a regime dominated by thermal noise, and what limits efficiency below the Carnot bound?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Direct single-molecule measurement of free energy dissipated as heat per step at varying loads is technically challenging — most measurements infer efficiency indirectly from force-velocity curves.", "The role of protein conformational dynamics (neck linker, cover-neck bundle) in filtering thermal noise vs. amplifying the power stroke is not resolved by current crystal structures.", "Whether efficiency at stall force is thermodynamically limited or kinetically limited (by ADP release rate) has not been definitively established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-kinesin-thermal-noise-efficiency.yaml" }, { "id": "u-met-channel-molecular-identity-pore-forming-subunit", "title": "Is TMC1/TMC2 the definitive pore-forming subunit of the hair cell mechanotransduction (MET) channel, and what is the complete molecular architecture (stoichiometry, auxiliary subunits, tip-link attachment site) of the native MET channel complex?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Cryo-EM structure of the native MET channel complex (TMC1/TMIE/LHFPL5/PCDH15) at atomic resolution has not been achieved; existing structures are partial.", "The force-transmission mechanism from tip-link to channel gate has not been directly visualized or simulated with accurate force fields.", "TMC1 point mutations that cause deafness have not all been mapped onto the gating spring model to explain the mechanistic effect." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-met-channel-molecular-identity-pore-forming-subunit.yaml" }, { "id": "u-mitochondrial-pmf-efficiency-carnot-bound", "title": "What is the theoretical maximum thermodynamic efficiency of the mitochondrial ATP synthase, and how close do in vivo P/O ratios come to this bound under physiological proton-motive force conditions?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "In vivo c-ring stoichiometry has not been measured dynamically under varying metabolic load", "Proton leak via uncoupling proteins is quantified in bulk but not at single-channel resolution", "Stochastic efficiency (per-cycle free energy transduction) has not been measured in intact organelles" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-mitochondrial-pmf-efficiency-carnot-bound.yaml" }, { "id": "u-muscle-crossbridge-kinetics", "title": "What are the complete rate functions f(x) and g(x) for myosin cross-bridge attachment and detachment in skeletal muscle, and how do they change with phosphorylation state and disease?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Single-molecule experiments measure average quantities but the variance and distribution of dwell times as a function of applied load x are not systematically characterized.", "How f(x) and g(x) are modified by myosin-binding protein C (MyBP-C) and troponin regulatory proteins is largely unknown.", "The rate functions have not been directly compared between fast and slow myosin isoforms in the context of the full Huxley ODE framework." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-muscle-crossbridge-kinetics.yaml" }, { "id": "u-phage-ejection-force-osmotic-mechanism", "title": "Is bacteriophage DNA ejection force quantitatively explained by osmotic pressure alone, or do electrostatic and entropic contributions require an extended model?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "No complete force-component breakdown (osmotic + electrostatic + entropic) for phage lambda", "Osmotic suppression experiments measure total force but not individual contributions", "Capsid mechanical compliance contribution to ejection dynamics not systematically measured" ], "suggested_hypotheses": [ "h-phage-ejection-force-osmotic-mechanism" ], "file": "unknowns-catalog/biophysics/u-phage-ejection-force-osmotic-mechanism.yaml" }, { "id": "u-prion-llps-nucleation-kinetics", "title": "Do prion conformational conversion and liquid-liquid phase separation nucleation share quantitatively identical nucleation rate laws, and can inhibitors of one process cross-inhibit the other?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "No systematic kinetic comparison of prion seeding vs LLPS nucleation under matched conditions", "No inhibitor cross-screen between anti-prion compounds and LLPS modulators", "Unified nucleation theory framework not yet applied to both phenomena" ], "suggested_hypotheses": [ "h-prion-llps-nucleation-kinetics" ], "file": "unknowns-catalog/biophysics/u-prion-llps-nucleation-kinetics.yaml" }, { "id": "u-stochastic-resonance-cell-signaling-bandwidth", "title": "Under what molecular and timescale constraints does stochastic resonance improve information throughput in cell signaling pathways?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Few studies jointly estimate mutual information and mechanistic kinetic parameters under controlled noise injection.", "Experimental protocols rarely separate resonance effects from drift, adaptation, and cell-state heterogeneity.", "Comparative datasets across pathway classes (ion-channel, GPCR, transcriptional) are limited." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-stochastic-resonance-cell-signaling-bandwidth.yaml" }, { "id": "u-thermodynamic-uncertainty-bound-biochemical-estimators", "title": "How tightly do thermodynamic uncertainty relations constrain practical precision limits of biochemical estimators in vivo?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Direct simultaneous measurements of entropy production proxies and estimator variance are rare.", "Finite-sample corrections and hidden-variable effects are inconsistently handled across studies.", "Experimental manipulations that vary energetic drive independently of network topology are limited." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-thermodynamic-uncertainty-bound-biochemical-estimators.yaml" }, { "id": "u-wound-healing-collective-migration-coordination", "title": "How do epithelial cells coordinate collective migration over distances of millimeters during wound healing without a central organizing signal, and what determines the leader cell identity?", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Leader cell selection has not been mechanistically explained; correlations with substrate stiffness exist but causation is unclear", "Long-range mechanical signaling through the epithelial sheet has been hypothesized but not measured at the required spatiotemporal resolution", "The Keller-Segel chemotaxis model has not been quantitatively parameterized for specific wound healing growth factors in vivo" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics/u-wound-healing-collective-migration-coordination.yaml" }, { "id": "u-yap-taz-stiffness-sensing-mechanism-molecular", "title": "What is the complete molecular mechanism by which YAP/TAZ sense substrate stiffness — specifically, which upstream mechanosensors (integrin clustering, actin cytoskeletal tension, nuclear deformation, or ion channels) are necessary and sufficient, and what quantitative stiffness threshold determines the cytoplasmic-to-nuclear translocation switch?\n", "status": "open", "domain": "biophysics", "systematic_gaps": [ "Causal sufficiency of individual upstream sensors (integrin, ROCK, Piezo1, nuclear pore) for YAP nuclear localisation has not been established by orthogonal reconstitution experiments.", "The quantitative stiffness threshold E* varies across cell types by >10-fold — whether this reflects differences in motor activity, linker compliance, or sensor expression is unknown.", "Whether the YAP/TAZ switch exhibits hysteresis (bistability consistent with positive feedback via YAP target gene CTGF promoting ECM stiffening) has not been systematically tested.", "The relative contributions of nuclear vs. cytoplasmic mechanosensing to YAP localisation remain unresolved — recent evidence for direct nuclear envelope tension-driven YAP import via nuclear pore opening complicates the actin-tension model." ], "suggested_hypotheses": [ "YAP nuclear translocation exhibits bistability with stiffness hysteresis width ~2 kPa, driven by a CTGF-ECM stiffening positive feedback loop — testable by cycling substrate stiffness using phototunable hydrogels while measuring single-cell YAP nuclear/cytoplasmic ratio by live imaging.\n" ], "file": "unknowns-catalog/biophysics/u-yap-taz-stiffness-sensing-mechanism-molecular.yaml" }, { "id": "u-flagellar-motor-stator-number-regulation-pmf", "title": "How does the flagellar motor dynamically regulate the number of active MotA/MotB stator units in response to proton motive force, load, and environmental conditions ΓÇö and what is the mechanochemical mechanism of stator incorporation and release?\n", "status": "open", "domain": "biophysics-motor", "systematic_gaps": [ "The molecular identity of the peptidoglycan-binding domain of MotB and how conformational changes open the proton channel upon assembly are not fully resolved.", "Whether stator number regulation responds directly to PMF (sensed by MotB) or to torque (sensed by FliG or C-ring) has not been determined.", "Single-molecule experiments tracking individual stator incorporation events in real-time with simultaneous torque measurement have not been performed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/biophysics-motor/u-flagellar-motor-stator-number-regulation-pmf.yaml" }, { "id": "u-microbial-fuel-cell-electron-transfer-limits", "title": "What are the fundamental rate limits on extracellular electron transfer in electrogenic bacteria, and can engineered cytochrome-c expression or synthetic conductive nanowires overcome the bottlenecks that currently cap microbial fuel cell power density below 10 W/m^2?", "status": "open", "domain": "biotechnology", "systematic_gaps": [ "In-situ measurement of electron-transfer kinetics within intact biofilms at nanometer resolution remains technically unavailable", "The mechanistic distinction between metallic vs. hopping conduction in Geobacter nanowires is unresolved; conflicting data from different labs", "Scalable MFC electrode architectures that maintain high surface area while supporting thick electroactive biofilms have not been optimized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/biotechnology/u-microbial-fuel-cell-electron-transfer-limits.yaml" }, { "id": "u-plant-tropism-auxin-gradient-mechanism", "title": "What molecular mechanism relocates PIN efflux carriers to the lower flank of a gravitropically stimulated root or shoot within minutes, and is the signal transduction chain better described by a Turing reaction-diffusion instability or by a mechanical strain-sensing model?", "status": "open", "domain": "botany", "systematic_gaps": [ "Live PIN polarity dynamics during gravity stimulus have only been imaged in 2D cross-sections, not 3D time-lapse", "Distinguishing reaction-diffusion from mechanical-strain models requires parameter-controlled perturbation experiments not yet performed", "The gravitropic setpoint angle mechanism in lateral roots and branches remains molecularly uncharacterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/botany/u-plant-tropism-auxin-gradient-mechanism.yaml" }, { "id": "u-autophagy-selectivity-cargo-receptor-hierarchy", "title": "How is cargo selectivity determined in autophagy when multiple cargo receptors (p62, NDP52, optineurin, NBR1, TAX1BP1) compete for LC3 binding and ubiquitinated substrates simultaneously?\n", "status": "open", "domain": "cell-biology", "systematic_gaps": [ "Quantitative competition assays between cargo receptors at physiological concentrations have not been performed systematically.", "The role of receptor oligomerization (p62 bodies, phase separation) in creating a threshold for autophagy initiation is not understood mechanistically.", "How cargo size (single protein vs. mitochondrion vs. bacteria) influences autophagosome sizing and LC3-II density has not been systematically measured." ], "suggested_hypotheses": [], "file": "unknowns-catalog/cell-biology/u-autophagy-selectivity-cargo-receptor-hierarchy.yaml" }, { "id": "u-boolean-network-attractor-landscape-reprogramming", "title": "Can the Boolean network attractor landscape of a cell type be empirically reconstructed from single-cell transcriptomic perturbation data, and does the number of attractors scale as sqrt(N) in real gene regulatory networks of measured connectivity K?\n", "status": "open", "domain": "cell-biology", "systematic_gaps": [ "The effective in-degree K of the human transcriptional regulatory network has not been measured at genome-scale with the accuracy needed to test the K=2 criticality hypothesis.", "No study has reconstructed the full basin-of-attraction landscape of even a 50-gene regulatory subnetwork from experimental single-cell perturbation data.", "The computational complexity of Boolean network attractor enumeration is PSPACE-complete; approximate methods for large N are not validated on biological networks." ], "suggested_hypotheses": [], "file": "unknowns-catalog/cell-biology/u-boolean-network-attractor-landscape-reprogramming.yaml" }, { "id": "u-stress-granule-phase-separation-pathology", "title": "What are the molecular determinants of the liquid-to-solid phase transition in stress granules associated with ALS and FTD, and can quantitative Flory-Huggins models of IDR phase behavior predict which mutations shift condensate viscoelasticity toward pathological hardening before cytotoxicity is observed?", "status": "open", "domain": "cell-biology", "systematic_gaps": [ "In-cell quantitative microrheology of stress granules at physiological protein concentrations is technically limited by optical access and throughput", "The molecular composition of pathological vs. normal stress granules has not been fully mapped by proximity proteomics in patient neurons", "Coarse-grained simulation force fields for IDR LLPS are not yet validated against condensate viscosity measurements" ], "suggested_hypotheses": [], "file": "unknowns-catalog/cell-biology/u-stress-granule-phase-separation-pathology.yaml" }, { "id": "u-ubiquitin-proteasome-proteostasis-collapse-threshold", "title": "What is the quantitative proteostasis collapse threshold — the misfolded protein flux above which the ubiquitin-proteasome system fails irreversibly — and how does this threshold decline with age?\n", "status": "open", "domain": "cell-biology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/cell-biology/u-ubiquitin-proteasome-proteostasis-collapse-threshold.yaml" }, { "id": "u-atmospheric-chemistry-aerosol-nucleation", "title": "What are the molecular mechanisms of atmospheric new particle formation, and which trace species drive nucleation under different atmospheric conditions?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The identity and concentration of all nucleating agents under ambient conditions are not measured in most atmospheric environments.", "HOMs from biogenic versus anthropogenic sources contribute differently to NPF but are not distinguished by current atmospheric models.", "The timescale from nucleation to cloud condensation nucleus activation is not accurately represented in global climate models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-atmospheric-chemistry-aerosol-nucleation.yaml" }, { "id": "u-battery-solid-electrolyte-stability", "title": "What determines the long-term electrochemical stability of solid electrolytes at electrode interfaces, and can this stability be predicted computationally?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The equilibrium DFT stability predictions are inconsistent with experimental observations in many electrode-electrolyte pairs due to kinetic passivation.", "Interface characterisation by cryo-electron microscopy and synchrotron techniques reveals unexpected phases not predicted by computational thermodynamics.", "The mechanical constraints (stack pressure, volume change on cycling) on interface stability are not incorporated into stability predictions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-battery-solid-electrolyte-stability.yaml" }, { "id": "u-bz-reaction-3d-scroll-wave-instability", "title": "Under what conditions do 3D scroll waves in the Belousov-Zhabotinsky reaction become unstable (negative filament tension), and can this mechanism explain the transition from organised to turbulent chemical waves analogous to cardiac fibrillation?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Filament tension has been measured in BZ only in limited parameter ranges", "3D BZ experiments in thick gels are technically difficult; most data is 2D", "Connection between negative-tension turbulence and cardiac fibrillation mechanisms remains unvalidated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-bz-reaction-3d-scroll-wave-instability.yaml" }, { "id": "u-catalyst-optimization-volcano-plots", "title": "Do Sabatier volcano plots have a universal mathematical form, and can machine learning identify the binding energy descriptors that place any catalyst near the volcano peak?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The mathematical form of volcano peaks (Gaussian, Lorentzian, asymmetric) has not been derived from first principles", "BEP scaling relations break down for strained surfaces and complex alloys; when and why is unknown", "ML-identified catalysts often lack interpretable physical descriptors" ], "suggested_hypotheses": [ "Volcano plot peak width scales as k_BT/E_act where E_act is the activation energy at the peak, giving a universal dimensionless volcano with peak width ~0.1-0.3 eV for typical catalytic reactions at 400-800 K" ], "file": "unknowns-catalog/chemistry/u-catalyst-optimization-volcano-plots.yaml" }, { "id": "u-chemical-garden-membrane-self-organization", "title": "What determines the spontaneous selection of tube diameter, wall thickness, and porosity in chemical garden precipitation membranes, and can these parameters be analytically predicted from the osmotic pressure, ion diffusion coefficients, and solubility products of the metal salt and silicate without free fitting?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Systematic phase diagram mapping across metal salt types and silicate concentrations has only been done for a few systems", "Phase-field simulations of chemical garden growth are computationally expensive and have not been validated against 3D tomography of tube cross-sections", "Ion selectivity of chemical garden membranes has not been systematically measured for energy or desalination applications" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-chemical-garden-membrane-self-organization.yaml" }, { "id": "u-chirality-emergence-prebiotic", "title": "How did biological homochirality (L-amino acids, D-sugars) emerge from a racemic prebiotic world — symmetry breaking, amplification, or selection?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No prebiotic scenario has produced 100% ee from racemic starting materials under plausible early-Earth conditions", "The universality class of the symmetry-breaking transition in autocatalytic chiral systems is unknown", "Whether the Soai reaction has prebiotic analogues (RNA, amino acids) has not been demonstrated" ], "suggested_hypotheses": [ "Chiral symmetry breaking in autocatalytic prebiotic systems is a first-order phase transition, requiring a minimum autocatalytic amplification factor of ~50 to produce >99% ee from thermal fluctuations within the lifetime of a prebiotic pool" ], "file": "unknowns-catalog/chemistry/u-chirality-emergence-prebiotic.yaml" }, { "id": "u-crn-multistability-biological", "title": "Which biological chemical reaction networks have the topological structure required for multistability, and does deficiency theory correctly predict their bistable phenotypes?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "A systematic computation of deficiency numbers for all KEGG metabolic network subgraphs has not been performed to test which are predicted bistable.", "Whether the deficiency number is robust to the coarse-graining of large biological networks (lumping multiple enzymatic steps) is unknown.", "No large-scale validation of deficiency theory predictions against measured bistability in synthetic biology circuits exists." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-crn-multistability-biological.yaml" }, { "id": "u-crystallization-kinetics-nucleation", "title": "Why does classical nucleation theory systematically underpredict nucleation rates by 10-20 orders of magnitude, and what is the correct free energy of critical nucleus formation?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No predictive theory for nucleation rates in two-step (solution → dense liquid → crystal) pathways", "Free energy of the dense liquid intermediate relative to solution and crystal is not measurable directly", "Role of heterogeneous nucleation sites (surfaces, impurities) in two-step nucleation not quantified" ], "suggested_hypotheses": [ "Two-step nucleation rate J_2step = J_CNT * exp(Delta_G_DL/k_BT) where Delta_G_DL is the free energy of the dense liquid intermediate, resolvable from PEG osmotic stress experiments with >3 orders of magnitude improvement in rate prediction" ], "file": "unknowns-catalog/chemistry/u-crystallization-kinetics-nucleation.yaml" }, { "id": "u-dac-sorbent-entropy-production-mechanism", "title": "Which process steps in the DAC thermal swing adsorption cycle produce the most entropy, and what molecular-level sorbent properties minimize irreversibility in each step?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The entropy production breakdown (adsorption exothermicity, sensible heat, heat of desorption, heat loss) for commercial DAC systems has not been published with sufficient detail for comparative analysis.", "Whether MOF sorbents with tunable binding enthalpy (25-60 kJ/mol CO₂) can achieve both fast kinetics and stable long-cycle performance in humid air is unknown.", "The effect of atmospheric moisture on DAC sorbent thermodynamics has not been systematically quantified — water co-adsorption can dominate the energy budget in humid climates." ], "suggested_hypotheses": [ "Amine-functionalized sorbents with binding enthalpy tuned to 40-50 kJ/mol (vs 80-90 kJ/mol for current best performers) can halve regeneration energy while maintaining adequate capacity, closing the efficiency gap to within 3× of the thermodynamic minimum." ], "file": "unknowns-catalog/chemistry/u-dac-sorbent-entropy-production-mechanism.yaml" }, { "id": "u-electrochemical-co2-reduction-selectivity", "title": "What determines product selectivity in electrochemical CO2 reduction, and can catalyst design achieve multicarbon product yields practical for carbon utilisation?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The active site structure of copper under CO2RR conditions is dynamic and not fully characterised by operando spectroscopy.", "Competing hydrogen evolution reduces faradaic efficiency for CO2RR products; the mechanism of HER suppression by CO2RR catalysts is not fully understood.", "Scale-up from laboratory cell to industrial electrolyser introduces mass transport, flooding, and durability challenges not captured in small-scale experiments." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-electrochemical-co2-reduction-selectivity.yaml" }, { "id": "u-endocrine-disruptor-dose-response-nonmonotonic", "title": "What are the molecular mechanisms generating non-monotonic dose-response (NMDR) curves for endocrine disruptors (BPA, phthalates, atrazine), and are these mechanisms sufficient to invalidate linear extrapolation from high-dose toxicology studies to regulatory low-dose safety limits?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Mechanistic identification of which receptor subtype combinations generate NMDR curves for specific endocrine disruptors", "Independent pre-registered replication of NMDR curves for BPA at doses below current regulatory limits (2.5 µg/kg/day)", "Whether NMDR curves in vitro predict NMDR in vivo with matched endpoints", "Bayesian meta-analysis of NMDR literature correcting for publication bias" ], "suggested_hypotheses": [ "h-lnt-model-invalid-endocrine-disruptors" ], "file": "unknowns-catalog/chemistry/u-endocrine-disruptor-dose-response-nonmonotonic.yaml" }, { "id": "u-enzyme-kinetics-x-michaelis-menten", "title": "How do multi-enzyme metabolic pathways coordinate kinetics to avoid toxic intermediate accumulation, and what determines the optimal Km/Vmax ratio for each enzyme in a pathway?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "In vivo Km values differ significantly from in vitro measurements due to macromolecular crowding", "Substrate channeling efficiency between consecutive enzymes in metabolons is not quantified", "Stochastic fluctuations in enzyme copy number affect pathway flux in ways not captured by deterministic Michaelis-Menten models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-enzyme-kinetics-x-michaelis-menten.yaml" }, { "id": "u-enzyme-surface-catalyst-design-principles", "title": "Can the Brønsted-Evans-Polanyi volcano plot framework from heterogeneous catalysis predict optimal transition state stabilization energies for enzyme active site design?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No systematic application of BEP volcano plots to enzyme active site design", "Sabatier principle not quantitatively tested for transition state analogue inhibitor design", "Cross-field comparison of optimal stabilization energies not performed" ], "suggested_hypotheses": [ "h-enzyme-surface-catalyst-design-principles" ], "file": "unknowns-catalog/chemistry/u-enzyme-surface-catalyst-design-principles.yaml" }, { "id": "u-enzyme-tunneling-quantum-mechanism", "title": "Do enzymes exploit quantum tunneling to enhance proton and hydride transfer rates beyond classical limits, and is this a general mechanism or specific to a few reactions?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Whether promoting vibrations are required for tunneling or merely correlate with it has not been resolved", "The fraction of enzyme active sites where tunneling contributes meaningfully (>10% rate enhancement) is unknown", "No computational method predicts KIE temperature dependence from sequence alone" ], "suggested_hypotheses": [ "Enzymes that evolved maximum tunneling contributions show active site geometries with donor-acceptor distances compressed to <2.7 Å in the Michaelis complex, predictable from crystal structures without MD simulations" ], "file": "unknowns-catalog/chemistry/u-enzyme-tunneling-quantum-mechanism.yaml" }, { "id": "u-graph-theory-x-molecular-structure", "title": "Is there a complete set of graph invariants that uniquely identifies all molecular graphs up to isomorphism, and can the graph isomorphism problem be solved in polynomial time for molecular graphs?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No set of polynomial-time computable graph invariants is known to completely distinguish all molecular graphs", "The graph isomorphism problem is not known to be in P for general graphs", "Topological index degeneracy (multiple molecules with identical index values) is unresolved for large molecular databases" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-graph-theory-x-molecular-structure.yaml" }, { "id": "u-hydrogen-bond-network-water-anomalies", "title": "Are water's thermodynamic anomalies (density maximum at 4°C, compressibility minimum at 46°C) fully explained by the two-liquid model, and where is the liquid-liquid critical point?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The LLCP has not been observed directly due to the crystallization problem in no-man's land", "Simulations disagree on LLCP existence (TIP4P/2005 shows it; ST2 shows it; SPC/E does not)", "Whether confined water (nanopores, protein surfaces) shows the same LLCP as bulk water" ], "suggested_hypotheses": [ "Ultrafast heating/quenching experiments using femtosecond X-ray free electron lasers will locate the LLCP at T = 220±10 K, P = 80-120 MPa, resolving the decades-long controversy" ], "file": "unknowns-catalog/chemistry/u-hydrogen-bond-network-water-anomalies.yaml" }, { "id": "u-md-force-field-transferability-accuracy-limit", "title": "What is the accuracy ceiling of classical and machine-learned force fields for free energy calculations, and how can transferability across chemical space be systematically improved?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No systematic benchmark of ML force field accuracy vs. gold-standard CCSD(T) binding free energies across diverse drug-like molecules in explicit solvent.", "Whether ML force fields preserve the symplectic structure needed for long-time MD stability (shadow Hamiltonian, microcanonical ensemble) has not been rigorously tested.", "Active learning strategies for ML force field training (selecting informative QM calculations) have not been benchmarked against random sampling for chemical space coverage." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-md-force-field-transferability-accuracy-limit.yaml" }, { "id": "u-metalloenzyme-design-principles", "title": "Can de novo metalloenzyme design achieve catalytic efficiency (kcat/KM) within 10-fold of natural enzymes by rational placement of first-shell ligands alone?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Role of second-shell residues in metalloenzyme efficiency has not been systematically quantified via mutagenesis", "Whether QM/MM potentials are accurate enough for metalloenzyme design without training data is unknown", "The minimum evolutionary steps required to go from de novo design to natural efficiency has not been measured" ], "suggested_hypotheses": [ "Second-shell hydrogen bond networks increase metalloenzyme kcat by tuning metal redox potential, and each additional second-shell H-bond adds ~2-fold rate enhancement, predictable by DFT electron density calculations without MD" ], "file": "unknowns-catalog/chemistry/u-metalloenzyme-design-principles.yaml" }, { "id": "u-nmr-effective-hamiltonian-calibration-open-system", "title": "How much do relaxation and diffusion losses distort rotating-frame effective Hamiltonian calibration across high-field clinical scanners versus benchtop quantum-sensing prototypes sharing pulse libraries?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Round-robin pulse benchmarking repositories tagging relaxation tensor anisotropy alongside nominal flip-angle tables", "Differentiable simulators coupling Lindblad terms with Magnus expansions used for uncertainty-aware pulse optimization in clinics" ], "suggested_hypotheses": [ "h-nmr-rotating-frame-x-effective-hamiltonian" ], "file": "unknowns-catalog/chemistry/u-nmr-effective-hamiltonian-calibration-open-system.yaml" }, { "id": "u-nucleation-x-first-passage", "title": "Can classical nucleation theory predict nucleation rates to within an order of magnitude, or are there fundamental corrections from non-classical mechanisms?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The size at which the surface tension (interfacial free energy) of a nucleus equals the bulk value — the crossover from non-classical to classical regime — has not been determined for most materials", "Forward flux sampling and other rare event methods can compute nucleation rates for simple models but computational cost prevents application to complex molecular systems (proteins, minerals)", "The quantitative contribution of two-step nucleation (liquid precursor phase) to total nucleation rate for protein crystallization has not been established experimentally" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-nucleation-x-first-passage.yaml" }, { "id": "u-oed-utility-misspecification-under-nonstationary-chemistry", "title": "How sensitive are Bayesian OED policies to utility misspecification in nonstationary chemistry campaigns?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Few robotic-chemistry benchmarks evaluate utility misspecification explicitly.", "Limited guidance on utility-robust OED under catalyst aging and feedstock drift." ], "suggested_hypotheses": [ "h-lookahead-oed-reduces-experiments-to-target-yield" ], "file": "unknowns-catalog/chemistry/u-oed-utility-misspecification-under-nonstationary-chemistry.yaml" }, { "id": "u-oer-scaling-relation-break", "title": "Can the universal OER scaling relation ΔG_OOH* − ΔG_OH* ≈ 3.2 eV be broken by novel catalyst architectures, enabling catalysts below the theoretical 0.4 V overpotential floor?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Whether the OER scaling relation is a fundamental thermodynamic constraint or an artifact of the single-site oxide model has not been proven/disproven with high-quality DFT+experimental benchmarks.", "Dual-site OER mechanisms have been proposed computationally but not unambiguously demonstrated experimentally at the single-site level.", "The stability of any catalyst that breaks the scaling relation (by having non-standard bonding geometry) under the oxidizing conditions of OER (>1.5 V vs RHE) is unknown." ], "suggested_hypotheses": [ "Dual-site catalysts (Fe-Ni or Ir-Ru adjacent pairs) with different M-O bond character for the two sites can reduce OER overpotential below 0.2 V by decoupling OOH* and OH* binding energies." ], "file": "unknowns-catalog/chemistry/u-oer-scaling-relation-break.yaml" }, { "id": "u-percolation-mapping-quantitative-gel-chemistry", "title": "For realistic multifunctional polymerizations with loops and substitution effects, how far does bond-percolation universality deviate from measured gel points across chemistries?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Limited systematic datasets pairing gel rheology onset with bond-percolation simulations per chemistry family", "Polydispersity coupling to cluster statistics rarely inverted jointly with percolation fits" ], "suggested_hypotheses": [ "h-percolation-threshold-x-polymer-gelation" ], "file": "unknowns-catalog/chemistry/u-percolation-mapping-quantitative-gel-chemistry.yaml" }, { "id": "u-photocatalysis-x-semiconductor-physics", "title": "What is the theoretical maximum solar-to-hydrogen efficiency for a single-absorber photocatalyst, and what material properties (band gap, carrier lifetime, surface kinetics) currently limit practical systems to <1% vs the ~18% Shockley-Queisser theoretical limit?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Time-resolved spectroscopy identifies recombination pathways but cannot deconvolve bulk vs surface contributions in particle photocatalysts", "Quantum yield measurements vary by 10-fold between labs; no standardized measurement protocol", "Computational band gap prediction (DFT+U, HSE06) for complex oxides has 0.3-0.5 eV errors; reliable guidance for material screening is limited" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-photocatalysis-x-semiconductor-physics.yaml" }, { "id": "u-polymer-glass-x-jamming-transition", "title": "Is the glass transition a true thermodynamic phase transition with a diverging correlation length, or only a kinetic phenomenon, and how does it unify with jamming?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No experiment has definitively detected a static structural length scale diverging at T_g, as predicted by RFOT theory", "The universality class of the jamming transition at point J (critical exponents for coordination number, bulk modulus, pressure) is debated between isostaticity theory and mean-field predictions", "Whether the glass and jamming transitions are the same universality class or distinct phenomena connected only topologically in the Liu-Nagel diagram is not resolved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-polymer-glass-x-jamming-transition.yaml" }, { "id": "u-protein-folding-thermodynamics-kinetics", "title": "Does the funnel energy landscape theory fully explain the Levinthal paradox, or do kinetic pathways violate thermodynamic predictions in meaningful biological cases?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The fraction of sequence space where funnel theory fails (rugged landscape) has not been mapped", "Whether IDP function requires a distinct theoretical framework or is a limit of funnel theory is unresolved", "Kinetics of prion templating violates simple funnel predictions; mechanism remains unclear" ], "suggested_hypotheses": [ "Metamorphic proteins reside on landscapes with two comparable-depth funnels separated by a barrier of height k_BT * ln(k_fold/k_switch), where k_switch is the spontaneous interconversion rate" ], "file": "unknowns-catalog/chemistry/u-protein-folding-thermodynamics-kinetics.yaml" }, { "id": "u-protein-protein-interaction-design", "title": "Can computational protein-protein interface design reliably produce binders with nanomolar affinity to any target protein surface?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Computational binder design success rates drop dramatically for non-concave target surfaces (flat or convex epitopes).", "Designed binders validated in vitro often fail in cell-based assays due to off-target interactions, aggregation, or cellular uptake barriers.", "Affinity maturation of computationally designed binders by directed evolution is still required for many targets; the role of starting sequence quality is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-protein-protein-interaction-design.yaml" }, { "id": "u-reaction-mechanism-automated-discovery", "title": "Can automated computational methods reliably discover novel reaction mechanisms and predict activation barriers without experimental calibration?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Machine learning potentials for reaction mechanism search extrapolate poorly to transition state geometries not well represented in training sets.", "The combinatorial explosion of possible reaction pathways in complex mixtures makes exhaustive automated exploration computationally infeasible.", "Validation of computationally predicted mechanisms against experiment is hampered by the difficulty of directly observing transition states." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-reaction-mechanism-automated-discovery.yaml" }, { "id": "u-reaction-networks-x-petri-nets", "title": "Can Petri net reachability analysis (PSPACE-complete in general) be applied tractably to biological regulatory networks of >100 species to verify persistence (no species goes extinct) and detect oscillatory behavior, and what is the computational boundary between tractable and intractable biological CRNs?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Deficiency zero theorem applies only to weakly reversible networks; most biological networks are not weakly reversible", "Siphon-based persistence analysis has exponential worst-case complexity; its practical complexity for signaling networks is unknown", "No comprehensive database of biological CRNs has been analyzed for Petri net liveness properties" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-reaction-networks-x-petri-nets.yaml" }, { "id": "u-rna-aptamer-design-principles", "title": "What physical principles govern RNA aptamer binding affinity and selectivity, and can they guide de novo design without combinatorial screening?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "RNA 3D structure prediction accuracy insufficient for binding site modeling", "The sequence-structure-function landscape of RNA aptamers has not been mapped", "Selectivity (binding one target vs. structurally similar alternatives) has no predictive theory" ], "suggested_hypotheses": [ "Aptamers with highest binding affinity adopt structures where the binding loop electrostatic potential matches the target surface potential to within 10% RMS error, predictable from APBS electrostatics without explicit MD simulations" ], "file": "unknowns-catalog/chemistry/u-rna-aptamer-design-principles.yaml" }, { "id": "u-self-replicating-molecules-minimal-criteria", "title": "What are the minimal chemical criteria for self-replication, and can a molecule shorter than 14 nucleotides replicate itself without external catalysts?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The minimum RNA length for self-replication has not been derived theoretically", "Whether self-replication can emerge from random sequence pools without design has not been tested systematically", "The error threshold for self-replicating RNA (maximum mutation rate before information loss) has not been measured" ], "suggested_hypotheses": [ "The minimum self-replicating RNA length is L_min = ceil(log4(k_cat * KM^{-1} / k_bond)) ≈ 12-16 nt, where k_cat is the minimum catalytic rate for template synthesis and k_bond is the spontaneous bond formation rate" ], "file": "unknowns-catalog/chemistry/u-self-replicating-molecules-minimal-criteria.yaml" }, { "id": "u-structure-uncertainty-propagation-from-alphafold-to-enzyme-design", "title": "How should confidence uncertainty in `b-alphafold-structure-priors-x-enzyme-engineering-screen-pruning` propagate into enzyme design ranking decisions?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Few datasets pair structure-confidence metrics with high-throughput activity outcomes.", "Decision-theoretic ranking rules are not standardized for uncertainty-aware screening." ], "suggested_hypotheses": [ "h-alphafold-confidence-weighted-screening-improves-enzyme-hit-rates" ], "file": "unknowns-catalog/chemistry/u-structure-uncertainty-propagation-from-alphafold-to-enzyme-design.yaml" }, { "id": "u-supramolecular-self-assembly-prediction", "title": "Can the self-assembly of supramolecular structures be predicted from molecular building block properties, and what determines assembly pathway selectivity?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Kinetic versus thermodynamic control of self-assembly has been characterised for specific systems but no general rules exist.", "The effect of minor impurities on self-assembly outcomes is not incorporated into predictive models.", "Hierarchical self-assembly (nano- to macro-scale) cannot be predicted by any current simulation method due to timescale bridging challenges." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-supramolecular-self-assembly-prediction.yaml" }, { "id": "u-transition-state-x-saddle-point", "title": "Can machine learning potentials accurately predict transition states and reaction rates for chemical reactions not represented in training data, and what training strategies ensure extrapolation to high-energy configurations?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Active learning protocols for saddle point sampling are not standardized across MLIP frameworks", "Error propagation from PES uncertainty to rate constant uncertainty is not systematically characterized", "Transferability of MLIP transition state predictions to new reaction classes is not benchmarked" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-transition-state-x-saddle-point.yaml" }, { "id": "u-unified-spectral-epsilon-model-across-vdw-casimir-length-scales", "title": "Can a single internally consistent dielectric function ε(ω) measured across bands from UV to microwave anchor joint predictions of molecular-scale dispersion coefficients and micrometer-scale Casimir forces on identical substrates without empirical stitching artifacts?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Broadband ellipsometry merged with atomic-scale benchmarks on identical material batches", "Error propagation from finite Matsubara sums into force uncertainty budgets" ], "suggested_hypotheses": [ "h-joint-fit-lifshitz-hamaker-colloid-force-curves" ], "file": "unknowns-catalog/chemistry/u-unified-spectral-epsilon-model-across-vdw-casimir-length-scales.yaml" }, { "id": "u-vae-catalyst-latent-disentanglement-validity", "title": "Do VAE latent dimensions for catalyst screening encode chemically meaningful, disentangled factors?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "Few benchmarks link latent directions to experimentally measurable catalyst properties.", "Synthesis feasibility constraints are often absent from latent optimization loops.", "Model uncertainty is underused in candidate triage decisions." ], "suggested_hypotheses": [ "h-vae-latent-regularization-improves-catalyst-hit-rate" ], "file": "unknowns-catalog/chemistry/u-vae-catalyst-latent-disentanglement-validity.yaml" }, { "id": "u-which-persistence-features-remain-stable-under-noisy-catalyst-screening-assays", "title": "What validation boundary conditions determine when `b-topological-data-analysis-x-catalyst-state-space-screening` remains decision-useful?", "status": "open", "domain": "chemistry", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-persistence-based-features-improve-active-catalyst-hit-rate-in-high-throughput-screening" ], "file": "unknowns-catalog/chemistry/u-which-persistence-features-remain-stable-under-noisy-catalyst-screening-assays.yaml" }, { "id": "u-xna-expanded-genetic-alphabet-catalysis", "title": "Can XNA or expanded-alphabet genetic polymers (>4 bases) achieve catalytic rates and substrate diversity comparable to ribozymes, and what backbone chemistry maximises both information-storage capacity and catalytic function?\n", "status": "open", "domain": "chemistry", "systematic_gaps": [ "The maximum achievable catalytic rate for HNA or FANA ribozymes has not been determined by exhaustive directed evolution.", "The structural basis for lower catalytic efficiency of XNA ribozymes vs. RNA ribozymes has not been resolved by X-ray crystallography or cryo-EM.", "Whether expanded alphabets (6 bases) improve or degrade ribozyme catalytic efficiency by changing folding energy landscapes is not tested experimentally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry/u-xna-expanded-genetic-alphabet-catalysis.yaml" }, { "id": "u-corrosion-inhibitor-molecular-mechanism", "title": "What are the molecular-scale mechanisms by which organic corrosion inhibitors adsorb on metal surfaces and arrest electrochemical dissolution, and can these mechanisms be predicted from molecular structure?", "status": "open", "domain": "chemistry-engineering", "systematic_gaps": [ "In-situ molecular-resolution imaging of inhibitor films under electrochemical conditions (STM, AFM in liquid) is technically demanding and rarely connected to macroscopic corrosion rate measurements.", "Machine learning models trained on inhibitor efficiency data have limited transferability across metal-environment combinations due to sparse, heterogeneous training data.", "The relationship between molecular dipole moment, HOMO energy (quantum chemistry descriptors) and inhibition efficiency (a macroscopic rate) involves uncharacterized mesoscale physics." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chemistry-engineering/u-corrosion-inhibitor-molecular-mechanism.yaml" }, { "id": "u-green-chemistry-pharmaceutical-e-factor-continuous-flow", "title": "Can continuous flow chemistry and catalytic process intensification reduce the pharmaceutical E-factor from the current 25-100 range to below 10 for complex multistep API synthesis, and what fraction of currently batch-manufactured drugs are chemically and operationally compatible with flow chemistry conversion?\n", "status": "open", "domain": "chemistry-engineering", "systematic_gaps": [ "Systematic E-factor audit of top 100 pharmaceutical APIs with identification of the worst-waste steps.", "Compatibility assessment of pharmaceutical reactions with flow conditions (solid formation, exothermicity, viscosity).", "Economic analysis of regulatory approval cost for process changes vs. waste reduction benefit.", "Biocatalysis-flow chemistry integration protocols for enzymatic steps." ], "suggested_hypotheses": [ "Converting the 5 highest-E-factor steps of the 10 top-selling APIs to continuous flow processes (where chemically feasible) would reduce pharmaceutical industry solvent waste by >30% without requiring new chemistry — demonstrating that engineering process design is the primary barrier, not molecular chemistry.\n" ], "file": "unknowns-catalog/chemistry-engineering/u-green-chemistry-pharmaceutical-e-factor-continuous-flow.yaml" }, { "id": "u-nafion-degradation-mechanism-longevity", "title": "Whether the dominant Nafion membrane degradation mechanism under fuel cell operating conditions (HO• radical attack, fluoride release, mechanical fatigue, or catalyst dissolution crossover) is sufficiently understood to design next-generation membranes with >80,000-hour lifetimes\n", "status": "open", "domain": "chemistry-engineering", "systematic_gaps": [ "Multiple degradation pathways operate simultaneously (chemical, mechanical, thermal) and their relative contributions depend on operating conditions; no unified model predicts membrane lifetime under arbitrary duty cycles.", "Hydroxyl radical (HO•) generated at both electrodes attacks the Nafion backbone (ether linkages) and side chains, but the rate constants in the confined membrane environment differ from solution-phase measurements.", "The correlation between accelerated stress test (AST) protocols and real-world automotive/stationary lifetime is uncertain; ASTs compress time but may not replicate all failure modes.", "Alternative PFSA membranes (3M, Aquivion) and hydrocarbon membranes (sulfonated PEEK, polybenzimidazole) have different degradation modes; comparative lifetime data under identical conditions is sparse." ], "suggested_hypotheses": [ "h-pem-membrane-beyond-nafion-high-temperature" ], "file": "unknowns-catalog/chemistry-engineering/u-nafion-degradation-mechanism-longevity.yaml" }, { "id": "u-sabatier-volcano-principle-multi-step-cascade-reaction-design", "title": "Does the Sabatier volcano principle — optimal catalyst binds intermediates with intermediate affinity — extend to multi-step cascade reactions (e.g. CO₂ reduction to methanol: CO₂→CO→HCHO→CH₃OH) where different steps have conflicting optimal binding energies, and can DFT-based multi-dimensional volcano plots predict optimal bifunctional or tandem catalyst designs?\n", "status": "open", "domain": "chemistry-engineering", "systematic_gaps": [ "Multi-dimensional volcano plots (2 or more binding energy descriptors) have been computed for a few reactions (ORR, CO₂R) but not systematically validated against experimental catalytic activity across material families.", "The optimal spatial proximity of bifunctional sites (Ångström vs. nm scale) for tandem catalysis has not been theoretically derived from reaction diffusion equations coupled to microkinetic models.", "Machine learning of multi-step reaction networks from DFT data to predict the full activity-selectivity landscape has not been demonstrated beyond 3-intermediate pathways.", "Whether scaling relations (correlations among binding energies of related intermediates, e.g. *CO and *CHO both scale with *C binding) impose fundamental limits on multi-step volcano optimisation is unresolved." ], "suggested_hypotheses": [ "h-dft-bep-relationship-enables-quantitative-catalyst-design-before-synthesis" ], "file": "unknowns-catalog/chemistry-engineering/u-sabatier-volcano-principle-multi-step-cascade-reaction-design.yaml" }, { "id": "u-solid-state-battery-sei-interface-resistance-origin", "title": "What is the atomic-scale origin of the anomalously high interfacial resistance between lithium metal anodes and oxide solid electrolytes (LLZO, LIPON), and what interface engineering strategies can reduce it below 1 Ω·cm²?", "status": "open", "domain": "chemistry-engineering", "systematic_gaps": [ "In-situ characterization of the Li/LLZO interface during cycling at atomic resolution (cryo-TEM, EELS) has been technically limited; most interface studies are ex-situ and do not capture the dynamic interface during Li plating/stripping.", "The relative contributions of chemical vs. mechanical vs. electronic mechanisms to interfacial resistance have not been separated quantitatively; each can explain the observed impedance magnitude but with different activation energies.", "The space charge layer width and its contribution to total interfacial impedance have only been estimated theoretically; direct measurement requires sub-nm resolution electrochemical imaging not yet achieved." ], "suggested_hypotheses": [ "The dominant resistance mechanism is mechanical delamination from Li creep, and applying moderate stack pressure (≥ 3 MPa) during cycling will reduce interfacial resistance by > 100× by maintaining contact area; this explains the strong batch-to-batch variability in published impedance data." ], "file": "unknowns-catalog/chemistry-engineering/u-solid-state-battery-sei-interface-resistance-origin.yaml" }, { "id": "u-chronotype-genetic-variants-full-population-distribution", "title": "What is the complete genetic architecture of human chronotype — which variants beyond CRY1 and PER3 explain the full population distribution of midsleep timing, and how do gene-environment interactions with light exposure and social schedules shape the phenotype?\n", "status": "open", "domain": "chronobiology", "systematic_gaps": [ "The identified GWAS loci have not been mechanistically characterized (most are non-coding; causal variant and target gene unknown for most loci).", "Gene-environment interaction — how light exposure history modifies the genetic chronotype effect — has not been studied in large populations with objective light monitoring.", "Cross-cultural and cross-latitude studies with objective actigraphy and light exposure data are lacking; most GWAS use self-reported chronotype." ], "suggested_hypotheses": [], "file": "unknowns-catalog/chronobiology/u-chronotype-genetic-variants-full-population-distribution.yaml" }, { "id": "u-circadian-prc-individual-variation-prediction", "title": "What genetic and molecular factors predict individual variation in the human circadian phase response curve, and can PRC differences explain chronotype (morning vs. evening person) and differential jet-lag susceptibility?\n", "status": "open", "domain": "chronobiology", "systematic_gaps": [ "Human PRCs have been measured in only ~100 subjects; population-level variation is unknown", "Genetic predictors of PRC amplitude and shape have not been identified", "Randomised clinical trials of PRC-personalised light therapy have not been conducted" ], "suggested_hypotheses": [], "file": "unknowns-catalog/chronobiology/u-circadian-prc-individual-variation-prediction.yaml" }, { "id": "u-abrupt-climate-transitions", "title": "What are the mechanisms of rapid Dansgaard-Oeschger events and can they occur in a warming world?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "DO events involve 10-15°C Greenland warming within decades", "Trigger mechanism and ocean-atmosphere coupling unresolved" ], "suggested_hypotheses": [ "Sea ice and AMOC positive feedback creates bistability enabling rapid transitions at certain threshold freshwater forcing values" ], "file": "unknowns-catalog/climate-science/u-abrupt-climate-transitions.yaml" }, { "id": "u-aerosol-cloud-indirect", "title": "What is the magnitude of the aerosol first and second indirect effects on global radiative forcing?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "IPCC AR6 estimates -0.45 W/m² with large uncertainty", "Cloud lifetime and precipitation suppression effects poorly separated" ], "suggested_hypotheses": [ "Aerosol-induced suppression of drizzle in stratocumulus clouds doubles the lifetime effect beyond current model estimates" ], "file": "unknowns-catalog/climate-science/u-aerosol-cloud-indirect.yaml" }, { "id": "u-aerosol-cloud-nucleation-uncertainty", "title": "What are the dominant sources of uncertainty in predicting global cloud condensation nucleus (CCN) concentrations from aerosol precursor emissions, and how do organic aerosol formation pathways and new particle formation rates limit climate model accuracy for aerosol indirect forcing?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "New particle formation in the upper free troposphere is difficult to measure directly and is undersampled by aircraft campaigns", "The nucleation mechanism for ternary H2SO4-NH3-H2O-organics systems remains controversial with competing kinetic vs thermodynamic models", "Cloud drop number concentration responds nonlinearly to CCN so global average CCN-forcing relationships are not straightforwardly applicable" ], "suggested_hypotheses": [], "file": "unknowns-catalog/climate-science/u-aerosol-cloud-nucleation-uncertainty.yaml" }, { "id": "u-amoc-collapse-threshold", "title": "What is the critical freshwater forcing threshold for AMOC collapse and is it within 21st-century projections?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Hosing experiments show bistability in models", "Real-world freshwater flux from Greenland melt poorly observed" ], "suggested_hypotheses": [ "AMOC crosses a saddle-node bifurcation at sustained Greenland melt exceeding 0.3 Sv, achievable under RCP8.5 by 2100" ], "file": "unknowns-catalog/climate-science/u-amoc-collapse-threshold.yaml" }, { "id": "u-antarctic-bottom-water", "title": "What controls Antarctic Bottom Water formation rate and how will it respond to ice sheet freshening?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "AABW has slowed 20-30% since the 1990s", "Freshwater sensitivity of AABW formation in models is poorly constrained" ], "suggested_hypotheses": [ "Ross Sea AABW formation crosses a threshold at sustained freshwater input >0.1 Sv and may not recover on century timescales" ], "file": "unknowns-catalog/climate-science/u-antarctic-bottom-water.yaml" }, { "id": "u-arctic-amplification-mechanism", "title": "What fraction of Arctic amplification is caused by local feedbacks versus poleward heat transport changes?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Sea ice-albedo feedback accounts for ~40% of amplification in models", "Poleward latent and dry static energy transport attribution is model-dependent" ], "suggested_hypotheses": [ "Increased poleward moisture transport driven by enhanced water vapor content accounts for the majority of polar amplification above 70°N" ], "file": "unknowns-catalog/climate-science/u-arctic-amplification-mechanism.yaml" }, { "id": "u-carbon-cycle-feedbacks", "title": "How do terrestrial carbon cycle feedbacks change sign under sustained high-CO2 forcing?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "CO2 fertilisation saturates above certain temperatures and CO2 concentrations", "Threshold for ecosystem carbon source transition poorly constrained" ], "suggested_hypotheses": [ "Tropical forests transition from carbon sinks to sources above 450 ppm CO2 when warming exceeds 2°C locally" ], "file": "unknowns-catalog/climate-science/u-carbon-cycle-feedbacks.yaml" }, { "id": "u-climate-damage-function-high-temperature-regime", "title": "What is the functional form of economic damages from climate change at global temperature anomalies above 3°C, where no modern empirical analog exists, and how should tipping point cascades, non-market damages, and distributional equity be incorporated into the damage function?\n", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Empirical damage estimates above 4°C warming from paleoclimate analogs", "Integration of tipping point probabilities into IAM damage functions", "Non-market damage quantification (biodiversity, human health, conflict)", "Fat-tail treatment of climate sensitivity uncertainty in cost-benefit analysis" ], "suggested_hypotheses": [ "h-scc-convex-damages-fat-tails" ], "file": "unknowns-catalog/climate-science/u-climate-damage-function-high-temperature-regime.yaml" }, { "id": "u-climate-ecs-feedback-uncertainty", "title": "What is the precise value of equilibrium climate sensitivity (ECS) and what cloud feedback processes drive the remaining uncertainty between 2.5 and 5.7 K per CO₂ doubling in CMIP6 models?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "The response of marine stratocumulus cloud fraction to SST warming is unresolved at the process level — both LES (large-eddy simulation) and GCMs disagree by factors of 2-5 in this feedback, and no observational constraint distinguishes them.", "Convective self-aggregation (spontaneous organization of tropical convection into dry and moist regions) may systematically bias ECS in GCMs; the mechanism is understood qualitatively but not quantitatively, and its real-world occurrence remains contested.", "Aerosol indirect effects (cloud lifetime effect, cloud brightening) introduce a negative forcing of −0.5 to −1.5 W/m² with 100% uncertainty in sign-at-scale, potentially masking greenhouse warming and biasing ECS estimates from the instrumental record." ], "suggested_hypotheses": [ "ECS is constrained to 2.8±0.4 K by combining three independent emergent constraints — observed cloud climatology, tropical cloud radiative effect, and Pleistocene temperature records — with each constraint reducing uncertainty orthogonally." ], "file": "unknowns-catalog/climate-science/u-climate-ecs-feedback-uncertainty.yaml" }, { "id": "u-climate-health-tipping-threshold", "title": "At what quantitative thresholds of climate forcing do population health outcomes undergo discontinuous phase transitions, and can these thresholds be predicted with bifurcation theory?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Current integrated assessment models treat health damage as smooth functions of temperature, missing threshold effects", "No empirical study has tested for bifurcation structure (early-warning indicators, hysteresis) in health-climate time series", "Wet-bulb temperature survivability threshold (~35°C) is established but population-level mortality bifurcation is unquantified", "Climate-disease cascade interactions (heat → harvest failure → malnutrition → immune suppression → infection) have no bifurcation model" ], "suggested_hypotheses": [ "Rising autocorrelation in weekly disease incidence data in climate-stressed regions constitutes a pre-tipping early warning signal, detectable with the same AR1 methodology used for climate tipping points", "The joint poverty-heat threshold defines a two-dimensional bifurcation surface in the inequality-temperature plane; populations near this surface are at highest risk of discontinuous health deterioration" ], "file": "unknowns-catalog/climate-science/u-climate-health-tipping-threshold.yaml" }, { "id": "u-climate-sensitivity-tails", "title": "What physical processes determine the long upper tail of equilibrium climate sensitivity distributions?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Most models cluster at 2.5-4 K ECS with fat right tail", "High-ECS models not obviously wrong but not constrained by observations" ], "suggested_hypotheses": [ "Cloud feedbacks over the Southern Ocean determine whether ECS exceeds 5 K, and present-day observations strongly constrain this" ], "file": "unknowns-catalog/climate-science/u-climate-sensitivity-tails.yaml" }, { "id": "u-cloud-feedback-sign", "title": "What is the net sign and magnitude of cloud feedback to CO2 forcing across all cloud types?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Low-cloud feedback is the dominant source of uncertainty in ECS", "Observational constraints from short satellite records are insufficient" ], "suggested_hypotheses": [ "Marine boundary layer cloud amount decreases with SST warming, making low-cloud feedback strongly positive and raising ECS above 4 K" ], "file": "unknowns-catalog/climate-science/u-cloud-feedback-sign.yaml" }, { "id": "u-cloud-seeding-efficacy", "title": "What is the true efficacy of cloud seeding for precipitation enhancement across different cloud types?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Randomised experiments are limited by small sample sizes", "Physical mechanism of ice nucleation enhancement under field conditions unclear" ], "suggested_hypotheses": [ "Glaciogenic cloud seeding increases orographic precipitation by 10-15% in convectively stable clouds with adequate supercooled liquid water" ], "file": "unknowns-catalog/climate-science/u-cloud-seeding-efficacy.yaml" }, { "id": "u-deep-ocean-carbon-sequestration", "title": "What fraction of anthropogenic CO2 can be sequestered in the deep ocean on centennial timescales?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Thermohaline circulation transports carbon-rich surface water to deep ocean", "Remineralisation depth and efficiency poorly constrained by observations" ], "suggested_hypotheses": [ "Biological pump efficiency increases under high-CO2 conditions, enhancing deep carbon sequestration by 15% per century" ], "file": "unknowns-catalog/climate-science/u-deep-ocean-carbon-sequestration.yaml" }, { "id": "u-diffusion-downscaling-physical-consistency-under-shift", "title": "Can diffusion-based climate downscaling preserve physical consistency under non-stationary climate shift?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-diffusion-downscaling-improves-extreme-precipitation-fidelity" ], "file": "unknowns-catalog/climate-science/u-diffusion-downscaling-physical-consistency-under-shift.yaml" }, { "id": "u-dro-ambiguity-set-specification-nonstationary-climate", "title": "How should ambiguity sets for distributionally robust adaptation decisions be specified under nonstationary climate statistics where historical samples misrepresent future tail dependence?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Limited comparative studies pairing storyline scenarios with formally defined ambiguity sets under identical stress targets.", "Sparse evaluation of robust solutions under out-of-sample structural breaks (policy shifts, tipping phenomena).", "Under-documented sensitivity of robust objectives to dependence modeling choices." ], "suggested_hypotheses": [ "h-wasserstein-dro-improves-tail-safe-adaptation-metrics" ], "file": "unknowns-catalog/climate-science/u-dro-ambiguity-set-specification-nonstationary-climate.yaml" }, { "id": "u-enso-predictability-limit", "title": "What determines the fundamental predictability limit of ENSO beyond one year?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Atmospheric noise forcing limits deterministic predictability", "Coupled model ensembles show skill loss after 12-18 months" ], "suggested_hypotheses": [ "Stochastic westerly wind burst forcing creates a chaotic barrier to ENSO predictability beyond 15 months" ], "file": "unknowns-catalog/climate-science/u-enso-predictability-limit.yaml" }, { "id": "u-hasselmann-stochastic-resonance-glacial-mechanism", "title": "Is stochastic resonance (Benzi et al. 1982) the primary mechanism for the 100-kyr glacial cycle, and can Hasselmann's linear stochastic climate model be extended to capture the observed asymmetry (gradual glaciation, rapid termination) and the 41-kyr to 100-kyr transition at the Mid-Pleistocene?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "A fully nonlinear stochastic climate model that reproduces the asymmetric 100-kyr glacial sawtooth waveform (gradual glaciation, rapid termination), the Mid-Pleistocene Transition, and correct spectral power at 23, 41, and 100 kyr simultaneously from first principles has not been constructed.", "The stochastic resonance hypothesis requires measuring the \"noise amplitude\" of internal climate variability at glacial-interglacial timescales — this requires climate model validation at millennial timescales where model tuning cannot compensate for structural errors.", "The role of CO₂ feedbacks in glacial terminations (CO₂ rises ~100 ppm during terminations, amplifying orbital forcing) has not been quantitatively separated from the orbital forcing itself; identifying the causal sequence (insolation → CO₂ → temperature vs. insolation → temperature → CO₂) requires temporal resolution of <500 years in ice core records." ], "suggested_hypotheses": [ "A nonlinear Hasselmann model with a cubic bistable potential and Milankovitch forcing reproduces the sawtooth 100-kyr cycle asymmetry and the Mid-Pleistocene Transition when the potential barrier height decreases linearly with CO₂ concentration, coupling the stochastic-resonance mechanism to CO₂ feedbacks." ], "file": "unknowns-catalog/climate-science/u-hasselmann-stochastic-resonance-glacial-mechanism.yaml" }, { "id": "u-ice-sheet-instability-modes", "title": "What are the dominant instability modes of the West Antarctic Ice Sheet under ocean warming?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Marine ice sheet instability theory predicts runaway retreat", "Ice cliff instability contested as physically unrealisable" ], "suggested_hypotheses": [ "Retrograde bed slope instability in Thwaites Glacier is irreversible once grounding line retreats 150 km into deep basin" ], "file": "unknowns-catalog/climate-science/u-ice-sheet-instability-modes.yaml" }, { "id": "u-kalman-smoothing-proxy-noise-tree-ring-reconstruction", "title": "How robust are state-space paleoclimate reconstructions to proxy-noise misspecification and temporal nonstationarity?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-kalman-smoother-outperforms-static-regression-for-tree-ring-temperature" ], "file": "unknowns-catalog/climate-science/u-kalman-smoothing-proxy-noise-tree-ring-reconstruction.yaml" }, { "id": "u-marine-ice-cliff-instability", "title": "Is marine ice cliff instability a physically realisable mechanism in Antarctica or limited by buttressing?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Theory predicts rapid retreat once cliff height exceeds ~90 m", "Laboratory and field evidence for catastrophic calving is limited" ], "suggested_hypotheses": [ "Firn compaction and englacial hydrofracture are required co-requisites for marine ice cliff instability to contribute materially to sea level rise" ], "file": "unknowns-catalog/climate-science/u-marine-ice-cliff-instability.yaml" }, { "id": "u-methane-clathrate-destabilization", "title": "Under what ocean temperature trajectories do seafloor methane clathrates destabilise and contribute to atmospheric methane?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Clathrate stability zone shoaling detected in some Arctic shelves", "Emission rates from destabilisation events poorly quantified" ], "suggested_hypotheses": [ "Shallow Arctic shelf clathrates are the most vulnerable and could contribute 0.5-1 Gt CH4/yr under 3°C ocean warming" ], "file": "unknowns-catalog/climate-science/u-methane-clathrate-destabilization.yaml" }, { "id": "u-monsoon-bifurcation", "title": "Can the South Asian summer monsoon bifurcate to a permanently weakened state under continued aerosol loading?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Regional aerosol forcing reduces land-sea temperature gradient", "Tipping point vs smooth transition in monsoon strength unresolved" ], "suggested_hypotheses": [ "Land-use change combined with absorbing aerosol loading can push the South Asian monsoon across a bifurcation to a persistent weak state" ], "file": "unknowns-catalog/climate-science/u-monsoon-bifurcation.yaml" }, { "id": "u-online-change-point-detection-false-alarm-rate-under-trends", "title": "How can Bayesian online change-point detection maintain low false-alarm rates under long-term glacier trend acceleration?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-bocd-with-hazard-adaptation-detects-glacier-regime-shifts-earlier" ], "file": "unknowns-catalog/climate-science/u-online-change-point-detection-false-alarm-rate-under-trends.yaml" }, { "id": "u-optimal-transport-shift-stability-under-extremes", "title": "Do optimal-transport climate bias-correction maps remain stable under nonstationary extreme-event regimes?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Sparse evaluation of OT methods on out-of-distribution extreme years.", "Limited comparison between monotone and entropic OT variants for extreme-tail fidelity." ], "suggested_hypotheses": [ "h-ot-bias-correction-improves-tail-risk-calibration" ], "file": "unknowns-catalog/climate-science/u-optimal-transport-shift-stability-under-extremes.yaml" }, { "id": "u-ozone-recovery-timeline", "title": "Will Antarctic ozone fully recover by 2070 and what are the confounding factors?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Montreal Protocol CFC phase-out is proceeding", "Short-lived halogens and climate-ozone interactions may delay recovery" ], "suggested_hypotheses": [ "Heterogeneous chemistry on polar stratospheric clouds extended by climate change delays full Antarctic ozone recovery to 2090" ], "file": "unknowns-catalog/climate-science/u-ozone-recovery-timeline.yaml" }, { "id": "u-peatland-carbon-dynamics", "title": "How much carbon stored in tropical and boreal peatlands is vulnerable to release under warming and drainage?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Tropical peatlands store ~550 Gt C with high vulnerability to fire", "Depth-resolved carbon dating shows heterogeneous age structure" ], "suggested_hypotheses": [ "Hydrological connectivity between peatland domes and surrounding landscapes determines whether drainage triggers deep carbon loss" ], "file": "unknowns-catalog/climate-science/u-peatland-carbon-dynamics.yaml" }, { "id": "u-permafrost-tipping-point", "title": "At what global temperature does permafrost carbon release become self-sustaining without further anthropogenic forcing?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Arctic permafrost holds ~1500 Gt C", "Feedback timescale and threshold temperature poorly constrained" ], "suggested_hypotheses": [ "A 2.5°C global mean warming triggers irreversible permafrost degradation releasing >200 Gt C by 2200" ], "file": "unknowns-catalog/climate-science/u-permafrost-tipping-point.yaml" }, { "id": "u-polar-vortex-disruption", "title": "What drives sudden stratospheric warming events and their link to extreme cold outbreaks at the surface?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "SSW events precede extreme cold by 2-6 weeks", "Predictive mechanism linking stratospheric and tropospheric dynamics unclear" ], "suggested_hypotheses": [ "Wave-2 Rossby wave breaking is the dominant trigger for major SSW events and accounts for 70% of observed polar vortex disruptions" ], "file": "unknowns-catalog/climate-science/u-polar-vortex-disruption.yaml" }, { "id": "u-regional-sea-level-acceleration", "title": "What drives regional sea level accelerations that exceed the global mean by factors of 2-5?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Gravitational fingerprinting from ice melt partially explains spatial variability", "Ocean dynamic effects poorly constrained at coastal scales" ], "suggested_hypotheses": [ "Weakening AMOC produces enhanced sea level rise along the US East Coast exceeding global mean by 30% through geostrophic adjustment" ], "file": "unknowns-catalog/climate-science/u-regional-sea-level-acceleration.yaml" }, { "id": "u-rossby-wave-climate-tipping", "title": "Can Rossby wave dynamics amplified by Arctic warming trigger irreversible climate tipping points in mid-latitude weather patterns?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "The theoretical framework for when Arctic amplification causes a dynamical bifurcation (rather than a smooth change) in jet stream behaviour has not been established.", "The connection between Rossby wave resonance (quasi-stationary waves) and extreme weather event frequency is statistically contested in the observational record.", "Whether Arctic sea ice loss can produce irreversible changes to the Rossby wave dispersion relation or whether changes are reversible with sea ice recovery is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/climate-science/u-rossby-wave-climate-tipping.yaml" }, { "id": "u-sai-side-effects", "title": "What are the regional precipitation and ozone consequences of stratospheric aerosol injection?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Volcanic analogues suggest monsoon weakening", "Spatial patterns of SAI vs volcanic forcing differ substantially" ], "suggested_hypotheses": [ "Equatorial SAI disproportionately weakens the West African monsoon while mid-latitude injection produces more uniform cooling" ], "file": "unknowns-catalog/climate-science/u-sai-side-effects.yaml" }, { "id": "u-soil-moisture-atmosphere-feedback", "title": "Does soil moisture-precipitation feedback create bistable wet-dry states in semi-arid regions?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Land-atmosphere coupling measured in some tropical and subtropical regions", "Threshold for bistability vs monotonic response poorly constrained" ], "suggested_hypotheses": [ "Vegetation-soil moisture feedback creates hysteresis in rainfall, and degraded semi-arid landscapes can shift to permanently dry attractors" ], "file": "unknowns-catalog/climate-science/u-soil-moisture-atmosphere-feedback.yaml" }, { "id": "u-stratosphere-troposphere-coupling", "title": "How does stratospheric dynamics modulate the tropospheric jet streams on multi-decadal timescales?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "QBO modulates extratropical weather regimes", "Long-term trends in stratospheric influence on surface climate unclear" ], "suggested_hypotheses": [ "Stratospheric water vapor trends control the strength of downward influence and explain a significant fraction of tropospheric jet variability" ], "file": "unknowns-catalog/climate-science/u-stratosphere-troposphere-coupling.yaml" }, { "id": "u-urban-heat-island-nonlinearity", "title": "Are urban heat island effects nonlinear with city size and density, and how do they interact with regional climate?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Linear scaling of UHI with population observed in some studies", "Mesoscale circulation feedbacks from large urban areas poorly understood" ], "suggested_hypotheses": [ "Urban areas above 10 million population cross a nonlinear threshold generating persistent mesoscale convergence zones that amplify regional precipitation" ], "file": "unknowns-catalog/climate-science/u-urban-heat-island-nonlinearity.yaml" }, { "id": "u-wildfire-climate-feedback", "title": "What is the net radiative feedback of increasing wildfire frequency and extent under climate change?", "status": "open", "domain": "climate-science", "systematic_gaps": [ "Black carbon from fires has warming effect; aerosols have cooling effect", "Net sign of global wildfire feedback unresolved" ], "suggested_hypotheses": [ "Increased wildfire aerosol loading has a net cooling effect at the global scale, partially offsetting regional warming from fire-vegetation feedbacks" ], "file": "unknowns-catalog/climate-science/u-wildfire-climate-feedback.yaml" }, { "id": "u-attention-spotlight-mechanism", "title": "How does selective attention filter sensory information and what are the neural mechanisms of the attentional spotlight?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Top-down signals from FEF and IPS modulate sensory cortex activity", "Whether attention operates through gain modulation, noise reduction, or synchronisation is unresolved" ], "suggested_hypotheses": [ "Attention selectively synchronises gamma-band oscillations between visual cortex and frontoparietal areas, implementing competitive selection through oscillatory gating" ], "file": "unknowns-catalog/cognitive-science/u-attention-spotlight-mechanism.yaml" }, { "id": "u-cognitive-reserve-mechanism", "title": "What neural mechanisms underlie cognitive reserve and how do they delay symptom onset in Alzheimer's disease?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Education and cognitive activity correlate with reserve", "Whether reserve reflects more synapses, more efficient networks, or compensatory recruitment is unresolved" ], "suggested_hypotheses": [ "Cognitive reserve is implemented through increased functional network redundancy that allows rerouting of processing around focal Alzheimer's pathology" ], "file": "unknowns-catalog/cognitive-science/u-cognitive-reserve-mechanism.yaml" }, { "id": "u-collective-memory-network-structure", "title": "How does the topology of social networks (clustering, path length, centrality) determine the accuracy, stability, and distribution of collective memory across groups?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Experimental studies of collective memory use small, artificially structured groups; natural social networks are rarely studied", "The role of repeated retrieval (retrieval-induced forgetting) in collective memory is not characterized at the group level", "Digital social media as external memory stores fundamentally changes collective memory dynamics, unstudied quantitatively" ], "suggested_hypotheses": [], "file": "unknowns-catalog/cognitive-science/u-collective-memory-network-structure.yaml" }, { "id": "u-creativity-neural-mechanism", "title": "What distinguishes the neural dynamics of creative versus routine cognition?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Default mode and executive control networks co-activate during creative tasks", "Whether DMN-ECN coupling is necessary or correlational is unclear" ], "suggested_hypotheses": [ "Transient synchronisation between default mode, salience, and executive networks creates a cognitive state enabling remote association that is the neural basis of creative insight" ], "file": "unknowns-catalog/cognitive-science/u-creativity-neural-mechanism.yaml" }, { "id": "u-decision-fatigue-neural", "title": "What neural mechanisms produce decision fatigue and degraded choice quality with repeated decisions?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Anterior cingulate activity declines with repeated decisions", "Metabolic depletion versus neural adaptation explanations are unresolved" ], "suggested_hypotheses": [ "Repeated engagement of conflict monitoring in ACC induces synaptic depression that reduces effortful deliberation quality independently of blood glucose levels" ], "file": "unknowns-catalog/cognitive-science/u-decision-fatigue-neural.yaml" }, { "id": "u-distributional-semantics-compositionality", "title": "Can distributional semantic models capture the compositionality of language (the meaning of a phrase from the meanings of its parts), and do compositional vector representations match human neural patterns for phrase-level meaning?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "No vector composition operation satisfies all formal semantic compositionality constraints", "Phrase-level fMRI representational similarity with SBERT embeddings has not been systematically characterized", "Distributional models fail on novel negations, quantifiers, and counterfactuals" ], "suggested_hypotheses": [], "file": "unknowns-catalog/cognitive-science/u-distributional-semantics-compositionality.yaml" }, { "id": "u-emotion-categorization", "title": "Are basic emotions universal biological categories or culturally constructed prototypes?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Cross-cultural facial expression studies show both universal and culture-specific patterns", "Methodological confounds in cross-cultural research unresolved" ], "suggested_hypotheses": [ "Core affect dimensions (valence, arousal) are universal neurobiological primitives, while discrete emotion categories are cultural conceptual overlays" ], "file": "unknowns-catalog/cognitive-science/u-emotion-categorization.yaml" }, { "id": "u-face-recognition-substrate", "title": "What is the computational and neural architecture of face recognition in humans versus other primates?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Fusiform face area and occipital face area form a cortical network", "Why faces engage specialised processing while other expert object categories do not is unclear" ], "suggested_hypotheses": [ "Face recognition employs a holistic configural processing strategy implemented in a partially specialised cortical network that develops through experience with faces" ], "file": "unknowns-catalog/cognitive-science/u-face-recognition-substrate.yaml" }, { "id": "u-hard-problem-consciousness", "title": "Why and how does subjective experience arise from physical brain processes?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Neural correlates of consciousness identified but not explanatory", "Integrated information theory and global workspace theory make conflicting predictions" ], "suggested_hypotheses": [ "Recurrent processing in higher cortical areas is necessary and sufficient for phenomenal consciousness, and feedforward-only processing is never conscious" ], "file": "unknowns-catalog/cognitive-science/u-hard-problem-consciousness.yaml" }, { "id": "u-hippocampal-spatial-code", "title": "How does the hippocampal-entorhinal spatial code scale to large environments and abstract cognitive maps?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Grid cells tile space with scale determined by entorhinal location", "How grid scale is set and whether maps are continuous or modular is unresolved" ], "suggested_hypotheses": [ "A hierarchy of grid scales from dorsal to ventral entorhinal cortex enables spatial representation across 7 orders of magnitude through nested modular maps" ], "file": "unknowns-catalog/cognitive-science/u-hippocampal-spatial-code.yaml" }, { "id": "u-implicit-explicit-memory-boundary", "title": "What determines whether a memory is expressed implicitly versus explicitly and can this boundary be shifted?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Hippocampus is necessary for explicit but not implicit memory", "Boundary conditions between systems and their interaction are poorly characterised" ], "suggested_hypotheses": [ "Retrieval context determines which memory system dominates expression, and sleep selectively consolidates hippocampal traces into neocortical representations available for explicit access" ], "file": "unknowns-catalog/cognitive-science/u-implicit-explicit-memory-boundary.yaml" }, { "id": "u-insight-problem-solving", "title": "What neural and computational processes underlie the sudden insight that solves previously stuck problems?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Gamma bursts in right temporal cortex precede insight reports", "Unconscious restructuring of problem representation has no agreed neural mechanism" ], "suggested_hypotheses": [ "Spreading activation in semantic networks accumulates below threshold until a contextual cue causes superadditive summation that crosses the threshold for conscious insight" ], "file": "unknowns-catalog/cognitive-science/u-insight-problem-solving.yaml" }, { "id": "u-language-critical-period", "title": "What biological mechanisms close the critical period for first language acquisition at puberty?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Myelination and synaptic pruning occur during the critical period", "Whether closure is driven by neural maturation or experience-dependent plasticity is unresolved" ], "suggested_hypotheses": [ "GABAergic maturation shifts the excitation-inhibition balance in language cortex, closing the critical period independently of language exposure" ], "file": "unknowns-catalog/cognitive-science/u-language-critical-period.yaml" }, { "id": "u-loss-aversion-neural-substrate", "title": "What is the specific neural circuit implementation of loss aversion, and why does the loss aversion coefficient lambda vary so widely across individuals and contexts?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "No causal manipulation (TMS, lesion, pharmacology) has definitively identified the necessary and sufficient circuit for loss aversion", "Individual differences in lambda are heritable but the genetic architecture is unknown", "Context-dependence of lambda (framing effects) is not captured by standard prospect theory" ], "suggested_hypotheses": [], "file": "unknowns-catalog/cognitive-science/u-loss-aversion-neural-substrate.yaml" }, { "id": "u-metacognition-substrate", "title": "What neural mechanisms allow metacognitive access to one's own cognitive states?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Prefrontal areas are necessary for metacognitive reports", "Whether metacognition uses a dedicated system or is a special case of general monitoring is unresolved" ], "suggested_hypotheses": [ "Hierarchical predictive processing in anterior prefrontal cortex generates second-order predictions about first-order confidence that constitute metacognitive representations" ], "file": "unknowns-catalog/cognitive-science/u-metacognition-substrate.yaml" }, { "id": "u-mind-wandering-function", "title": "What adaptive function does mind wandering serve and what determines its content?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Mind wandering correlates with future-oriented prospective thinking", "Whether spontaneous thought is content-random or systematically biased toward concerns is debated" ], "suggested_hypotheses": [ "Mind wandering implements offline prospective simulation that prioritises unresolved personal goals, serving planning and autobiographical memory consolidation" ], "file": "unknowns-catalog/cognitive-science/u-mind-wandering-function.yaml" }, { "id": "u-neural-correlates-self", "title": "What neural substrates constitute the minimal self and how do they generate a sense of personal identity?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Default mode network implicated in self-referential processing", "Bodily self, autobiographical self, and narrative self have different substrates" ], "suggested_hypotheses": [ "Interoceptive prediction error signals from the insula construct the minimal bodily self, and disruption of this signal explains depersonalisation" ], "file": "unknowns-catalog/cognitive-science/u-neural-correlates-self.yaml" }, { "id": "u-perceptual-binding-problem", "title": "How does the brain bind features processed in different cortical areas into unified percepts?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Synchronous gamma oscillations proposed as binding mechanism", "No single mechanism has withstood experimental scrutiny" ], "suggested_hypotheses": [ "Recurrent feedback from higher areas imposes coherent phase relationships on lower-area gamma oscillations, implementing binding without requiring synchrony as an independent mechanism" ], "file": "unknowns-catalog/cognitive-science/u-perceptual-binding-problem.yaml" }, { "id": "u-sleep-creative-insight", "title": "How does sleep enhance creative problem solving and what stages are critical?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "REM sleep associated with remote association improvements", "NREM sleep role in creative insight distinct from its role in procedural memory is unclear" ], "suggested_hypotheses": [ "REM sleep reactivates weakly associated memory traces and enhances semantic network connectivity, producing novel associations detectable as creative insight on waking" ], "file": "unknowns-catalog/cognitive-science/u-sleep-creative-insight.yaml" }, { "id": "u-social-cognition-architecture", "title": "What is the neural architecture of social cognition and how does it differ from non-social cognition?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Temporoparietal junction and medial prefrontal cortex implicated in mentalizing", "Whether social cognition uses domain-specific or domain-general mechanisms is disputed" ], "suggested_hypotheses": [ "Social cognition uses partially specialised neural systems with a domain-general predictive coding substrate modified by statistical structure specific to social agents" ], "file": "unknowns-catalog/cognitive-science/u-social-cognition-architecture.yaml" }, { "id": "u-theory-of-mind-substrate", "title": "What is the minimal neural substrate for theory of mind and when does it develop ontogenetically?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "TPJ and mPFC are reliably activated in explicit ToM tasks", "Whether implicit ToM in infancy uses the same substrate as explicit ToM in adults is unresolved" ], "suggested_hypotheses": [ "Implicit ToM uses an automatic subcortical route through the superior colliculus and pulvinar while explicit ToM additionally recruits prefrontal deliberative processes" ], "file": "unknowns-catalog/cognitive-science/u-theory-of-mind-substrate.yaml" }, { "id": "u-time-perception-mechanism", "title": "What neural mechanisms produce subjective time perception and what causes its distortions?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Interval timing in the seconds range involves basal ganglia and supplementary motor area", "Mechanism of temporal distortion under emotion or attention load unclear" ], "suggested_hypotheses": [ "Dopaminergic striatal activity encodes subjective time by setting the rate of pacemaker-like oscillatory cycles that accumulate in working memory" ], "file": "unknowns-catalog/cognitive-science/u-time-perception-mechanism.yaml" }, { "id": "u-working-memory-capacity", "title": "What neural and computational mechanisms impose the ~4-item limit of working memory?", "status": "open", "domain": "cognitive-science", "systematic_gaps": [ "Gamma-theta oscillatory coding has been proposed", "Whether capacity limit reflects interference, resource, or slot-based constraints is unresolved" ], "suggested_hypotheses": [ "Competitive attractor dynamics in prefrontal cortex allow at most 4 stable simultaneously active representations due to inhibitory normalisation constraints" ], "file": "unknowns-catalog/cognitive-science/u-working-memory-capacity.yaml" }, { "id": "u-aco-convergence-routing-instances", "title": "For industrial-scale routing instances with thousands of edges, which ant colony hyperparameter schedules admit PAC-style guarantees versus empirical leaderboard wins alone — and how do they compare to simulated annealing baselines under identical compute budgets?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Standardized routing benchmark suites with contractual disclosure of realized compute envelopes including parallel colony counts", "Hybrid algorithm registry documenting failure modes where ACO trails evolutionary algorithms on correlated-traffic routing graphs" ], "suggested_hypotheses": [ "h-ant-colony-optimization-x-gradient-free-metaheuristics" ], "file": "unknowns-catalog/computer-science/u-aco-convergence-routing-instances.yaml" }, { "id": "u-algorithm-discovery-automation", "title": "Can machine learning systems autonomously discover novel algorithms and mathematical proofs beyond human-designed heuristics?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Current ML-based algorithm discovery systems do not generalise to problems structurally different from training instances.", "The formal relationship between training data coverage and discoverable algorithm complexity has not been characterised.", "Automated theorem proving has not cracked any of the major open mathematical conjectures despite advances." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-algorithm-discovery-automation.yaml" }, { "id": "u-astrocyte-memory-replay-transformers", "title": "Can astrocyte-inspired memory compression and replay mechanisms eliminate catastrophic forgetting in long-context transformers while maintaining O(1) storage cost per context token?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether astrocyte-inspired memory compression provides any advantage over existing O(1) attention approximations (Performer, Mamba, RetNet) on genuinely long-range tasks has not been benchmarked.", "The biological accuracy of the astrocyte model (does it reflect known astrocyte calcium signaling dynamics?) has not been assessed by computational neuroscientists.", "The information-theoretic loss bound of astrocyte-inspired compression has not been derived." ], "suggested_hypotheses": [ "Astrocyte-inspired memory compression achieves the same perplexity as full attention on 100K-token contexts while using 100x less memory, because biological replay preferentially preserves high-entropy (surprising) tokens, matching the information-theoretic optimum." ], "file": "unknowns-catalog/computer-science/u-astrocyte-memory-replay-transformers.yaml" }, { "id": "u-byzantine-fault-tolerance-practical", "title": "What are the practical engineering limits of Byzantine fault-tolerant consensus in real-world deployments, and can BFT achieve performance competitive with non-Byzantine systems?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No comprehensive empirical study of BFT protocol performance under realistic Byzantine failures (not crash failures or all-adversarial) in production deployments.", "The communication complexity lower bound for BFT under partial synchrony is not precisely known.", "Incentive-compatible BFT (rational Byzantine, not adversarial) may require fewer replicas but lacks formal analysis." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-byzantine-fault-tolerance-practical.yaml" }, { "id": "u-cache-efficient-algorithm-design", "title": "Can memory hierarchy-aware algorithm design principles be formalised to automatically optimise cache efficiency across heterogeneous hardware?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Cache-oblivious analysis applies only to simple two-level memory models; generalisation to real multi-level hierarchies is unsolved.", "Automatic code generation that is cache-efficient across x86, ARM, and GPU architectures requires hardware-specific knowledge not captured in any abstract model.", "The tradeoff between cache efficiency and algorithmic parallelism in heterogeneous computing environments is not formalised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-cache-efficient-algorithm-design.yaml" }, { "id": "u-cahn-hilliard-segmentation-parameter-transfer-limits", "title": "Which phase-field parameters from Cahn-Hilliard-style models transfer into practical diffuse-interface image segmentation, and where does the physical analogy break under nonconserved labels and learned features?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Controlled segmentation benchmarks varying interface-width and curvature penalties.", "Explicit tests of conserved versus nonconserved dynamics for label maps." ], "suggested_hypotheses": [ "h-interface-width-regularization-predicts-segmentation-stability" ], "file": "unknowns-catalog/computer-science/u-cahn-hilliard-segmentation-parameter-transfer-limits.yaml" }, { "id": "u-cellular-automata-complexity-classification", "title": "What is the computational characterization of Wolfram's four behavioral classes of cellular automata, and does Class IV (complex) behavior always correspond to computational universality or are there Class IV automata that are not Turing complete?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Only a few CAs have been proven Turing complete; the majority of Class IV CAs are conjectured universal without proof", "The relationship between Wolfram classes and formal language theory (what regular/context-free/RE languages CAs can compute) is incomplete", "Two-dimensional CAs have different universality properties than 1D CAs, and the classification taxonomy has not been rigorously extended" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-cellular-automata-complexity-classification.yaml" }, { "id": "u-cellular-automata-x-computational-universality", "title": "What is the minimum computational resource (space-time complexity) for a cellular automaton to be universal, and are there self-replicating CA rules that are computationally simpler than von Neumann's construction?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Minimum state complexity for Turing-complete self-replicating CA is unknown; best known lower bounds are not tight", "Physical implementation of universal CAs in molecular systems (DNA computing, chemical reaction networks) is not demonstrated", "Relationship between CA computational universality and the physical notion of computational substrate (Landauer principle) is not formalized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-cellular-automata-x-computational-universality.yaml" }, { "id": "u-computational-irreducibility-physical-systems-scope", "title": "Which classes of physical and biological systems are computationally irreducible in a formal complexity-theoretic sense, and does irreducibility correspond to empirically observed limits of prediction in weather, ecology, and economics?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Formal computational complexity analysis of most physical dynamical systems is absent", "Mapping between classical chaos (sensitive dependence) and computational irreducibility is incomplete", "Quantum speedup for simulation of irreducible classical systems has not been fully characterised" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-computational-irreducibility-physical-systems-scope.yaml" }, { "id": "u-continuous-symmetry-neural-topology", "title": "Do continuous symmetries in neural population codes enable dynamic topological reconfiguration of network connectivity as a computational primitive, beyond what discrete architectures can achieve?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether continuous-symmetry networks can compute functions that fixed-topology networks of equivalent size cannot has not been established in terms of expressivity theory.", "The learning dynamics of networks with continuous symmetry (do they converge faster? to better optima?) relative to standard networks has not been analyzed theoretically.", "Whether biological neural circuits exhibit dynamic topology changes consistent with continuous symmetry groups has not been measured in in vivo electrophysiology." ], "suggested_hypotheses": [ "Neural networks with continuous rotational symmetry in their weight space learn visual representations faster than fixed-architecture networks on rotated MNIST, because weight space rotations implement data augmentation exactly rather than approximately." ], "file": "unknowns-catalog/computer-science/u-continuous-symmetry-neural-topology.yaml" }, { "id": "u-contrastive-ssl-energy-model-bridge", "title": "Can temperature parameters in contrastive SSL be rigorously interpreted as controlling an effective free-energy landscape curvature during training, beyond qualitative analogy?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Non-equilibrium training dynamics lack a canonical partition function interpretation.", "Hard-negative distributions shift during training, unlike fixed thermal baths." ], "suggested_hypotheses": [ "h-contrastive-loss-implements-high-temperature-energy-comparison" ], "file": "unknowns-catalog/computer-science/u-contrastive-ssl-energy-model-bridge.yaml" }, { "id": "u-cpc-negative-sampling-bias-temporal-structure", "title": "How sensitive are CPC-style representations to negative sampling bias when temporal autocorrelation violates independence assumptions commonly used in contrastive bounds?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Limited standardized audits reporting effective negative distributions versus theory assumptions for sequential scientific data.", "Sparse linkage between temporal autocorrelation strength and downstream calibration under covariate shift.", "Under-studied alternatives (hard negatives, graph-structured negatives) for laboratory stimulus designs." ], "suggested_hypotheses": [ "h-predictive-cpc-loss-improves-downstream-transfer-under-shift" ], "file": "unknowns-catalog/computer-science/u-cpc-negative-sampling-bias-temporal-structure.yaml" }, { "id": "u-cut-cell-segmentation-interface-consistency", "title": "Can explicit finite-volume-style flux consistency constraints at curved boundaries reduce topological leakage and boundary jitter in voxel medical segmentations compared with unconstrained CNN softmax outputs — without sacrificing recall?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Public MRI/CT volumes with subvoxel surface truth suitable for flux-style penalties near thin structures.", "Training protocols comparing Dice versus flux-balanced losses with matched compute budgets." ], "suggested_hypotheses": [ "h-cut-cell-conservative-flux-reduces-leakage-medical-seg" ], "file": "unknowns-catalog/computer-science/u-cut-cell-segmentation-interface-consistency.yaml" }, { "id": "u-deq-solver-tolerance-versus-generalization-gap", "title": "How sensitive are DEQ generalization metrics to forward fixed-point solver tolerances and backward adjoint solve accuracy — does premature termination bias gradients enough to shift validation error beyond optimizer noise?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Multi-seed studies isolating forward versus backward tolerance interactions on identical architectures", "Comparison of Jacobian-free adjoint approximations versus exact implicit differentiation in small models" ], "suggested_hypotheses": [ "h-anderson-acceleration-deq-forward-steps-correlate-with-val-loss" ], "file": "unknowns-catalog/computer-science/u-deq-solver-tolerance-versus-generalization-gap.yaml" }, { "id": "u-discrete-convolution-theorem-cnn-inductive-bias", "title": "How much of CNN generalization on natural images is explained by implicit spectral tilting induced by architecture depth, kernel size, and pooling versus task-specific learning?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Nonlinearities prevent clean diagonalization; lack of unified spectral theory for deep stacks.", "Equivariance is approximate under padding and downsampling; error propagation poorly characterized." ], "suggested_hypotheses": [ "h-cnn-layers-approximate-localized-spectral-filters" ], "file": "unknowns-catalog/computer-science/u-discrete-convolution-theorem-cnn-inductive-bias.yaml" }, { "id": "u-edmd-deep-koopman-spectral-bias-nonlinear-video", "title": "When do deep Koopman-style linearizations avoid spectral bias that limits EDMD on chaotic or multi-scale video dynamics relevant to laboratory monitoring?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Few standardized long-horizon benchmarks reporting spectral residuals alongside pixel metrics for scientific video.", "Limited head-to-head comparisons between classical EDMD dictionaries and neural lifts under identical cameras.", "Under-studied uncertainty propagation for safety-critical monitoring uses." ], "suggested_hypotheses": [ "h-data-driven-koopman-basis-improves-long-horizon-video-prediction" ], "file": "unknowns-catalog/computer-science/u-edmd-deep-koopman-spectral-bias-nonlinear-video.yaml" }, { "id": "u-emergent-capabilities-llm-prediction", "title": "Are emergent capabilities in large language models predictable from scaling laws, or do they represent genuine phase transitions in capability space?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The methodology for measuring emergence is disputed; Schaeffer et al. show many emergent capabilities disappear with continuous evaluation metrics.", "No mechanistic theory predicts which capabilities will emerge at which scale.", "Cross-model and cross-architecture comparisons of emergence are confounded by different training regimes and data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-emergent-capabilities-llm-prediction.yaml" }, { "id": "u-federated-learning-privacy-utility", "title": "What is the fundamental tradeoff between differential privacy guarantees and model utility in federated learning, and how close are current implementations to the Pareto frontier?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The optimal noise mechanism for federated DP learning (Gaussian, Laplace, Skellam) depends on model architecture and has not been systematically compared.", "Client-level versus sample-level DP have different privacy semantics and utility costs not jointly analysed across applications.", "Inference attacks on federated models (gradient inversion, membership inference) have outpaced defence development in realistic settings." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-federated-learning-privacy-utility.yaml" }, { "id": "u-fractional-spiking-neural-memory", "title": "Does fractional-order differentiation in spiking neural networks capture long-range temporal dependencies that integer-order models cannot, and is this biologically realized in slow adaptation currents?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether fractional-order spiking networks are strictly more computationally powerful (in the sense of approximating a wider class of time series) than integer-order spiking networks of the same size has not been proven.", "The biologically observed distribution of alpha values (estimated from in vivo spike train statistics) across cortical areas has not been measured.", "Whether fractional-order SNN dynamics can be implemented in analog neuromorphic hardware (e.g., Intel Loihi) and what the energy cost is relative to integer-order implementation is unknown." ], "suggested_hypotheses": [ "The optimal fractional order alpha for natural speech processing equals 0.7 ± 0.1, matching the value estimated from cortical spike train power spectra, because both systems have adapted to the 1/f temporal correlations of natural language." ], "file": "unknowns-catalog/computer-science/u-fractional-spiking-neural-memory.yaml" }, { "id": "u-genetic-algorithm-x-natural-selection", "title": "Under what fitness landscape structures do genetic algorithms outperform gradient-based optimization, and how can evolutionary computation borrow population genetics theory to design better crossover operators?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Fitness landscape statistics for real combinatorial optimization problems (TSP, protein folding) are not well characterized", "Optimal crossover operator design for preserving building blocks depends on unknown problem structure", "Theory of GA population diversity maintenance (niching, speciation) lacks quantitative predictive power" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-genetic-algorithm-x-natural-selection.yaml" }, { "id": "u-graph-algorithm-quantum-speedup", "title": "Which graph algorithms admit quantum speedup beyond classical near-linear time complexity, and what are the practical costs of quantum graph computation?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Quantum speedup for maximum flow and minimum cut in general graphs has not been established beyond specific graph families.", "The quantum query complexity of fundamental graph properties is unknown for several important cases.", "Practical quantum graph computation requires efficient quantum RAM (QRAM) whose implementation is not feasible at scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-graph-algorithm-quantum-speedup.yaml" }, { "id": "u-graph-neural-network-x-spectral-graph-theory", "title": "What is the expressive power of spectral GNNs for distinguishing non-isomorphic graphs, and how do spectral filters on graphs generalize to dynamic and hypergraphs?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Expressiveness hierarchy between spectral GNNs (full spectrum) and higher-order WL tests (k-WL) is not fully established", "Efficient spectral GNN for large graphs requires approximate eigendecomposition; approximation error's effect on expressiveness is not bounded", "Spectral graph theory for directed graphs lacks a unique canonical Laplacian definition, creating ambiguity in GNN design" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-graph-neural-network-x-spectral-graph-theory.yaml" }, { "id": "u-graph-percolation-lateral-movement-detection-threshold", "title": "Can enterprise identity graphs be reduced to percolation models with identifiable p_eff and p_c such that SOC alerts meaningfully predict approach to criticality before crown-jewel reachability spikes?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No open benchmarks linking MITRE technique success rates to graph percolation exponents.", "Temporal dynamics (patch Tuesday, credential rotation) make static p dubious." ], "suggested_hypotheses": [ "h-zero-trust-control-raises-effective-percolation-threshold" ], "file": "unknowns-catalog/computer-science/u-graph-percolation-lateral-movement-detection-threshold.yaml" }, { "id": "u-hopfield-capacity-modern-architectures", "title": "Does the spin-glass memory capacity bound (alpha_c ~ 0.14 per neuron) generalize to modern transformer attention heads, and can spin-glass replica theory predict catastrophic forgetting thresholds in large language models?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Replica theory capacity bounds not tested against empirical in-context learning limits in transformers", "Relationship between spin-glass temperature parameter and transformer temperature not formalized", "Catastrophic forgetting onset not analyzed as a spin-glass phase transition" ], "suggested_hypotheses": [ "h-hopfield-capacity-modern-architectures" ], "file": "unknowns-catalog/computer-science/u-hopfield-capacity-modern-architectures.yaml" }, { "id": "u-immune-system-x-anomaly-detection", "title": "How does the adaptive immune system avoid missing novel pathogens while maintaining tolerance to self, and what computational principles underlie cross-reactive memory?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The mathematical theory of T-cell receptor cross-reactivity (how similar must epitopes be for recognition) lacks a complete quantitative framework", "How the thymic selection process sets the optimal decision boundary for self/non-self discrimination under evolutionary pressure is not understood", "The computational equivalence between affinity maturation (B-cell receptor optimization) and meta-learning / few-shot learning algorithms has not been formalized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-immune-system-x-anomaly-detection.yaml" }, { "id": "u-legal-argumentation-formal-completeness", "title": "Can formal argumentation frameworks capture the full range of legal reasoning patterns including analogy, precedent, and equitable discretion, or are there fundamental limits to the formalization of law?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No large-scale empirical test of whether formal argumentation models predict court decisions better than baseline", "Analogical reasoning in legal decisions has not been successfully reduced to formal attack relations", "Judicial discretion and value-based judgment resist formalization in any existing framework" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-legal-argumentation-formal-completeness.yaml" }, { "id": "u-lwe-hardness-proof-quantum-reduction", "title": "Is Learning With Errors (LWE) provably hard against quantum computers — and what is the precise quantum query complexity of the best LWE algorithm as a function of lattice dimension n, modulus q, and error rate α?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "A purely classical hardness assumption that implies LWE hardness against quantum adversaries has not been established — existing reductions are quantum-to-quantum.", "Concrete quantum gate counts for BKZ-based quantum attacks on Kyber/Dilithium parameter sets have not been agreed upon, leading to uncertainty in security margins.", "The relationship between LWE hardness and the quantum random oracle model (QROM) security of Kyber/Dilithium KEMs has not been fully analyzed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-lwe-hardness-proof-quantum-reduction.yaml" }, { "id": "u-neural-architecture-search-x-evolutionary-biology", "title": "Do the fitness landscapes of neural architecture search share quantitative properties (ruggedness, neutrality, evolvability) with natural fitness landscapes for protein sequences, and what does this imply about optimal search algorithms?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "NAS fitness landscape characterization requires many expensive training runs; most studies sample < 0.1% of search space", "NAS landscape properties depend strongly on the training procedure (early stopping, batch size) not just the architecture", "Direct quantitative comparison of NAS and protein fitness landscape statistics has not been performed" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-neural-architecture-search-x-evolutionary-biology.yaml" }, { "id": "u-neural-network-generalisation-theory", "title": "Why do overparameterised neural networks generalise well despite interpolating training data, contradicting classical statistical learning theory?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Pac-Bayes and margin-based bounds are not tight enough to explain the generalisation of practical deep networks.", "The implicit regularisation of gradient descent has been characterised for linear models but not for non-linear networks.", "Double descent curves have been observed empirically but their theoretical explanation does not generalise across architectures." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-neural-network-generalisation-theory.yaml" }, { "id": "u-neural-ode-x-dynamical-systems", "title": "Do Neural ODEs learn physically meaningful vector fields, and when do they exhibit bifurcations or chaos that limit generalization?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The Lyapunov stability spectrum of trained Neural ODE vector fields has not been systematically measured across architectures and tasks", "Whether Neural ODEs can represent chaotic dynamics (positive Lyapunov exponents) and whether this correlates with poor generalization has not been studied", "The relationship between the geometric structure of the learned flow (volume-preserving, gradient flow, Hamiltonian) and the network's inductive bias has not been characterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-neural-ode-x-dynamical-systems.yaml" }, { "id": "u-neuromorphic-thermodynamic-energy", "title": "Do neuromorphic processors approach thermodynamic (Landauer) energy efficiency limits that silicon von Neumann architectures cannot, and what circuit mechanisms enable this?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The energy consumption per synaptic event in biological cortical synapses (in vivo, at physiological firing rates) has not been measured with sufficient precision to establish the ratio to the Landauer limit.", "Whether neuromorphic processors can in principle approach the Landauer limit (or are fundamentally limited by circuit noise) has not been analyzed thermodynamically.", "The role of stochastic resonance and noise-assisted computation in reducing effective energy consumption below the deterministic Landauer limit in biological systems is unknown." ], "suggested_hypotheses": [ "Biological synapses achieve near-Landauer efficiency because they operate in a noise-dominated (stochastic resonance) regime where thermal noise is a feature, not a bug - reducing required signal power at a thermodynamic cost that falls below the deterministic equivalent." ], "file": "unknowns-catalog/computer-science/u-neuromorphic-thermodynamic-energy.yaml" }, { "id": "u-optimal-bridge-density-knowledge-graph", "title": "What is the minimum number of cross-domain bridges required for a scientific knowledge graph to exhibit \"giant component\" connectivity, enabling any domain to reach any other within 2-3 bridge steps?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The degree distribution exponent γ of the USDR knowledge graph has not been measured, so it is unknown whether the graph is in the scale-free regime (γ < 3) or intermediate (γ ≈ 3) where logarithmic corrections matter.", "The minimum bridge count and placement strategy (random vs. hub-targeted) for achieving diameter ≤ 3 across all domain pairs has not been computed for the current graph.", "Whether cross-domain hub nodes (phase transitions, information entropy, percolation) are sufficient to provide backbone connectivity, or whether many small-degree bridges are also required, has not been quantified.", "The relationship between bridge \"quality\" (formal translation table completeness) and its contribution to navigable connectivity has not been modeled." ], "suggested_hypotheses": [ "A hub-targeted bridge addition strategy (prioritizing bridges that connect to high-degree nodes) achieves giant-component connectivity at 3–5× fewer total bridges than a random addition strategy, due to the scale-free structure of the knowledge graph.", "The current USDR graph (~860 nodes, ~135 bridges) is below the giant-component threshold for domain-level nodes, and adding ~50 hub-targeted bridges would reduce the mean cross-domain distance from >5 steps to ≤3 steps." ], "file": "unknowns-catalog/computer-science/u-optimal-bridge-density-knowledge-graph.yaml" }, { "id": "u-optimal-cooling-schedule-convergence", "title": "What is the optimal annealing schedule for simulated annealing to guarantee convergence with polynomial-time complexity for NP-hard problems?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No general theory connects problem structure (clause density, constraint graph topology) to optimal cooling schedule parameters.", "The relationship between simulated annealing hardness and worst-case NP-hardness complexity is not well understood.", "Adaptive cooling schedules that adjust T based on acceptance rate have not been rigorously analyzed for convergence guarantees." ], "suggested_hypotheses": [ "h-simulated-annealing-quantum-speedup" ], "file": "unknowns-catalog/computer-science/u-optimal-cooling-schedule-convergence.yaml" }, { "id": "u-oscillatory-spiking-neural-computation", "title": "Do learnable neural oscillations implement a form of analog temporal computation that provably outperforms digital spiking networks on continuous-time sequence modeling tasks?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether phase-coded oscillatory networks are computationally universal in a sense that rate-coded spiking networks are not has not been established.", "The information capacity of phase-coded computation (bits per synapse per second) relative to rate-coded computation has not been formally compared.", "Whether learnable oscillation frequencies converge to biologically observed frequency bands (gamma 30-80Hz, theta 4-8Hz) during training on natural data has not been tested." ], "suggested_hypotheses": [ "Learnable oscillatory networks trained on natural speech converge to oscillation frequency distributions matching human cortical frequency bands, because natural speech statistics select for the same temporal basis functions that evolution tuned in biological brains." ], "file": "unknowns-catalog/computer-science/u-oscillatory-spiking-neural-computation.yaml" }, { "id": "u-p-vs-np-geometric-barrier", "title": "What geometric or algebraic barriers prevent proof of P != NP, and do known techniques suffice if correctly applied?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether geometric complexity theory can circumvent known barriers is unresolved.", "The relationship between P vs NP and the structure of the polynomial hierarchy is not fully exploited.", "No oracle separation completely captures the difficulty of the problem." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-p-vs-np-geometric-barrier.yaml" }, { "id": "u-pagerank-x-markov-chain", "title": "What is the optimal teleportation parameter alpha in PageRank for different network topologies, and how does mixing time scale with web graph structure?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Theoretical analysis of how the optimal alpha depends on web graph spectral properties (degree distribution, clustering coefficient) has not been performed", "Dynamic PageRank algorithms with guaranteed convergence bounds for graphs with continuous edge/node additions have not been established", "The mixing time scaling law for PageRank on real-world scale-free web graphs has not been measured empirically vs. random graph predictions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-pagerank-x-markov-chain.yaml" }, { "id": "u-parallel-tempering-cost-benefit-large-language-model-posteriors", "title": "What is the compute-benefit frontier for parallel tempering in large language model posterior sampling?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No standardized reporting of ESS-per-joule for tempering versus non-tempering baselines in large models.", "Limited evidence on adaptive ladder policies under realistic accelerator constraints." ], "suggested_hypotheses": [ "h-adaptive-temperature-ladders-improve-posterior-mixing" ], "file": "unknowns-catalog/computer-science/u-parallel-tempering-cost-benefit-large-language-model-posteriors.yaml" }, { "id": "u-physics-informed-nn-fourier-convergence", "title": "When do physics-informed neural networks (PINNs) with domain-aware Fourier features provably converge to true PDE solutions, and what is the error bound as a function of network size and feature frequency?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No theorem exists bounding the PINN approximation error in terms of both network size AND Fourier feature frequencies simultaneously.", "The optimal Fourier feature frequency distribution for a given PDE (elliptic, parabolic, hyperbolic) has not been derived theoretically.", "Whether domain-aware Fourier PINNs achieve the same approximation rate as classical spectral methods (which is O(N^{-s}) for smooth s-order solutions) has not been established." ], "suggested_hypotheses": [ "PINNs with domain-aware Fourier features achieve the same approximation rate as classical spectral methods for smooth PDE solutions when the Fourier feature bandwidth matches the solution's effective bandwidth, providing a principled replacement for spectral methods in high dimension." ], "file": "unknowns-catalog/computer-science/u-physics-informed-nn-fourier-convergence.yaml" }, { "id": "u-predictive-coding-motion-illusion", "title": "What neural circuit mechanism explains why predictive coding networks trained on natural images generate the same motion illusions as human visual perception, and is this convergence inevitable or accidental?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether non-predictive-coding neural networks (CNNs, ViTs) trained on the same natural image statistics also generate the same motion illusions has not been systematically tested.", "Whether the illusion strength (perceived motion magnitude) is quantitatively predicted by the predictive error magnitude in the model has not been measured.", "Whether the complete catalog of human geometric-optical illusions is reproduced by predictive coding models trained on natural images has not been compiled." ], "suggested_hypotheses": [ "All neural network architectures trained on natural image statistics generate human-matching motion illusions, regardless of architecture, because the illusions are Bayesian-optimal inferences from natural image statistics, not artifacts of predictive coding." ], "file": "unknowns-catalog/computer-science/u-predictive-coding-motion-illusion.yaml" }, { "id": "u-program-synthesis-completeness", "title": "Can program synthesis systems automatically generate programs from specifications for any computable function, and what are the practical limits?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The sample complexity of synthesis (how many input-output examples are needed) as a function of program complexity is not characterised.", "Verifying that synthesised programs are correct for all inputs rather than just specified examples requires formal verification not integrated into current synthesis pipelines.", "Synthesised programs fail on distribution shift from the specification; robustness of synthesis is not measured." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-program-synthesis-completeness.yaml" }, { "id": "u-quantum-cognition-lindblad-decisions", "title": "Is the Gorini-Kossakowski-Sudarshan-Lindblad (GKSL) master equation the correct quantum formalism for modeling order effects and conjunction fallacies in human decision-making?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether GKSL open-system quantum cognition makes empirically distinguishable predictions from unitary quantum cognition on existing experimental datasets has not been tested.", "The psychological interpretation of the Lindblad dissipation operators (what cognitive processes do they represent?) has not been developed.", "Whether quantum-like models (GKSL or otherwise) outperform classical Bayesian updating plus response bias in predicting order effects across published experiments has not been meta-analytically assessed." ], "suggested_hypotheses": [ "GKSL quantum cognition models with environmental coupling rates proportional to task difficulty outperform unitary quantum cognition models in predicting within-subject order effect magnitudes, with AIC advantage > 2 per study." ], "file": "unknowns-catalog/computer-science/u-quantum-cognition-lindblad-decisions.yaml" }, { "id": "u-quantum-error-correction-overhead-reduction", "title": "What is the minimum physical qubit overhead required for fault-tolerant quantum computation, and can quantum LDPC codes achieve constant overhead with practical decoders?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Whether qLDPC codes with constant overhead and polynomial-time decoders exist that work under realistic noise models (with measurement errors, correlated noise) is unproven.", "The hardware connectivity requirements of high-performance qLDPC codes may be incompatible with nearest-neighbor-only quantum hardware (superconducting qubits, ion traps).", "The threshold error rate for the best known qLDPC decoders under circuit-level noise is unknown and may be lower than the surface code threshold." ], "suggested_hypotheses": [ "Fiber-bundle and hypergraph product qLDPC codes with belief propagation + ordered statistics decoders can achieve sub-100:1 physical-to-logical qubit overhead at p = 0.1% error rate." ], "file": "unknowns-catalog/computer-science/u-quantum-error-correction-overhead-reduction.yaml" }, { "id": "u-quantum-zeno-watchdog-quantitative-mapping", "title": "Can pedagogical mappings from quantum Zeno measurement-rate curves to embedded-system sampling/hazard models measurably improve engineering students’ quantitative reasoning about watchdog timing versus fault dynamics — without inducing misconceptions about quantum mechanics in silicon?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Pre/post assessments separating algebraic cadence skills from conceptual misconceptions about quantum projection", "Replication across institutions with varying quantum-lab access" ], "suggested_hypotheses": [ "h-student-transfer-zeno-curve-to-sampling-stability-drills" ], "file": "unknowns-catalog/computer-science/u-quantum-zeno-watchdog-quantitative-mapping.yaml" }, { "id": "u-reinforcement-learning-x-bellman-equation", "title": "Does the Bellman optimality equation have a unique solution for infinite-horizon deep RL with function approximation, and what conditions prevent divergence?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The precise conditions on the function approximator class that guarantee convergence of deep Q-learning to the true Q* have not been established beyond linear approximation", "The relationship between the deadly triad instability and the existence of multiple fixed points of the Bellman operator under neural approximation has not been characterized", "Whether distributional RL (C51, QR-DQN) avoids the convergence issues of point-estimate Q-learning due to better preservation of the Bellman contraction property has not been proved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-reinforcement-learning-x-bellman-equation.yaml" }, { "id": "u-reservoir-computing-x-dynamical-systems", "title": "What is the optimal reservoir architecture (topology, spectral radius, sparsity) for tasks requiring different timescales of memory, and can criticality-tuned reservoirs outperform trained recurrent networks on real-world time series?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No closed-form relationship between spectral radius ρ, task memory horizon T, and generalisation error", "Physical reservoir computers have not been benchmarked against trained LSTMs on identical tasks", "Whether cortical circuits satisfy the echo state property (fading memory) under in vivo conditions is untested" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-reservoir-computing-x-dynamical-systems.yaml" }, { "id": "u-robustness-distribution-shift", "title": "What training and architectural modifications make machine learning models robust to real-world distribution shift, and how much robustness is achievable?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No training method consistently improves OOD performance across diverse shift types (covariate, label, and concept shift) simultaneously.", "Benchmarks for distribution robustness are not standardised; results are not comparable across papers.", "The theoretical conditions under which a model trained on one distribution can generalise to another are known only for specific model classes." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-robustness-distribution-shift.yaml" }, { "id": "u-sat-phase-transition-p-np", "title": "Does the statistical-physics description of the SAT phase transition (replica symmetry breaking, glass phase) provide a proof strategy for P≠NP, or are worst-case and average-case hardness fundamentally different?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The relationship between replica symmetry breaking in random CSPs and circuit complexity lower bounds has not been formalized.", "Whether the \"hard phase\" in planted random 3-SAT is provably hard (requiring super-polynomial time for any algorithm) remains open.", "The exact value of α_c has been rigorously established only recently (Ding, Sly, Sun 2015) — the full complexity landscape around α_c is still being mapped.", "No complexity-theoretic consequence of the statistical-physics glass transition has been rigorously proved." ], "suggested_hypotheses": [ "The information-theoretic threshold for planted 3-SAT (where no efficient algorithm can distinguish planted from unplanted) coincides with the replica-symmetry-breaking transition." ], "file": "unknowns-catalog/computer-science/u-sat-phase-transition-p-np.yaml" }, { "id": "u-sat-spin-glass-algorithm-design", "title": "Can spin glass replica symmetry breaking theory predict the optimal algorithmic strategy for SAT instances near the phase transition boundary, and does survey propagation achieve the theoretical cavity method performance bound?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "RSB order parameters not systematically compared to SP runtime profiles near alpha_c", "Performance bound from cavity method not tested against modern CDCL solvers", "Phase transition structure of structured (non-random) industrial SAT instances not characterized" ], "suggested_hypotheses": [ "h-sat-spin-glass-algorithm-design" ], "file": "unknowns-catalog/computer-science/u-sat-spin-glass-algorithm-design.yaml" }, { "id": "u-satisfiability-x-constraint-propagation", "title": "What is the tightest polynomial-time propagation algorithm for general k-ary CSPs that subsumes both arc consistency and unit propagation, and does it close the SAT-CSP complexity gap?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No polynomial-time propagation algorithm achieves singleton arc consistency for general binary CSPs", "The formal equivalence of AC-3 and unit propagation has not been extended to k-ary constraints", "Empirical benchmarks comparing CSP and SAT solvers on identical problem instances are limited" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-satisfiability-x-constraint-propagation.yaml" }, { "id": "u-spectral-clustering-x-graph-laplacian", "title": "What is the optimal graph Laplacian normalisation (unnormalised, symmetric, random-walk) for spectral clustering on real-world networks with heterogeneous degree distributions, and can the Cheeger bound be tightened to a polynomial approximation guarantee?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No empirical benchmark comparing all three Laplacian normalisations on real heterogeneous networks exists", "The Cheeger bound is tight but no polynomial-factor approximation guarantee for spectral clustering is known", "Whether spectral clustering achieves consistent community recovery in the stochastic block model is proven only for restricted parameter ranges" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-spectral-clustering-x-graph-laplacian.yaml" }, { "id": "u-spin-glass-optimization-hardness-phase-transition", "title": "Does the computational hardness of random k-SAT peak exactly at the replica-symmetry-breaking transition, and can spin glass theory predict average-case algorithmic complexity for structured (non-random) instances?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-spin-glass-optimization-hardness-phase-transition.yaml" }, { "id": "u-stdp-reward-modulation-rl-equivalence", "title": "Is reward-modulated spike-timing-dependent plasticity (R-STDP) mathematically equivalent to a form of policy gradient reinforcement learning, and does this equivalence hold at the circuit level in biological brains?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The exact mathematical equivalence conditions between R-STDP and policy gradient RL have not been derived for multi-layer spiking networks (only proven for single-layer in certain limits).", "Whether dopamine timing in biological circuits satisfies the mathematical requirements for policy gradient estimation (correct temporal credit assignment) has not been verified quantitatively.", "Whether R-STDP approximates actor-critic (vs. REINFORCE) algorithms when applied in networks with separate \"value\" cells has not been established." ], "suggested_hypotheses": [ "R-STDP implements a biologically plausible approximation of the proximal policy optimization (PPO) clipped objective when the reward signal is low-pass filtered with the time constant of dopamine clearance (~200ms)." ], "file": "unknowns-catalog/computer-science/u-stdp-reward-modulation-rl-equivalence.yaml" }, { "id": "u-swarm-intelligence-x-distributed-computing", "title": "What is the computational complexity of problems solvable by ant colony optimization, and can quorum sensing achieve Byzantine fault tolerance without central coordination?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "The worst-case runtime complexity of ACO for TSP and graph coloring as a function of pheromone evaporation rate and ant count has not been established theoretically", "Formal proof that honeybee quorum sensing satisfies Byzantine fault tolerance guarantees (correct decision with >2/3 honest scouts) has not been given", "Whether distributed biological algorithms can be provably optimal (achieve information-theoretic lower bounds) for any non-trivial distributed computing problem has not been established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-swarm-intelligence-x-distributed-computing.yaml" }, { "id": "u-synaptic-tag-cache-analogy-quantitative-test", "title": "Can any quantitative isomorphism be defended between synaptic-tag lifetimes and cache write-buffer flush intervals beyond metaphor for pedagogy?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Joint datasets pairing tagged synapse dwell-time distributions with neuromorphic hardware timing logs using comparable stimuli protocols (currently absent)", "Formal dynamical-system models proving isomorphism classes empty under stated assumptions" ], "suggested_hypotheses": [ "h-tag-decay-timescale-vs-write-buffer-lifetime-correlation-classroom-only" ], "file": "unknowns-catalog/computer-science/u-synaptic-tag-cache-analogy-quantitative-test.yaml" }, { "id": "u-transformer-attention-biological-plausibility", "title": "To what degree does the transformer self-attention mechanism replicate the computations performed by neural attention circuits in the primate visual cortex?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No quantitative comparison between transformer attention weight matrices and neural modulation patterns measured simultaneously with multi-electrode arrays in performing primates exists.", "Whether attention head specialisation in transformers mirrors the functional specialisation of cortical attention areas (V4, MT, FEF) is not tested.", "The temporal dynamics of neural attention (oscillations, saccadic resets at ~250 ms) have no counterpart in feedforward transformers and have not been addressed by recurrent transformer variants." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-transformer-attention-biological-plausibility.yaml" }, { "id": "u-transformer-scaling-law-limits", "title": "When and why do Chinchilla scaling laws break down, and what architectural innovations can improve compute efficiency beyond current scaling predictions?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Scaling laws for multimodal, embodied, and reinforcement learning models have not been established.", "The quality of training data (not just quantity) breaks scaling law predictions in ways not formalised.", "Whether architectural improvements can shift the compute-efficiency frontier beyond current predictions is not predictable." ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-transformer-scaling-law-limits.yaml" }, { "id": "u-unique-games-conjecture-sdp-approximation-tight-gap", "title": "Is the Unique Games Conjecture (UGC) true — i.e., does the Goemans-Williamson 0.878 approximation ratio for MAX-CUT represent an absolute computational barrier — and what is the true approximation ratio achievable in polynomial time if UGC is false?", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No proof of UGC is known; no refutation is known. After 20 years, the computational complexity community has made very limited progress on direct proof approaches.", "Sub-exponential algorithms (exp(n^ε)) for unique games exist, suggesting UGC hardness might require stronger assumptions; the relationship between UGC and quasi-polynomial hardness (ETH, QSETH) is not fully characterised.", "The \"Unique Games with expanding graphs\" variant is known to have polynomial algorithms; whether restricting unique games to non-expanding instances preserves the hardness gap needed for the SDP lower bound is unknown." ], "suggested_hypotheses": [ "UGC is false — there exists a polynomial-time algorithm achieving (0.878 + Ω(1))-approximation for MAX-CUT using a Sum-of-Squares SDP hierarchy of constant degree, exploiting the expanding structure of random instances and disproving the need for exponential hardness in UG.\n" ], "file": "unknowns-catalog/computer-science/u-unique-games-conjecture-sdp-approximation-tight-gap.yaml" }, { "id": "u-variational-inference-x-free-energy", "title": "What determines the expressiveness vs. computational cost trade-off for variational families in high-dimensional Bayesian inference, and how does it relate to free energy landscape topology?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "No general theory predicts when mean-field variational inference fails vs. succeeds based on properties of the target distribution's free energy landscape", "The connection between variational inference approximation error and thermodynamic free energy barriers (phase transitions in the posterior) is not quantified", "Renormalization group methods from statistical mechanics have not been systematically applied to design variational families that capture multi-scale correlations" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computer-science/u-variational-inference-x-free-energy.yaml" }, { "id": "u-wgan-gp-tightness-versus-exact-lipschitz-projections", "title": "How tightly do gradient-penalty WGAN critics approximate true 1-Lipschitz Kantorovich potentials on benchmark image manifolds compared with spectral normalization or exact orthogonal layers — measured with operator-norm audits during training?\n", "status": "open", "domain": "computer-science", "systematic_gaps": [ "Standardized evaluation suites reporting ‖∇f‖ statistics along real vs synthetic interpolants during collapse events", "Cross-architecture replication controlling dataset and optimizer noise" ], "suggested_hypotheses": [ "h-gradient-penalty-magnitude-tracks-dual-feasibility-proxy-metrics" ], "file": "unknowns-catalog/computer-science/u-wgan-gp-tightness-versus-exact-lipschitz-projections.yaml" }, { "id": "u-evolutionary-algorithms-replicator-dynamics", "title": "Do genetic and evolutionary algorithms converge via the continuous-time replicator dynamics of evolutionary game theory?", "status": "open", "domain": "computing", "systematic_gaps": [ "The replicator equation (Taylor & Jonker 1978) is the continuous-time limit of selection in evolutionary biology — no proof exists that standard GA selection (tournament, proportional) converges to the same fixed points", "cs.NE arXiv 2026: 'The working principles of model-based GAs fall within the PAC framework' analyzes GAs via PAC learning theory — but does not connect to replicator dynamics", "If EA convergence = replicator dynamics, then known results about Nash equilibria and ESS directly constrain GA solution stability: deceptive functions correspond to unstable Nash equilibria", "The Price equation (Price 1970) provides a general formulation of selection that applies to both biological evolution and GAs — but has not been used to analyze EA performance on combinatorial problems" ], "suggested_hypotheses": [], "file": "unknowns-catalog/computing/u-evolutionary-algorithms-replicator-dynamics.yaml" }, { "id": "u-grokking-criticality-universality-class", "title": "What is the universality class of the grokking phase transition, and does it match any known universality class in statistical physics?", "status": "open", "domain": "computing", "systematic_gaps": [ "Grokking has been characterized empirically (training loss, test accuracy, weight norms) but the critical exponents have not been measured systematically", "The 'Dimensional Criticality at Grokking' preprint (nlin:AO arXiv 2026) identifies a dimension-halving transition — but does not compute critical exponents delta, nu, beta", "If grokking belongs to the 2D Ising universality class, predictions follow: finite-size scaling, divergent susceptibility, data-collapse — none of these have been tested", "Different tasks that exhibit grokking (modular arithmetic, permutation groups, sparse parities) may belong to different universality classes — not yet tested", "The relationship between the universality class and the inductive bias of the architecture (MLP vs. Transformer vs. CNN) is completely open" ], "suggested_hypotheses": [ "h-grokking-criticality-universality" ], "file": "unknowns-catalog/computing/u-grokking-criticality-universality-class.yaml" }, { "id": "u-stdp-criticality-mechanism", "title": "Is spike-timing-dependent plasticity (STDP) the biological mechanism by which cortical networks self-organize to the SOC critical point?", "status": "open", "domain": "computing", "systematic_gaps": [ "STDP is known to regulate synaptic weights based on the relative timing of pre- and post-synaptic spikes — but no theory explicitly proves it drives the network to the SOC fixed point", "Computational models (Levina et al. 2007 Nat Phys) show that short-term synaptic depression can drive criticality in spiking networks — but STDP (the actual biological rule) has not been shown to do the same analytically", "Recent cs.NE work (Reward-Modulated STDP, arXiv:2603.x) shows STDP + reward modulation achieves stable coding — but the avalanche statistics were not measured", "If STDP → SOC, then disrupting STDP (as in NMDA-receptor hypofunction in schizophrenia) should shift the network subcritical — testable prediction that has not been systematically evaluated" ], "suggested_hypotheses": [ "h-criticality-conscious-integration" ], "file": "unknowns-catalog/computing/u-stdp-criticality-mechanism.yaml" }, { "id": "u-magnons-collective-excitations", "title": "How do magnon-magnon and magnon-phonon interactions lead to non-trivial magnon lifetime and thermal conductivity in magnon-polaronic systems, and can these be engineered for spin caloritronics?", "status": "open", "domain": "condensed-matter", "systematic_gaps": [ "The four-magnon scattering rate as a function of temperature has been measured in few systems (YIG) and not systematically compared to theoretical predictions from spin-wave theory.", "The magnon-polaron contribution to spin Seebeck effect has been confirmed but the optimal material design rules (exchange stiffness, magnetoelastic coupling strength) are not established.", "Whether topological magnon bands (magnon Hall effect) can survive magnon-phonon scattering at experimentally accessible temperatures is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/condensed-matter/u-magnons-collective-excitations.yaml" }, { "id": "u-symmetry-breaking-goldstone", "title": "In non-relativistic condensed matter systems, why does the Nielsen-Chadha theorem allow fewer Goldstone bosons than broken generators, and what is the physical meaning of type-II (quadratic dispersion) Goldstone modes?", "status": "open", "domain": "condensed-matter", "systematic_gaps": [ "A systematic classification of all symmetry-breaking patterns in experimentally relevant condensed matter systems (superconductors, liquid crystals, antiferromagnets) by Goldstone mode count and type has not been compiled.", "Whether topological protection can prevent the acquisition of a gap by type-II Goldstone modes under perturbations that break the symmetry partially is unknown.", "The effective field theory of Goldstone modes in active matter (where time-reversal is broken by activity) is not fully established; active Goldstone bosons may have exotic dispersion not covered by Nielsen-Chadha." ], "suggested_hypotheses": [], "file": "unknowns-catalog/condensed-matter/u-symmetry-breaking-goldstone.yaml" }, { "id": "u-topological-insulator-surface-state-interactions", "title": "How do electron-electron interactions and disorder modify topological surface states in real topological insulators beyond the free-fermion Z2 classification?", "status": "open", "domain": "condensed-matter", "systematic_gaps": [ "No experimental demonstration of an interacting topological insulator phase beyond the free-fermion paradigm", "Cobordism classification of interacting SPT phases is mathematically complete but predictions are untested", "Magnetic topological insulators (MnBi2Te4) show complex behavior not captured by Z2 invariants alone" ], "suggested_hypotheses": [], "file": "unknowns-catalog/condensed-matter/u-topological-insulator-surface-state-interactions.yaml" }, { "id": "u-symplectic-discretization-bias-long-horizon-control", "title": "How much long-horizon policy bias is attributable to non-symplectic discretization in mechanics-dominated control tasks?", "status": "open", "domain": "control-engineering", "systematic_gaps": [ "Benchmarks rarely isolate integrator-induced bias from optimizer and model errors.", "Invariant-drift metrics are inconsistently reported in control algorithm comparisons.", "Sensitivity to actuator saturation and contact events under symplectic schemes is not well characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/control-engineering/u-symplectic-discretization-bias-long-horizon-control.yaml" }, { "id": "u-inflation-epidemic-analogy-falsifiability-limits", "title": "What empirical predictions — if any — could ever falsify informal inflation–epidemic exponential metaphors without trivializing either discipline’s validated models?", "status": "open", "domain": "cosmology", "systematic_gaps": [ "Scholarly ethics guidelines specifically discouraging inflation–disease metaphors during active public-health crises absent rigorous mathematical linkage", "Philosophical taxonomy separating pedagogical phase-plane similarity from causal claims" ], "suggested_hypotheses": [ "h-shared-tangent-field-exponential-region-only-logarithmic-visual-overlap" ], "file": "unknowns-catalog/cosmology/u-inflation-epidemic-analogy-falsifiability-limits.yaml" }, { "id": "u-inflation-slow-roll-end-reheating-mechanism", "title": "What mechanism ends slow-roll inflation and efficiently converts inflaton energy into the Standard Model particles of the hot Big Bang (reheating), and what observational signatures distinguish different reheating scenarios?\n", "status": "open", "domain": "cosmology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/cosmology/u-inflation-slow-roll-end-reheating-mechanism.yaml" }, { "id": "u-embedding-dimension-selection-for-icu-trajectory-instability-detection", "title": "What failure boundaries determine when `b-delay-embedding-x-icu-deterioration-early-warning` remains decision-useful?", "status": "open", "domain": "critical-care", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-delay-embedding-indicators-improve-icu-deterioration-lead-time" ], "file": "unknowns-catalog/critical-care/u-embedding-dimension-selection-for-icu-trajectory-instability-detection.yaml" }, { "id": "u-missingness-aware-lstm-training-for-icu-forecasts", "title": "Which missingness models are required for safe deployment of `b-lstm-sequence-memory-x-icu-physiology-forecasting`?", "status": "open", "domain": "critical-care", "systematic_gaps": [ "Missingness mechanisms are rarely validated against actual bedside workflows.", "External validation under changing monitoring practices is limited." ], "suggested_hypotheses": [ "h-missingness-augmented-lstm-models-improve-icu-decompensation-horizon-accuracy" ], "file": "unknowns-catalog/critical-care/u-missingness-aware-lstm-training-for-icu-forecasts.yaml" }, { "id": "u-neural-cde-icu-robustness-to-missingness-patterns", "title": "How robust are neural CDE ICU forecasts to clinically realistic, nonrandom missingness patterns?", "status": "open", "domain": "critical-care", "systematic_gaps": [ "Benchmarks rarely separate random dropout from workflow-driven missingness.", "Lead-time gains are underreported relative to false-alarm burden.", "Few studies test calibration drift after unit-level protocol changes." ], "suggested_hypotheses": [ "h-neural-cde-models-improve-icu-event-lead-time" ], "file": "unknowns-catalog/critical-care/u-neural-cde-icu-robustness-to-missingness-patterns.yaml" }, { "id": "u-qkd-practical-implementation-side-channels", "title": "Can quantum key distribution systems achieve information-theoretic security in practice when realistic detector and source imperfections create side-channel vulnerabilities not covered by idealized security proofs?", "status": "open", "domain": "cryptography", "systematic_gaps": [ "No systematic security evaluation framework covers all known side-channel attack vectors for QKD hardware", "DI-QKD has only been demonstrated at short distances (<500 m) due to detection efficiency requirements", "The key rate-distance tradeoff for QKD in real fiber networks with finite-key security bounds is not optimized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/cryptography/u-qkd-practical-implementation-side-channels.yaml" }, { "id": "u-axelrod-model-empirical-validation-cultural-diversity", "title": "Has the Axelrod cultural dissemination model ever been empirically validated against real-world cultural diversity data ΓÇö what observable predictions does the phase transition make about cultural boundary formation, and which datasets could test them?\n", "status": "open", "domain": "cultural-dynamics", "systematic_gaps": [ "Empirical mapping of cultural diversity data (World Values Survey, ethnolinguistic fractionalization indices) onto the Axelrod model's (F, q) parameter space has not been attempted systematically.", "The model's prediction that network topology (scale-free vs. lattice) changes the phase transition location has not been tested against real social network data.", "Time series of cultural change at the country/region level have not been analyzed for signatures of the Axelrod phase transition (boundary formation, frozen states)." ], "suggested_hypotheses": [], "file": "unknowns-catalog/cultural-dynamics/u-axelrod-model-empirical-validation-cultural-diversity.yaml" }, { "id": "u-optimal-cybersecurity-investment-under-adversarial-uncertainty", "title": "What is the optimal cybersecurity investment strategy for an organization under adversarial uncertainty — when the attacker's capabilities, objectives, and rationality are unknown and the defender cannot observe the true threat landscape?\n", "status": "open", "domain": "cybersecurity", "systematic_gaps": [ "No empirical validation of whether real-world security investment levels match any game-theoretic equilibrium prediction.", "The security production function (probability of breach as a function of investment level) has not been estimated empirically from breach data at scale.", "Multi-organization interdependence (security externalities, contagion) is theoretically modeled but not empirically estimated for specific sectors." ], "suggested_hypotheses": [], "file": "unknowns-catalog/cybersecurity/u-optimal-cybersecurity-investment-under-adversarial-uncertainty.yaml" }, { "id": "u-gyrification-mechanics-developmental-timing", "title": "What determines the timing, location, and degree of cortical gyrification (brain folding) during development, and can mechanical models predict individual variation in sulcal patterns?", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "No model predicts individual sulcal variability from developmental parameters", "The relative contribution of tangential growth vs. axonal tension is not quantified", "The critical period during which folding pattern is determined is not established" ], "suggested_hypotheses": [ "Cortical thickness at the beginning of the third trimester determines gyrification index through a elastic buckling wavelength scaling as (E_cortex/E_subcortex)^1/3 × thickness" ], "file": "unknowns-catalog/developmental-biology/u-gyrification-mechanics-developmental-timing.yaml" }, { "id": "u-morphogen-gradient-robustness-scaling", "title": "How do morphogen gradient systems achieve robustness against noise and scaling with organism size, when the diffusion-based gradient length √(D/k) is fixed by biochemical constants?", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "The mechanism of Bicoid gradient scaling with embryo length in different Drosophila species is not resolved quantitatively.", "The noise buffering mechanism that reduces positional error below the single-molecule diffusion limit has not been identified.", "Whether robustness and scaling use the same molecular mechanism or different ones is unknown.", "Quantitative predictions connecting gradient noise to cell fate boundary sharpness are not experimentally tested across multiple systems." ], "suggested_hypotheses": [ "Morphogen gradient scaling in Drosophila is achieved through feedback regulation of the Bicoid synthesis rate by a posterior-derived inhibitor that reports embryo length." ], "file": "unknowns-catalog/developmental-biology/u-morphogen-gradient-robustness-scaling.yaml" }, { "id": "u-topological-defect-morphogenesis-3d-tissue", "title": "Do topological defects in three-dimensional active nematic tissues drive morphogenetic events such as lumen formation, tube branching, and organ folding in developing embryos, and can Q-tensor simulations parameterized by single-cell imaging predict tissue shape outcomes quantitatively?\n", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "No live-imaging study has tracked 3D nematic topological defects through a complete morphogenetic event (e.g., neural tube closure, organoid lumenogenesis) with simultaneous cell fate and mechanical force measurements.", "Q-tensor continuum models of 3D active nematics have not been parameterized from experimental data for any developing tissue; all existing simulations use synthetic parameter regimes.", "The role of tissue curvature feedback on defect dynamics (curved surfaces impose topological constraints) has been studied theoretically but not experimentally in vivo." ], "suggested_hypotheses": [], "file": "unknowns-catalog/developmental-biology/u-topological-defect-morphogenesis-3d-tissue.yaml" }, { "id": "u-turing-morphogen-identity-in-vivo-diffusion-measurement", "title": "What are the directly measured in vivo diffusion coefficients D_A and D_I for proposed Turing activator-inhibitor pairs (Sox9/BMP in digit spacing; melanophore/ xanthophore signals in zebrafish), and do these satisfy the Turing instability condition D_I/D_A > f_A²/(4 det J) with independently measured reaction kinetics?\n", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "In vivo FRAP / FCS / single-particle tracking of candidate Turing morphogens in developing zebrafish skin and mouse limb buds at single-cell resolution has not been published with sufficient sample sizes for statistical quantification of D_A and D_I.", "The Turing reaction kinetics (∂F/∂A at steady state = f_A; det J) have not been measured by quantitative phosphoproteomics or optogenetic perturbation in the same developmental system where pattern wavelength was measured.", "Synthetic Turing circuits in mammalian cells (enabling controlled D_A, D_I, f_A measurements) have been built in bacteria (E. coli) but not in cell types relevant to mammalian development." ], "suggested_hypotheses": [ "The effective in vivo diffusion ratio D_I/D_A for the BMP (inhibitor) / Sox9 downstream FGF signal (activator) in mouse limb buds is ≥ 10, satisfying the Turing condition; measurement via fluorescently-tagged BMP2 and FGF8 FRAP in organoid limb-patterning systems will confirm the condition and predict digit wavelength to within 20% using independently measured reaction rates.\n" ], "file": "unknowns-catalog/developmental-biology/u-turing-morphogen-identity-in-vivo-diffusion-measurement.yaml" }, { "id": "u-turing-patterning-3d-robustness", "title": "How do Turing reaction-diffusion mechanisms maintain robust spatial patterning in three-dimensional growing tissues despite molecular noise, geometric constraints, and cell division?", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "In vivo diffusion coefficients of key morphogens measured by FRAP are highly variable and may not satisfy Turing instability conditions", "The coupling between tissue mechanics (growth, folding) and RD pattern formation is not captured by current Turing models", "Large-scale validation of Turing predictions across species and body plans has not been performed" ], "suggested_hypotheses": [], "file": "unknowns-catalog/developmental-biology/u-turing-patterning-3d-robustness.yaml" }, { "id": "u-waddington-canalization-mechanism", "title": "What molecular and network-level mechanisms implement developmental canalization — the robustness of cell fate specification against genetic and environmental perturbations — and can the Waddington landscape topology be quantitatively reconstructed from single-cell transcriptomic data?", "status": "open", "domain": "developmental-biology", "systematic_gaps": [ "Single-cell RNA-seq captures a snapshot of expression states but cannot directly measure the vector field F(X) driving dynamics", "Noise levels in gene expression vary between cells and cell cycle stages, making it difficult to separate stochastic noise from deterministic attractor dynamics", "The high dimensionality of gene expression space (>20,000 genes) makes attractor identification computationally intractable without strong dimensionality reduction" ], "suggested_hypotheses": [], "file": "unknowns-catalog/developmental-biology/u-waddington-canalization-mechanism.yaml" }, { "id": "u-allelopathy-invasive-plant-mycorrhizal-disruption", "title": "What is the quantitative relationship between invasive plant allelochemical concentration in soil and the degree of mycorrhizal network disruption, and can mycorrhizal inoculation or rhizobacterial biofilms restore native plant competitive ability against allelopathic invaders?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "No full dose-response curve for isothiocyanate → AMF colonisation inhibition across ecologically relevant soil types and AMF species.", "Field-scale mycorrhizal network disruption by garlic mustard has been hypothesised but not directly measured using isotope tracer or eDNA methods.", "Restoration experiments using isothiocyanate-degrading rhizobacteria have not been published in peer-reviewed literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-allelopathy-invasive-plant-mycorrhizal-disruption.yaml" }, { "id": "u-bef-relationship-agricultural-context", "title": "How does the biodiversity-ecosystem function relationship differ between natural and agricultural ecosystems, and at what minimum biodiversity level do ecosystem services collapse in intensively managed farmland?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Large-scale agricultural BEF experiments are rare; most evidence comes from natural grasslands", "The role of functional diversity vs. species richness in agricultural BEF is contested", "Landscape context (surrounding habitat) modifies local BEF but is not captured in field-scale models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-bef-relationship-agricultural-context.yaml" }, { "id": "u-bet-hedging-correlation-structure-across-taxa", "title": "How empirically structured are environmental covariance tensors governing bet hedging versus portfolio analogies across marine vs terrestrial vs microbial taxa?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Sparse long-term datasets coupling demographic variance decomposition with climate modes across replicate populations", "Microbial laboratory evolution studies measuring geometric mean fitness without field correlation structure" ], "suggested_hypotheses": [ "h-bet-hedging-x-portfolio-diversification" ], "file": "unknowns-catalog/ecology/u-bet-hedging-correlation-structure-across-taxa.yaml" }, { "id": "u-biodiversity-productivity-relationship", "title": "Is the biodiversity-ecosystem productivity relationship hump-shaped, monotonic, or context-dependent — and what mechanism drives the relationship?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Whether the diversity-productivity relationship is monotonic or hump-shaped depends on spatial scale in ways not yet predicted", "The relative contribution of complementarity vs. selection effects cannot be separated without trait data", "Whether the relationship reverses direction at very high productivity (eutrophication) is contested" ], "suggested_hypotheses": [ "At spatial scales where environmental heterogeneity exceeds typical species' niche breadths, the BEF relationship is monotonically positive; at smaller homogeneous scales, selection effects dominate and the relationship is flat" ], "file": "unknowns-catalog/ecology/u-biodiversity-productivity-relationship.yaml" }, { "id": "u-control-lyapunov-safe-harvest-policy-ecology", "title": "Can control-Lyapunov and barrier constraints produce practically enforceable harvest policies that improve ecological resilience?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Few empirical evaluations compare certificate-based control policies against incumbent rule-based quotas.", "Data assimilation uncertainty is rarely propagated through stability guarantees.", "Governance and enforcement frictions are not integrated into control feasibility analyses." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-control-lyapunov-safe-harvest-policy-ecology.yaml" }, { "id": "u-coral-bleaching-thermal-stress", "title": "What is the molecular mechanism by which Symbiodiniaceae clade D confers ~1-2°C higher thermal tolerance to coral hosts, and can this tolerance be transferred to bleaching-susceptible clades via synthetic biology?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Comparative transcriptomics of clade D vs. clade C under heat stress has identified candidate tolerance genes but none have been functionally validated by knockout/overexpression.", "The thermotolerance-photosynthesis tradeoff has not been quantified across a wide enough panel of Symbiodiniaceae strains to establish whether all high-tolerance strains pay the same growth cost.", "Assisted evolution protocols for producing CITES-compliant, field-deployable thermotolerant symbionts have not been developed or regulated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-coral-bleaching-thermal-stress.yaml" }, { "id": "u-digital-commons-governance-principles", "title": "Do Ostrom's eight design principles for sustainable common pool resource governance apply to digital commons (open-source software, Wikipedia, scientific data repositories), and what adaptations are required?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No large-scale quantitative study has systematically coded Ostrom's eight principles across hundreds of open-source projects and correlated them with sustainability outcomes.", "Digital commons governance often lacks graduated sanctions — banning is all-or-nothing, unlike Ostrom's graduated fines.", "The interaction between open-source governance and commercial appropriation (companies free-riding on open-source) has no clear analog in physical CPR governance." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-digital-commons-governance-principles.yaml" }, { "id": "u-dryland-vegetation-pattern-formation", "title": "What determines the wavelength, orientation, and stability of dryland vegetation patterns (bands, spots, gaps) predicted by the Klausmeier model, and can remote sensing of pattern geometry be used to infer soil hydraulic properties and proximity to desertification tipping points?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Ground-truth measurements of soil water diffusivity and root-zone hydraulic conductivity in remote dryland sites are sparse", "Long time series of vegetation pattern change in the same location are rare; most pattern observations are single snapshots", "Three-dimensional soil structure (crusting, bioturbation) modifies the 2D Klausmeier predictions in ways not formally incorporated" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-dryland-vegetation-pattern-formation.yaml" }, { "id": "u-ecological-succession-x-markov", "title": "Is ecological succession in real ecosystems well-approximated by a time-homogeneous Markov chain (transition probabilities constant over time), or do climate trends, soil development, and species introductions create non-stationary transition matrices that invalidate climax community predictions?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No long-term dataset (>100 years) with regular censusing has tested Markovianity of forest succession at the community level", "Soil carbon and nitrogen dynamics create ecological memory that violates the Markov assumption; no formal test has been applied", "Non-stationary Markov succession models have not been fitted to climate-envelope-adjusted transition matrices for any major biome" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-ecological-succession-x-markov.yaml" }, { "id": "u-ecology-x-coexistence-theory", "title": "Can the storage effect quantitatively predict biodiversity loss under climate change (reduced temporal variance and altered autocorrelation) in empirical plant communities, and is the stabilising niche difference measurable in situ?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Empirical measurements of MCT parameters (Δi, ηi) in real communities are available for fewer than 20 species pairs", "Whether the storage effect is sufficient to maintain diversity under projected climate change autocorrelation shifts is unquantified", "MCT assumes stable coexistence but most natural communities are in non-equilibrium transient states" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-ecology-x-coexistence-theory.yaml" }, { "id": "u-ecosystem-engineer-legacy-effects", "title": "Do ecosystem engineers (beavers, elephants, earthworms) leave persistent legacy effects detectable centuries after their removal, and can these legacies be quantified from soil and sediment records?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No universal model predicts engineer legacy persistence time from species traits", "Paleoecological records of engineer legacies are sparse and rarely quantitatively analyzed", "Whether reintroduced engineers can activate dormant legacies (dormant seeds, preserved sediments) has not been tested experimentally" ], "suggested_hypotheses": [ "Ecosystem engineer legacy persistence time (years) scales as body_mass^{0.5} * legacy_intensity / disturbance_rate, giving beavers ~50-200 year legacies and elephants ~200-500 year legacies" ], "file": "unknowns-catalog/ecology/u-ecosystem-engineer-legacy-effects.yaml" }, { "id": "u-ecosystem-services-valuation-market-failure", "title": "Can ecosystem service valuations be made precise enough to design efficient Pigouvian taxes and subsidies for biodiversity conservation, and what institutional mechanisms can internalize natural capital into market decisions at the required scale?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Spatially explicit, high-resolution (< 1 km²) ecosystem service maps that are sufficiently accurate for individual land-use decisions do not exist for most biomes — InVEST and other tools produce estimates with 50-100% uncertainty that cannot support defensible Pigouvian tax calculations.", "The dynamic externality from biodiversity loss (future option value of unknown species, genetic resources, ecosystem function insurance) has not been quantified using option-pricing theory or real options analysis despite the formal equivalence to financial option valuation.", "International payment mechanisms for transboundary ecosystem services (coral reefs, migratory species, atmospheric CO₂ sequestration) lack enforcement mechanisms and suffer from free-rider problems that pure Pigouvian analysis does not resolve." ], "suggested_hypotheses": [ "Biodiversity credits using satellite-verified species occupancy indices (analogous to carbon MRV — Measurement, Reporting, Verification) can achieve additionality and permanence standards comparable to carbon markets within 5 years of methodological standardization, enabling $50B/year of ecosystem service payments by 2035." ], "file": "unknowns-catalog/ecology/u-ecosystem-services-valuation-market-failure.yaml" }, { "id": "u-ecosystem-tipping-point-early-warning-false-positive-rate", "title": "What is the false positive rate of critical slowing down early warning signals (rising variance and AR(1)) for ecosystem tipping points, and under what conditions do EWS fail to detect impending fold bifurcations in ecological time series?", "status": "open", "domain": "ecology", "systematic_gaps": [ "A systematic meta-analysis of EWS performance (AUC, sensitivity, specificity) across all published empirical ecosystem transitions has not been conducted with standardised methods; existing meta-analyses have methodological inconsistencies.", "The statistical power of standard EWS tests (Kendall's τ on variance and AR(1) trend) as a function of time series length, noise level, and distance to bifurcation has not been fully characterised analytically; only Monte Carlo results exist for specific model systems.", "Methods to distinguish CSD from non-bifurcation EWS mimics (non-stationarity, stochastic transitions) using only the observed time series have not been validated in field datasets." ], "suggested_hypotheses": [ "For typical ecological monitoring time series (≤ 50 years, annual resolution), standard CSD EWS have true positive rate < 0.6 and false positive rate > 0.3, making them insufficient for management decisions without supplementary mechanistic modelling." ], "file": "unknowns-catalog/ecology/u-ecosystem-tipping-point-early-warning-false-positive-rate.yaml" }, { "id": "u-environmental-justice-cumulative-impact-assessment-methodology", "title": "What is the appropriate methodology for cumulative environmental impact assessment in environmental justice contexts — how should multiple simultaneous burdens (air pollution, noise, flooding, heat, food access, healthcare) be combined into a single index that supports regulatory action without masking within-population heterogeneity?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Causal inference methods (instrumental variables, difference-in-differences) for estimating the health burden attributable to environmental injustice specifically (controlling for correlated socioeconomic factors).", "Longitudinal EJ index validation: does a high index score predict future health outcomes after controlling for baseline health and SES?", "Bayesian hierarchical models for small-area EJ estimation that propagate measurement uncertainty and borrow strength across geographic units.", "Community-based participatory research on which burdens affected communities prioritize — necessary for legitimate index construction." ], "suggested_hypotheses": [ "CalEnviroScreen and EPA EJScreen will rank census tracts in the same quintile in <60% of cases when applied to the same geographic area, demonstrating that current cumulative impact methodology differences are too large for the indices to serve as consistent regulatory standards without harmonization.\n" ], "file": "unknowns-catalog/ecology/u-environmental-justice-cumulative-impact-assessment-methodology.yaml" }, { "id": "u-ess-higher-order-interactions-ecosystem", "title": "How do higher-order (non-pairwise) ecological interactions — where the effect of species A on B depends on the presence of species C — modify the predictions of evolutionarily stable strategy theory and replicator dynamics for ecosystem stability and biodiversity?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Empirical quantification of HOI magnitudes across diverse ecosystem types", "Mathematical theory of ESS for tensor (multi-player) payoff structures", "Extension of replicator dynamics to include n-player games", "Computational methods for finding ESS in high-dimensional strategy spaces" ], "suggested_hypotheses": [ "h-cyclic-dominance-spatial-heterogeneity-biodiversity" ], "file": "unknowns-catalog/ecology/u-ess-higher-order-interactions-ecosystem.yaml" }, { "id": "u-fire-regime-ecological-threshold", "title": "What determines fire regime thresholds in different ecosystems, and at what fuel load and climate conditions do ecosystems cross from fire-maintained to fire-transformed states?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The fuel accumulation rate and moisture deficit required for threshold transitions are ecosystem-specific and not generalised.", "Feedback between fire, vegetation, and soil carbon alters fire regimes in ways that create non-linear dynamics not included in vegetation models.", "Human fire suppression and prescribed burning interact with climate drivers in ways that are not predictable from physical models alone." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-fire-regime-ecological-threshold.yaml" }, { "id": "u-forest-canopy-clumping-beer-lambert-deviation", "title": "How much does leaf spatial clumping cause real forest canopies to deviate from Beer-Lambert exponential light extinction, and can this deviation be predicted from stand structure parameters alone?\n", "status": "open", "domain": "ecology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-forest-canopy-clumping-beer-lambert-deviation.yaml" }, { "id": "u-forest-fire-soc-climate-change-modification", "title": "How does climate-change-driven drought and fuel accumulation modify the power-law exponent of forest fire size distributions, and is the SOC critical state preserved or destroyed under extreme warming scenarios?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Time-series analysis of fire-size power-law exponents before and after major drought events has not been performed systematically across multiple biomes.", "Theoretical models of how increased fuel dryness (reduced ignition threshold) shifts the SOC critical point have not been developed for the Drossel-Schwabl model.", "Whether fire suppression policies combined with climate change create a sub-critical state with anomalously large eventual fires exceeds SOC power-law predictions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-forest-fire-soc-climate-change-modification.yaml" }, { "id": "u-gap-recruitment-neutral-theory-goodness-of-fit", "title": "Across temperate and tropical forests with mapped canopy gaps, when does neutral biodiversity theory provide statistically adequate fits to species-abundance distributions in gap recruits compared with niche-structured hierarchical models that include trait covariates?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Joint datasets linking gap-age, dispersal distances, and genomic pedigree inference for recruits", "Cross-biome replication controlling for logging legacies" ], "suggested_hypotheses": [ "h-neutral-theta-estimates-converge-pre-post-gap-chronosequence" ], "file": "unknowns-catalog/ecology/u-gap-recruitment-neutral-theory-goodness-of-fit.yaml" }, { "id": "u-gut-brain-axis-causal-mechanism", "title": "What are the quantitative causal mechanisms by which specific gut microbial taxa and their metabolites (SCFAs, tryptophan metabolites, LPS) modulate brain function and behavior, and can these mechanisms explain the microbiome-depression correlation?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Quantitative dose-response relationships between specific SCFA concentrations in portal blood and brain gene expression changes", "Whether vagus nerve or blood-borne metabolites are the dominant route for microbiome-to-brain signaling", "Identification of the specific gut taxa whose depletion causally predicts depression onset (not just correlation)", "Mechanism by which stress-induced sympathetic activation alters gut microbiome composition (brain→gut causality)" ], "suggested_hypotheses": [ "h-microbiome-diversity-host-resilience" ], "file": "unknowns-catalog/ecology/u-gut-brain-axis-causal-mechanism.yaml" }, { "id": "u-intermediate-disturbance-diversity-peak", "title": "Under what community composition, disturbance type, and spatial scale conditions does the Intermediate Disturbance Hypothesis correctly predict a diversity peak, and what ecological mechanisms cause the IDH to fail in communities where competitive exclusion timescales are much shorter than disturbance return intervals?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Most IDH tests measure one community at one time without manipulating disturbance frequency and intensity independently", "The IDH was developed for tropical forests and coral reefs; its applicability to grasslands, alpine meadows, and microbiomes is untested", "Competition-colonization tradeoffs are rarely measured directly; their existence is inferred from relative abundance patterns" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-intermediate-disturbance-diversity-peak.yaml" }, { "id": "u-invasive-species-reaction-diffusion", "title": "When do Allee effects make invasion fronts 'pushed' rather than 'pulled', and how does the transition between these regimes affect management control point placement?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The critical Allee strength at which an invasion transitions from pulled to pushed has not been calibrated against empirical invasion datasets.", "Optimal control of pushed vs. pulled fronts (placement of culling effort) has not been analyzed under budget constraints in realistic heterogeneous landscapes.", "Detecting Allee effects in time series data for established invasions is confounded by demographic stochasticity and spatial heterogeneity." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-invasive-species-reaction-diffusion.yaml" }, { "id": "u-invasive-species-threshold", "title": "Is there a universal population density threshold above which invasive species become impossible to eradicate, and what biological traits determine this threshold?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No universal formula predicts eradication threshold from species traits and habitat connectivity", "Whether invasion percolation dynamics match ecological data across >10 taxa has not been tested", "The role of spatial heterogeneity (refugia, corridors) in determining effective percolation threshold is unquantified" ], "suggested_hypotheses": [ "Invasive species eradication becomes impossible when population connectivity exceeds the percolation threshold: the critical patch occupancy fraction p_c is predictable from dispersal distance / habitat patch size using mean-field percolation theory" ], "file": "unknowns-catalog/ecology/u-invasive-species-threshold.yaml" }, { "id": "u-keystone-species-identification", "title": "Can keystone species be identified from food web structure and interaction strengths before their removal, or only recognized retrospectively?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No food web structural signature reliably predicts keystoneness prospectively across ecosystems", "Whether keystoneness is stable across environmental perturbations or context-dependent is unknown", "The relationship between keystoneness and species rarity, body size, or trophic position lacks a unified theory" ], "suggested_hypotheses": [ "Keystone species occupy high-centrality positions in the mutualism network (not just the predation network), predictable from plant-pollinator + plant-herbivore combined food web centrality measures with >80% retrospective accuracy" ], "file": "unknowns-catalog/ecology/u-keystone-species-identification.yaml" }, { "id": "u-lcs-retention-coastal-recruitment-transfer", "title": "How often do Lagrangian coherent-structure retention metrics outperform simpler Eulerian frontal indices for predicting coastal larval settlement when species-specific vertical migration and mortality are included?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Paired settlement surveys + high-resolution circulation ensembles with species-specific PLD priors for rigorous skill scoring.", "Standardized metrics comparing LCS-based retention integrals to alongshore distance-based proxies across ecosystems." ], "suggested_hypotheses": [ "h-ftle-ridge-threshold-correlates-larval-retention-proxy" ], "file": "unknowns-catalog/ecology/u-lcs-retention-coastal-recruitment-transfer.yaml" }, { "id": "u-lotka-volterra-hamiltonian-real-ecosystem-conservation", "title": "Is the Lotka-Volterra Hamiltonian approximately conserved in real predator- prey systems over ecologically relevant timescales, and how quickly does the conservation break down under realistic ecological perturbations?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "High-resolution experimental predator-prey microcosm data for testing H conservation is rare", "Perturbation expansion around Lotka-Volterra Hamiltonian with logistic correction has not been computed", "KAM-like stability analysis for ecological Hamiltonian has not been applied" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-lotka-volterra-hamiltonian-real-ecosystem-conservation.yaml" }, { "id": "u-lyme-ohio-surveillance-gap", "title": "What is the true epidemiological landscape of Lyme disease in Ohio and the Great Lakes region, and how does Scioto River watershed tick habitat connect to human exposure risk — given that passive surveillance captures only ~10% of actual cases?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "No systematic active tick surveillance (drag-cloth sampling for nymph density + Borrelia infection rate) has been conducted across the Scioto River watershed, Hocking Hills, or Wayne National Forest areas", "Ohio Department of Health Lyme disease case counts are not corrected for the ~10x underreporting factor, leading to systematically underestimated true incidence", "Deer population density maps (from ODNR) have not been spatially integrated with tick habitat suitability models for southeastern Ohio", "Climate projections (IPCC AR6) for tick habitat expansion have not been downscaled to Ohio county-level resolution for public health planning", "No patient-level survey study has been conducted in Ohio to estimate the proportion of Lyme-consistent illness that is not diagnosed or attributed to Lyme disease" ], "suggested_hypotheses": [ "h-ohio-lyme-deer-management-intervention" ], "file": "unknowns-catalog/ecology/u-lyme-ohio-surveillance-gap.yaml" }, { "id": "u-maxent-species-abundance-prediction", "title": "Can maximum entropy (MaxEnt) models reliably predict species abundance distributions and community structure from macroecological constraints alone?", "status": "open", "domain": "ecology", "systematic_gaps": [ "METE's predictive accuracy across biome types, taxonomic groups, and disturbance gradients has not been comprehensively tested with consistent methodology.", "No formal theory identifies which additional ecological constraints (trait distributions, phylogeny, spatial structure) should be added to MaxEnt for non-equilibrium communities.", "The relationship between the METE equilibrium assumption and successional dynamics (time to reach 'ecological equilibrium') has not been measured." ], "suggested_hypotheses": [ "h-hill-numbers-unify-diversity-indices" ], "file": "unknowns-catalog/ecology/u-maxent-species-abundance-prediction.yaml" }, { "id": "u-maxent-species-range-shift-climate", "title": "Can MaxEnt species distribution models accurately predict range shifts under climate change, and what are the limits of their out-of-sample extrapolation?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Retrospective validation of MaxEnt range projections against observed post-projection species occurrences has not been systematically conducted across taxa.", "Methods for quantifying extrapolation uncertainty (outside the convex hull of training climatic space) do not give calibrated coverage guarantees for species range shifts.", "The non-stationarity of the species-environment relationship under rapid climate change (phenotypic plasticity, rapid evolution, community reassembly) is not incorporated in standard MaxEnt models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-maxent-species-range-shift-climate.yaml" }, { "id": "u-metabolic-scaling-exponent-deviation-extremes", "title": "Under what environmental or physiological conditions do metabolic scaling exponents deviate significantly from 3/4, and can deviations be predicted from first principles?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Metabolic scaling in unicellular eukaryotes spans exponents from 0.6-1.0 without clear mechanistic explanation", "The temperature correction has been measured primarily in endotherms; ectotherm activation energies show higher variance", "Ecosystem-level tests of MTE predictions require long-term flux tower data rarely linked to individual organism physiology" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-metabolic-scaling-exponent-deviation-extremes.yaml" }, { "id": "u-metacommunity-dispersal-diversity", "title": "How does dispersal rate interact with local and regional processes to determine metacommunity diversity, and when does dispersal enhance versus homogenise communities?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Estimating actual dispersal rates in natural metacommunities is methodologically very difficult; most tests use proxies.", "The metacommunity theory framework assumes fixed environments; climate change dynamically alters dispersal-diversity relationships in unmodelled ways.", "Different metacommunity paradigms (species sorting, patch dynamics, mass effects, neutral) make similar predictions in many scenarios; distinguishing them requires data not typically collected." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-metacommunity-dispersal-diversity.yaml" }, { "id": "u-mutualism-network-robustness", "title": "Are mutualistic networks (plant-pollinator, plant-seed disperser) more robust to species loss than random networks, and does nestedness or modularity drive this robustness?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The relative contributions of nestedness vs. modularity to robustness are not separable in empirical networks", "Whether robustness predictions from network models hold in real-world extinction sequences is not tested", "How climate change-induced phenological mismatches affect nestedness and hence robustness is unknown" ], "suggested_hypotheses": [ "Pollination networks are more nested than seed-dispersal networks because pollen specialization costs are lower, and this nestedness predicts 2x greater robustness to random species loss in pollination vs. dispersal networks" ], "file": "unknowns-catalog/ecology/u-mutualism-network-robustness.yaml" }, { "id": "u-nestedness-mutualistic-network-robustness", "title": "Does nestedness in mutualistic networks causally increase robustness to species extinctions, or is it a byproduct of neutral assembly processes, and can nestedness metrics predict extinction cascades in empirical plant-pollinator networks under realistic pollinator decline scenarios?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Experimental manipulation of mutualistic network structure (removing generalist vs specialist species) is technically challenging in field settings", "The timescale of extinction cascades in mutualistic networks is rarely observed empirically because cascades are slow relative to monitoring periods", "Seasonal network variation means static nestedness metrics may not capture dynamic robustness over a full year" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-nestedness-mutualistic-network-robustness.yaml" }, { "id": "u-nestedness-stability-causal-mechanism", "title": "Does the nested structure of mutualistic bipartite networks causally increase robustness to extinction cascades, or is nestedness a byproduct of other network assembly rules with robustness arising from degree heterogeneity alone?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "No empirical test with manipulated nestedness holding degree sequence constant.", "MaxEnt null models for bipartite networks are contested.", "Mechanistic models connecting interaction strength distributions to nestedness degree are lacking." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-nestedness-stability-causal-mechanism.yaml" }, { "id": "u-niche-construction-feedback-tempo", "title": "How fast does niche construction-driven ecological inheritance alter selection coefficients relative to genetic evolution in natural populations, and what conditions determine whether eco-evolutionary feedbacks accelerate or impede local adaptation?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Multigenerational field experiments tracking both allele frequencies and environmental modification simultaneously are extremely rare", "The ecological inheritance term in the Price equation requires measuring environment transmission between generations, which is technically demanding in most field systems", "Population genomic signatures of niche construction vs. standard selection are theoretically underdeveloped" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-niche-construction-feedback-tempo.yaml" }, { "id": "u-ocean-acidification-ecosystem-effects", "title": "How will ocean acidification affect marine ecosystem structure and functioning, and which species and communities are most vulnerable?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The synergistic effects of acidification, warming, and deoxygenation on marine communities are not modelled; most experiments manipulate one variable.", "Evolutionary adaptation to ocean acidification operates on timescales potentially comparable to the acidification rate but is not included in projections.", "The economic valuation of marine ecosystem service losses from acidification is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-ocean-acidification-ecosystem-effects.yaml" }, { "id": "u-ocean-mixing-parameterization-climate-models", "title": "How should spatially and temporally variable diapycnal mixing be parameterized in global climate models to reduce the principal source of centennial ocean circulation uncertainty?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The fraction of internal wave energy that is locally dissipated vs. radiated to remote mixing sites is measured globally to only ~30% accuracy.", "Langmuir turbulence parameterizations are absent from most production climate models despite factor 2-10 mixing enhancement at the ocean surface.", "Machine learning parameterization of mixing (trained on observational microstructure data) has not been incorporated into a coupled climate model for multi-decadal runs." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-ocean-mixing-parameterization-climate-models.yaml" }, { "id": "u-patch-foraging-partial-observability-wild", "title": "How often do wild foragers operate under partial observability regimes invalidating deterministic marginal-value predictions derived from fully observed patch maps?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Field datasets coupling cue reliability experiments with GPS-resolved patch schedules across seasons", "Computational benchmarks comparing partially observable RL policies vs MVT baselines on identical telemetry-derived graphs" ], "suggested_hypotheses": [ "h-reinforcement-learning-x-foraging-patch-models" ], "file": "unknowns-catalog/ecology/u-patch-foraging-partial-observability-wild.yaml" }, { "id": "u-percolation-threshold-habitat-connectivity", "title": "Does habitat connectivity in real fragmented landscapes undergo a percolation transition at the theoretically predicted threshold (h_c ~ 0.593 for 2D site percolation), and can finite-size scaling analysis of satellite habitat maps predict minimum viable corridor widths without species-specific movement data?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No systematic measurement of the power-law exponent of patch size distributions near fragmentation threshold in empirical landscape data", "No finite-size scaling analysis of real landscapes to estimate the true percolation threshold and universality class", "Percolation-based predictions for minimum viable habitat fraction not validated against observed species persistence data" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-percolation-threshold-habitat-connectivity.yaml" }, { "id": "u-plume-intermittency-foraging-optimal-rules", "title": "Which behavioral policies are optimal under measured turbulent odor intermittency versus Gaussian plume approximations for insects navigating weak winds?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Freely flying synchronized fluid-plume tomography at relevant Reynolds numbers near vegetation clutter", "Partial information POMDP benchmarks translating intermittent sniff traces into decision-theoretic casting gains" ], "suggested_hypotheses": [ "h-advection-diffusion-x-odor-plume-search" ], "file": "unknowns-catalog/ecology/u-plume-intermittency-foraging-optimal-rules.yaml" }, { "id": "u-predator-prey-cycle-amplitude-stochastic", "title": "How do demographic and environmental stochasticity interact with Hopf bifurcation dynamics to determine observed cycle amplitude and period variability in real predator-prey systems?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Long-term ecological time series (> 50 years) sufficient for spectral analysis are rare", "Parameter estimation for RM models is underdetermined from abundance data alone", "Cycle period variability is often confounded with changing environmental conditions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-predator-prey-cycle-amplitude-stochastic.yaml" }, { "id": "u-predator-prey-oscillation-damping", "title": "Why do observed predator-prey cycles in nature dampen, shift phase, or stop, contrary to Lotka-Volterra predictions of persistent oscillations?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Distinguishing deterministic cycles from stochastic fluctuations with similar power spectra requires long time series not available for most systems.", "The relative importance of trophic (food) versus non-trophic (habitat) factors in shaping cycle amplitude is not established.", "Spatial coupling of populations through dispersal can synchronise or dampen cycles in ways that depend on landscape structure not captured in point models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-predator-prey-oscillation-damping.yaml" }, { "id": "u-range-shift-pace-climate-change", "title": "Can species track climate change fast enough to avoid extinction, and what determines the rate of range shifts?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The relative contribution of dispersal limitation versus niche limitation to observed range shift rates has not been separated.", "Rapid evolutionary adaptation (rather than range shift) to climate change has been documented in few species and its prevalence is unknown.", "Connectivity of habitat for range shifting is projected to decline as land use and climate change interact, but threshold connectivity requirements are not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-range-shift-pace-climate-change.yaml" }, { "id": "u-red-queen-molecular-clock-arms-race", "title": "Can molecular evolutionary rate analysis (dN/dS ratios at interacting protein interfaces) quantitatively detect and measure the pace of ongoing coevolutionary arms races in wild populations?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No system has both sufficient geographic sampling of dN/dS variation and sufficient ecological data on local selection intensity to test Thompson's mosaic theory quantitatively at the molecular level.", "Whether molecular co-evolutionary clocks run at rates predicted by measured selection coefficients from field experiments has not been tested.", "The contribution of horizontal gene transfer vs. de novo mutation to rapid coevolutionary response in host-microbe systems is poorly quantified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-red-queen-molecular-clock-arms-race.yaml" }, { "id": "u-redfield-ratio-evolutionary-constraint", "title": "Is the Redfield ratio (C:N:P = 106:16:1) in marine phytoplankton an evolutionary optimum, a physiological constraint, or a community-level emergent property?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No quantitative mechanistic model successfully predicts Redfield deviations from first principles (temperature, light, nutrient availability).", "The relative contributions of physiological flexibility vs. community composition shifts to observed stoichiometric variation are unmeasured at global scale.", "Whether the deep ocean Redfield ratio is a cause or consequence of phytoplankton stoichiometry remains debated (co-evolutionary hypothesis untested)." ], "suggested_hypotheses": [ "h-liebig-minimum-generalizes-le-chatelier" ], "file": "unknowns-catalog/ecology/u-redfield-ratio-evolutionary-constraint.yaml" }, { "id": "u-redfield-ratio-evolutionary-origin-mechanism", "title": "Why do marine phytoplankton maintain a nearly universal C:N:P ratio of 106:16:1 (Redfield ratio) — is this ratio fixed by universal biochemistry, imposed by ocean chemistry feedback, or a contingent evolutionary outcome that could differ on other ocean worlds?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "The quantitative contributions of biochemical constraint vs. ecological feedback vs. evolutionary optimization to setting the Redfield ratio have not been disentangled in any model or dataset.", "Systematic measurement of elemental stoichiometry across the full diversity of marine phytoplankton (including uncultured lineages in the Tara Oceans dataset) has not been synthesized to test universality vs. taxon-specific variation.", "Paleoproxy records sufficient to determine whether the Redfield ratio was maintained during the Great Oxygenation Event (~2.4 Ga) have not been developed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-redfield-ratio-evolutionary-origin-mechanism.yaml" }, { "id": "u-replicator-model-identifiability-multispecies-field-data", "title": "Under multispecies competition with spatial structure and measurement noise, when are payoff matrices for replicator dynamics identifiable from longitudinal abundance data?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Few standardized identifiability diagnostics published alongside ESS fits.", "Limited coupling between spatially explicit models and reduced replicator summaries.", "Sparse reporting of uncertainty for fitness proxies derived from noisy census data." ], "suggested_hypotheses": [ "h-replicator-residual-tests-improve-ess-prediction-under-competition" ], "file": "unknowns-catalog/ecology/u-replicator-model-identifiability-multispecies-field-data.yaml" }, { "id": "u-rewilding-ecosystem-outcomes", "title": "Do rewilding initiatives restore ecosystem function and self-regulation, and which reintroduced species produce the largest trophic cascade effects?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The conditions under which top predator reintroduction produces measurable trophic cascades versus negligible effects are not predictable in advance.", "Long-term (>20 year) outcomes of rewilding projects have not been systematically evaluated.", "The socioeconomic conditions under which rewilding is politically sustainable are not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-rewilding-ecosystem-outcomes.yaml" }, { "id": "u-seed-dispersal-levy-flight", "title": "Do empirical seed dispersal kernels have genuine power-law tails consistent with Lévy flights, or are they better described by composite exponential models that mimic fat tails over limited observation scales?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No dispersal study has tracked seeds across scales from 1m to 100km needed to distinguish power-law vs. exponential tails with statistical confidence.", "The physical mechanism connecting animal gut retention time distribution to seed dispersal kernel shape has not been tested quantitatively across species pairs.", "Lévy exponent estimates from the same datasets using different statistical methods (MLE vs. rank plots) give inconsistent results." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-seed-dispersal-levy-flight.yaml" }, { "id": "u-soil-carbon-cue-temperature-response", "title": "How does microbial carbon use efficiency respond to warming, and will the negative CUE-temperature relationship cause soil carbon stocks to decline faster than current models predict under climate change?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Direct measurements of CUE are technically challenging; most estimates use indirect proxies (specific respiration rates)", "Long-term thermal adaptation of soil microbial communities alters their CUE-temperature relationship; this is ignored in most models", "The spatial heterogeneity of soil CUE across biomes is understudied relative to its importance for global carbon budgets" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-soil-carbon-cue-temperature-response.yaml" }, { "id": "u-soil-cue-temperature-sensitivity-warming-feedback", "title": "How does soil microbial carbon use efficiency (CUE) respond to long-term warming (+2–4°C), and does microbial thermal adaptation (acclimation of metabolic rates) reduce or amplify the initial warming-driven increase in soil CO₂ efflux, determining whether the soil carbon climate feedback is transient or persistent over decades?\n", "status": "open", "domain": "ecology", "systematic_gaps": [ "Long-term (>10 year) warming experiments that directly measure CUE (not inferred from respiration/growth ratios) using ¹³C pulse-labelling at regular intervals are lacking; most CUE estimates are from short incubations (<30 days).", "The role of microbial community compositional change (bacteria vs. fungi ratio, specific growth rates) in altering CUE under long-term warming has not been quantified with sufficient taxonomic resolution.", "Organo-mineral association dynamics under warming — does thermal desorption of SOC from Fe/Al oxides accelerate at higher temperature? — is not included in any Earth system model." ], "suggested_hypotheses": [ "Microbial communities in long-term warming plots show compositional shifts toward oligotrophic taxa (Actinobacteria, Acidobacteria) with inherently higher CUE than copiotrophic communities — partially compensating for the thermodynamic CUE decrease — resulting in soil carbon release of only 30±10 Gt C by 2100, not 55 Gt C as projected by static CUE models.\n" ], "file": "unknowns-catalog/ecology/u-soil-cue-temperature-sensitivity-warming-feedback.yaml" }, { "id": "u-soil-food-web-stability-topology", "title": "What network topological properties (connectance, modularity, interaction strength distribution) determine the resistance and resilience of soil food webs to perturbations such as pesticide application, drought, and agricultural intensification?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Standardized sampling protocols for soil mesofauna across biomes do not exist, preventing robust comparative network analysis", "The interaction strengths in soil food web matrices are typically estimated from steady-state production ratios rather than measured directly", "Dynamic resilience experiments (press and pulse perturbations) in intact soil food webs are rare outside controlled mesocosm studies" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-soil-food-web-stability-topology.yaml" }, { "id": "u-soil-microbiome-carbon-cycling", "title": "How does soil microbial community composition determine carbon turnover rates, and can manipulating microbiomes enhance soil carbon sequestration?", "status": "open", "domain": "ecology", "systematic_gaps": [ "The relative importance of microbial community composition versus environmental conditions (temperature, moisture, pH) in controlling carbon turnover rates is not resolved.", "Microbial carbon use efficiency (fraction of consumed carbon retained in biomass vs respired) varies widely but its determinants are not established.", "Whether targeted manipulation of soil microbiomes can reliably increase carbon sequestration without unintended consequences has not been demonstrated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-soil-microbiome-carbon-cycling.yaml" }, { "id": "u-species-abundance-distribution", "title": "Why do species abundance distributions follow log-normal or log-series patterns across ecosystems, and what does this reveal about assembly rules?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Neutral theory and niche theory predict similar SADs but have different species-area and species-time predictions not consistently tested.", "Sampling effects (insufficient survey effort) confound SAD measurement in most community datasets.", "How SADs change with environmental degradation and whether they serve as indicators of ecosystem health is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-species-abundance-distribution.yaml" }, { "id": "u-species-area-exponent-prediction", "title": "Can the species-area exponent z be predicted from first principles given only the fractal dimension of habitat patches and the dispersal kernel of target species?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No predictive model for z from landscape structure exists that has been validated across multiple independently sampled landscapes.", "Whether z is universal (same for all taxa in the same landscape) or taxon-specific (depending on dispersal distance) has not been resolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-species-area-exponent-prediction.yaml" }, { "id": "u-stoichiometry-food-web-stability", "title": "Does stoichiometric mismatch between consumer body C:N:P and food C:N:P destabilize food webs by creating nutrient-recycling feedbacks, and can this explain oscillatory consumer-resource dynamics?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Stoichiometric limit cycles predicted by Loladze model have not been observed in natural food webs", "Whether stoichiometric feedbacks strengthen or weaken with increasing food web complexity is unknown", "The relationship between P-recycling rates and food web stability has not been parameterized across biomes" ], "suggested_hypotheses": [ "Lake food webs with high C:P mismatch (diatom-dominated, low dissolved P) show stoichiometrically-driven phytoplankton-zooplankton oscillations with period ~3-6 weeks, distinguishable from classical predator-prey cycles by the lag structure in C:P ratio" ], "file": "unknowns-catalog/ecology/u-stoichiometry-food-web-stability.yaml" }, { "id": "u-trophic-cascade-motif-universality", "title": "Do the same network motif signatures predict trophic cascade strength universally across terrestrial, freshwater, and marine food webs, or are motif-cascade relationships ecosystem-specific?\n", "status": "open", "domain": "ecology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-trophic-cascade-motif-universality.yaml" }, { "id": "u-trophic-cascade-predictability", "title": "Can trophic cascade strength be predicted from food web topology and body-size ratios, or is it inherently unpredictable from species-level traits?", "status": "open", "domain": "ecology", "systematic_gaps": [ "No mechanistic model predicts trophic cascade strength from food web topology with >70% accuracy", "The relative contribution of trait-mediated vs density-mediated effects is not quantified across systems", "How omnivory and intraguild predation attenuate cascade strength has no quantitative theory" ], "suggested_hypotheses": [ "Trophic cascade strength (log plant biomass increase per log apex predator density) scales as body_mass_ratio^{0.75} * connectance^{-1}, combining metabolic scaling theory with food web complexity" ], "file": "unknowns-catalog/ecology/u-trophic-cascade-predictability.yaml" }, { "id": "u-turing-pattern-selection-ecology", "title": "What determines which spatial pattern (stripes, spots, labyrinths) emerges from Turing instabilities in ecological systems, and how do these patterns change with environmental degradation?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Diffusion coefficients for ecological species are scale-dependent and rarely measured at the relevant spatial scale", "Distinguishing Turing patterns from patterns driven by heterogeneous environments or disturbance is unresolved", "Most Turing models assume linear diffusion; animal movement is highly non-Fickian (Levy walks)" ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-turing-pattern-selection-ecology.yaml" }, { "id": "u-vicsek-noise-raft-jitter-quantitative-mapping", "title": "Is there a quantitative scaling map between Vicsek angular noise amplitude and Raft consensus latency jitter parameters that preserves stability phase diagrams under rescaling time units?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Published mappings translating stochastic Vicsek parameters into discrete-time Raft Markov chain transition probabilities with falsifiable predictions", "Empirical telemetry comparing bird flock turning noise spectra with production Raft RPC histograms (distinct domains)" ], "suggested_hypotheses": [ "h-critical-noise-sweep-scaling-parallels-election-timeout-sweep-phenomenologically" ], "file": "unknowns-catalog/ecology/u-vicsek-noise-raft-jitter-quantitative-mapping.yaml" }, { "id": "u-vit-crop-stress-generalization-across-sensors", "title": "Can vision-transformer crop stress models generalize across sensor platforms and seasons?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-vit-based-phenotyping-improves-early-crop-stress-detection" ], "file": "unknowns-catalog/ecology/u-vit-crop-stress-generalization-across-sensors.yaml" }, { "id": "u-wildlife-corridor-percolation-threshold", "title": "Does the percolation threshold (~59% suitable habitat for square grids) accurately predict landscape-scale connectivity collapse for real species in real landscapes, and how does matrix permeability modify the effective threshold?", "status": "open", "domain": "ecology", "systematic_gaps": [ "Empirical validation of circuit theory vs. least-cost path connectivity predictions using actual genetic data (FST, assignment tests) across multiple species in the same landscape is rare.", "The relationship between landscape graph topology (Fiedler eigenvalue) and population viability (MVP analysis) has not been established empirically.", "Dynamic percolation models that account for gradual habitat loss (not random removal) have not been tested against real habitat fragmentation trajectories." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology/u-wildlife-corridor-percolation-threshold.yaml" }, { "id": "u-chaotic-population-cycles-detection-noise", "title": "How reliably can chaotic dynamics be distinguished from stochastic noise in real ecological time series, and what minimum time series length and signal-to-noise ratio are required for statistically valid Lyapunov exponent estimation from field population counts?\n", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "No validated method for Lyapunov exponent estimation in time series shorter than 100 points with measurement error.", "The distinction between edge-of-chaos and fully chaotic dynamics requires more sensitive metrics than current ecological data can support.", "Mechanistic vs phenomenological chaos models make different predictions that cannot be distinguished from field data alone." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology-mathematics/u-chaotic-population-cycles-detection-noise.yaml" }, { "id": "u-demographic-stochasticity-extinction-threshold", "title": "At what population size does demographic stochasticity overwhelm deterministic dynamics to make extinction inevitable, and can master equation theory predict this threshold for real species?", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "MVP estimates have not been rigorously derived from master equation theory accounting for age structure.", "The interaction between demographic stochasticity and environmental stochasticity in setting extinction thresholds is analytically intractable for realistic life histories.", "Empirical tests of master equation predictions for extinction timing are limited by the rarity of carefully monitored declining populations." ], "suggested_hypotheses": [], "file": "unknowns-catalog/ecology-mathematics/u-demographic-stochasticity-extinction-threshold.yaml" }, { "id": "u-extinction-debt-lag-time-empirical-quantification-fragmented-landscapes", "title": "What is the empirical distribution of extinction debt lag times across taxonomic groups and landscape fragmentation histories — specifically, what fraction of species committed to extinction by historical deforestation have not yet gone extinct, and can the stochastic population model prediction T_ext ~ exp(2rK/σ²)/r be quantitatively validated at landscape scale?\n", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "No study has validated the exponential T_ext ~ exp(K) prediction quantitatively using empirically estimated K values and observed extinction waiting times in the same system.", "The demographic variance σ² is difficult to estimate for wild populations and is rarely reported in conservation assessments.", "Remote sensing provides area time series but converting area to K requires species-area relationships that vary across ecosystems and taxa.", "The lag time distribution across the ~8,000 threatened species on the IUCN Red List has not been estimated, preventing prioritisation of conservation interventions by urgency." ], "suggested_hypotheses": [ "h-extinction-time-exponential-k-demographic-stochasticity-confirmed" ], "file": "unknowns-catalog/ecology-mathematics/u-extinction-debt-lag-time-empirical-quantification-fragmented-landscapes.yaml" }, { "id": "u-invasion-fat-tailed-dispersal-empirical-detection", "title": "How can fat-tailed dispersal kernels and the resulting accelerating invasion dynamics be reliably detected from field data, distinguishing true superdiffusive spread from methodological artifacts (sampling bias, detection lags, environmental heterogeneity) in invasive species surveillance?\n", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "Statistical tests for fat-tailed vs. thin-tailed dispersal that account for observation bias and heterogeneous detection probability.", "Standardized invasion surveillance protocols that enable retrospective statistical analysis of spread rate changes.", "Genetic approaches (propagule pressure tracking via microsatellites) to distinguish constant-front advance from rare long-distance colonization events.", "Bayesian model comparison (IDE with fat-tailed kernel vs. thin-tailed) using hierarchical models incorporating detection probability." ], "suggested_hypotheses": [ "Genetic analysis of invasion fronts (whole-genome sequencing, low diversity at front = bottleneck from thin-tailed spread; high diversity = multiple independent colonists = fat-tailed rare long-distance events) will show that ≥50% of empirically documented \"accelerating\" invasions reflect fat-tailed dispersal rather than environmental heterogeneity or surveillance artifacts.\n" ], "file": "unknowns-catalog/ecology-mathematics/u-invasion-fat-tailed-dispersal-empirical-detection.yaml" }, { "id": "u-metapopulation-climate-velocity-extinction-debt", "title": "How does climate velocity (rate of isotherm shift) interact with metapopulation dispersal capacity to create an extinction debt in fragmented landscapes?", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "No empirical dataset tracks metapopulation dynamics across a climate velocity gradient", "The interaction between patch creation rate (dynamic landscapes) and extinction debt is unmodelled", "The lag time between climate shift and observed extinction (realisation of debt) is empirically unknown" ], "suggested_hypotheses": [ "Extinction debt is irreversible when climate velocity exceeds 3× the effective dispersal rate across the landscape (empirical threshold from metapopulation simulations)" ], "file": "unknowns-catalog/ecology-mathematics/u-metapopulation-climate-velocity-extinction-debt.yaml" }, { "id": "u-neutral-vs-niche-ecology-partitioning", "title": "Whether neutral theory or niche theory better explains observed species abundance distributions and community assembly, and whether any operational test can partition the relative contribution of drift vs. niche differentiation in a given community\n", "status": "open", "domain": "ecology-mathematics", "systematic_gaps": [ "Neutral theory and niche models often predict identical species abundance distributions (SADs), making model selection from SADs alone statistically underpowered (McGill et al. 2006).", "The \"neutral\" prediction of Hubbell's theory matches tropical forest species abundance data quantitatively, despite clearly non-neutral species (different body sizes, growth rates, dispersal abilities) being present.", "A unified framework that interpolates between fully neutral and fully niche-differentiated communities as a function of measurable parameters does not exist.", "Temporal dynamics (time series of community composition) provide more statistical power to distinguish neutral from niche assembly, but long-term community datasets are rare." ], "suggested_hypotheses": [ "h-may-stability-real-ecosystem-applicability" ], "file": "unknowns-catalog/ecology-mathematics/u-neutral-vs-niche-ecology-partitioning.yaml" }, { "id": "u-gravity-model-trade-structural-estimation-welfare", "title": "Can the gravity model of trade be structurally estimated with sufficient accuracy to calculate the welfare gains from trade agreements and optimal tariff structures, and what is the correct functional form for trade costs at different distance scales?\n", "status": "open", "domain": "economic-geography", "systematic_gaps": [ "The trade cost function ╧ä_{ij} is not directly observable; structural gravity inverts it from trade flows, but identification requires strong assumptions about CES preferences that may not hold.", "The distance puzzle (why gravity exponent on distance has increased despite lower transport costs) has no consensus explanation; information costs, trust, and supply chain complexity are candidates.", "Welfare calculations from gravity are sensitive to the assumed trade elasticity (╧â-1)╬│; the range of plausible estimates implies factor of 3-5 uncertainty in welfare gains from any specific trade policy." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economic-geography/u-gravity-model-trade-structural-estimation-welfare.yaml" }, { "id": "u-agency-cost-entropy-maximization", "title": "Can agency costs be quantitatively predicted from the effective temperature of information asymmetry in the principal-agent relationship, and does the statistical mechanics free energy formulation improve on standard incentive theory predictions of optimal contract design?", "status": "open", "domain": "economics", "systematic_gaps": [ "No empirical test of the Boltzmann distribution model for agent effort choice", "No estimation of effective information-asymmetry temperature from compensation data", "Statistical mechanics predictions for optimal equity stakes not derived nor tested" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-agency-cost-entropy-maximization.yaml" }, { "id": "u-agent-based-models-x-emergent-markets", "title": "Do financial market crashes exhibit the universal signatures of first-order phase transitions (spinodal decomposition, nucleation), and can the proximity to the spinodal be measured from order book data to predict crash probability?", "status": "open", "domain": "economics", "systematic_gaps": [ "Crash prediction models have high false positive rates; statistical significance of post-hoc pattern matching is debated", "The relationship between microscopic order book dynamics and the agent-based phase transition is not derived from first principles", "Market regulation and circuit breakers modify crash dynamics, complicating comparison to unregulated theoretical models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-agent-based-models-x-emergent-markets.yaml" }, { "id": "u-auction-design-x-complexity-theory", "title": "What is the optimal approximation ratio achievable by polynomial-time computable auction mechanisms for multi-item combinatorial auctions, and does P≠NP separate achievable from unachievable revenue guarantees?", "status": "open", "domain": "economics", "systematic_gaps": [ "The optimal approximation ratio for multi-bidder multi-item auctions is not known; current bounds have large gaps", "Whether truthfulness imposes an approximation cost beyond NP-hardness is open (related to the 'Price of Anarchy' for mechanism design)", "Empirical auction data rarely identifies the theoretical revenue-maximizing benchmark, making validation of approximation bounds difficult" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-auction-design-x-complexity-theory.yaml" }, { "id": "u-auction-theory-x-mechanism-design", "title": "What is the optimal mechanism for multi-item auctions with budget-constrained bidders and correlated values, and can the Myerson optimal auction be extended to these settings?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Optimal multi-item mechanism design is computationally intractable in general; best known results are approximate", "Budget constraints fundamentally break revenue equivalence; optimal budget-feasible mechanisms are not known beyond simple cases", "Empirical validation of mechanism design predictions in real markets (FCC spectrum auctions, Google ad auctions) is limited by data access" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-auction-theory-x-mechanism-design.yaml" }, { "id": "u-automation-employment-equilibrium", "title": "Will automation and AI cause persistent unemployment, or will labour markets adapt through new job creation and sectoral reallocation?", "status": "open", "domain": "economics", "systematic_gaps": [ "Distinguishing automation that complements labour from automation that substitutes for it is difficult with available data on job tasks.", "The speed of AI capability improvement relative to the speed of occupational adaptation is not empirically characterised.", "General equilibrium effects of widespread AI adoption on wages, prices, and new job creation have not been modelled with sufficient empirical grounding." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-automation-employment-equilibrium.yaml" }, { "id": "u-behavioral-economics-policy-effectiveness", "title": "Which behavioural economics interventions (nudges) generalise robustly across cultural and institutional contexts, and which fail to replicate?", "status": "open", "domain": "economics", "systematic_gaps": [ "Effect sizes for nudge interventions shrink dramatically from laboratory to field settings, with no agreed explanation.", "Adaptation and habituation effects reduce nudge effectiveness over time in ways not modelled in most evaluations.", "The ethical limits of nudging — when does it cross into manipulation — are not agreed normatively or legally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-behavioral-economics-policy-effectiveness.yaml" }, { "id": "u-blackscholes-x-diffusion-equation", "title": "How should the Black-Scholes diffusion equation be modified to capture fat-tailed return distributions, jumps, and stochastic volatility observed in real financial markets?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No consensus model captures all statistical properties of financial returns (tail index, volatility autocorrelation, leverage effect) simultaneously", "Calibration of stochastic volatility models to options data is numerically unstable and non-unique", "Extreme event (crash) statistics are inherently non-Gaussian and may not be captured by any diffusion framework" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-blackscholes-x-diffusion-equation.yaml" }, { "id": "u-business-cycle-prediction-limits", "title": "What are the fundamental limits of macroeconomic forecasting, and why do professional forecasters systematically fail to predict recessions in advance?", "status": "open", "domain": "economics", "systematic_gaps": [ "Whether business cycle forecast failure reflects rational market efficiency or model failure has not been distinguished empirically.", "Machine learning models trained on historical macro data do not consistently outperform simpler econometric forecasts.", "The relationship between forecast horizon and uncertainty does not follow calibrated Bayesian prediction in central bank models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-business-cycle-prediction-limits.yaml" }, { "id": "u-carbon-price-optimal-level", "title": "What is the optimal carbon price for achieving climate stabilisation goals, and why do economic estimates vary by more than two orders of magnitude?", "status": "open", "domain": "economics", "systematic_gaps": [ "The choice of discount rate alone explains most of the variance in SCC estimates across studies.", "Damage functions in IAMs are poorly constrained at high temperature levels and are not validated against historical climate-economy relationships.", "The distribution of climate damages across income groups and nations is not incorporated into social welfare functions in a principled way." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-carbon-price-optimal-level.yaml" }, { "id": "u-causal-forest-policy-effect-transportability", "title": "When do causal-forest heterogeneity estimates transport across regions with different institutions?", "status": "open", "domain": "economics", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-causal-forest-heterogeneity-improves-policy-targeting-efficiency" ], "file": "unknowns-catalog/economics/u-causal-forest-policy-effect-transportability.yaml" }, { "id": "u-causal-inference-heterogeneous-treatment-effects-identification", "title": "Can heterogeneous treatment effects (HTE) — the individual-level variation in causal treatment response — be identified and estimated at scale from observational data, and under what assumptions do machine learning methods (causal forests, meta-learners) provide valid confidence intervals for HTEs?", "status": "open", "domain": "economics", "systematic_gaps": [ "Valid finite-sample confidence intervals for CATE(x) from observational data that account for both estimation uncertainty and confounding bias have not been derived for general ML methods; existing results require semiparametric efficiency conditions rarely verified.", "The power of standard tests for treatment effect heterogeneity (e.g. Best Linear Predictor test) in realistic observational datasets with n = 1000-10,000 has not been characterised through systematic simulation studies.", "Causal forest HTE estimates have not been systematically validated against experimental ground truth (RCT data with the same covariates) across multiple domains to establish their calibration in practice." ], "suggested_hypotheses": [ "Causal forest CATE estimates from observational data with n > 5,000 and measured confounders have calibration error < 20% relative to RCT CATE in the same population, when cross-fitting is applied — making observational HTE estimation practically useful for policy targeting despite theoretical limitations.\n" ], "file": "unknowns-catalog/economics/u-causal-inference-heterogeneous-treatment-effects-identification.yaml" }, { "id": "u-cbdc-monetary-policy-implications", "title": "What are the implications of central bank digital currencies for financial stability, monetary policy transmission, and bank disintermediation?", "status": "open", "domain": "economics", "systematic_gaps": [ "The bank disintermediation effect of CBDCs depends on design choices (remuneration, holding limits) whose equilibrium consequences are not modelled.", "Whether CBDCs strengthen or weaken monetary policy transmission depends on assumptions about bank lending behaviour that are contested.", "Privacy and surveillance implications of CBDC have not been formally included in welfare models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-cbdc-monetary-policy-implications.yaml" }, { "id": "u-central-bank-independence-effectiveness", "title": "Does central bank independence cause lower inflation, and what are the political economy limits of central bank independence under fiscal dominance?", "status": "open", "domain": "economics", "systematic_gaps": [ "Instrumental variable strategies to identify the causal effect of central bank independence on inflation are not convincing.", "The conditions under which central bank independence is politically sustainable (financial repression, high debt) are not established.", "The appropriate division of responsibilities between central banks and fiscal authorities for financial stability is not resolved after 2008." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-central-bank-independence-effectiveness.yaml" }, { "id": "u-chemical-potential-utility-non-equilibrium-markets", "title": "Can non-equilibrium thermodynamic extensions of chemical potential (Onsager coefficients, entropy production rates) be directly mapped onto dynamic models of market disequilibrium, price adjustment kinetics, and out-of-equilibrium utility flows in financial crises?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No empirical study has measured economic analogs of Onsager coefficients (cross-effects between markets) and tested reciprocity symmetry as a constraint on cross-price elasticities.", "The definition of entropy production in an economic system has no consensus; multiple proposals (Georgescu-Roegen, Foley, Mimkes) are not operationally testable.", "Financial crisis dynamics have not been modeled using non-equilibrium thermodynamic frameworks with quantitative predictions tested against historical data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-chemical-potential-utility-non-equilibrium-markets.yaml" }, { "id": "u-collective-risk-pool-stability-evolution", "title": "How well do laboratory collective-risk games predict field adoption of insurance-like institutions when payoffs include social signaling and enforcement?", "status": "open", "domain": "economics", "systematic_gaps": [ "Sparse longitudinal datasets linking game parameters to real premium uptake.", "Moral hazard analogs in biological cooperation (cheating) differ from insurance fraud but interact similarly." ], "suggested_hypotheses": [ "h-risk-pooling-institutions-shift-evolutionary-stable-cooperation" ], "file": "unknowns-catalog/economics/u-collective-risk-pool-stability-evolution.yaml" }, { "id": "u-complexity-economics-policy-design-far-equilibrium", "title": "How should economic policy be designed in complexity-economics frameworks where markets exhibit multiple attractors, path dependence, and agent-strategy ecology — and can minority-game simulations predict when a policy intervention will flip a market from an inferior locked-in attractor to a superior one?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No validated agent-based model exists that correctly predicts real technology lock-in dynamics and can be used for counterfactual policy analysis.", "Early warning signals for market tipping points have been proposed but not validated in real financial or technology adoption data.", "The relationship between minority-game equilibria and real market microstructure is not formally established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-complexity-economics-policy-design-far-equilibrium.yaml" }, { "id": "u-creative-economy-measurement", "title": "How should the creative economy be measured in national accounts, and does it drive innovation spillovers to other sectors?", "status": "open", "domain": "economics", "systematic_gaps": [ "No consistent international definition of the creative economy enables cross-country comparison.", "The economic spillovers from creative clusters to other industries are estimated with inconsistent methods.", "Digital disruption of creative industries has changed value creation in ways not reflected in national accounts." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-creative-economy-measurement.yaml" }, { "id": "u-cryptocurrency-value-store-viability", "title": "Can cryptocurrencies function as long-term stores of value, and what determines whether any given cryptocurrency survives versus fails?", "status": "open", "domain": "economics", "systematic_gaps": [ "The determinants of cryptocurrency adoption equilibria (multiple equilibria vs winner-take-all) are not established theoretically or empirically.", "Whether Bitcoin's fixed supply schedule creates deflationary spirals in hypothetical widespread adoption scenarios is debated.", "Regulatory treatment heterogeneity across jurisdictions prevents clean natural experiments on crypto adoption." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-cryptocurrency-value-store-viability.yaml" }, { "id": "u-degrowth-economic-viability", "title": "Can wealthy economies deliberately degrow GDP while maintaining or improving wellbeing, and what are the macroeconomic mechanisms required?", "status": "open", "domain": "economics", "systematic_gaps": [ "Macroeconomic models of stable no-growth economies have been developed theoretically but not validated empirically against real country trajectories.", "The employment and income distribution effects of targeted degrowth in specific high-footprint sectors are not modelled.", "International competitiveness effects of unilateral degrowth in an open economy are not estimated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-degrowth-economic-viability.yaml" }, { "id": "u-doppler-redshift-option-carry-speculative-analogy", "title": "Is there any falsifiable econometric use of redshift/Doppler line-of-sight formalism beyond pedagogy when studying option-adjusted carry, or does the analogy collapse once microstructure and credit events enter?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No peer-reviewed paper proposes a testable mapping from cosmological observables to bond carry.", "Microstructure discontinuities in markets lack a clean physical counterpart in homogeneous expansion." ], "suggested_hypotheses": [ "h-doppler-carry-yield-curve-steepness-speculative-parallels" ], "file": "unknowns-catalog/economics/u-doppler-redshift-option-carry-speculative-analogy.yaml" }, { "id": "u-economic-dissipation-entropy-measure", "title": "Can economic entropy production be measured as a physically meaningful quantity, and does it predict economic volatility or growth?", "status": "open", "domain": "economics", "systematic_gaps": [ "A thermodynamically consistent definition of economic entropy production that can be measured from economic data does not exist.", "Whether measures of economic irreversibility (e.g. bid-ask spreads, transaction costs, market impact) have predictive power for macroeconomic volatility or crisis has not been tested.", "The connection between physical entropy production (material throughput) and economic value added is empirically poorly established at the firm or sector level." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-economic-dissipation-entropy-measure.yaml" }, { "id": "u-ellsberg-ambiguity-aversion-neural-circuit", "title": "What neural circuits implement ambiguity aversion, and does the brain represent ambiguous uncertainty as a set of possible probability distributions or as a single imprecise probability estimate?\n", "status": "open", "domain": "economics", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-ellsberg-ambiguity-aversion-neural-circuit.yaml" }, { "id": "u-entropy-maximization-x-income-distribution", "title": "At what saving propensity threshold does the income distribution transition from exponential to Pareto, and can this predict real-world inequality tipping points?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "The critical saving propensity threshold lambda_c for the exponential-to-Pareto transition in heterogeneous agent models with realistic exchange rules has not been derived", "Whether the observed increase in global income inequality (Gini 0.6 -> 0.7 in many countries) corresponds to approach toward a condensation critical point has not been tested", "Non-equilibrium contributions to income distribution (technological disruption, globalization as external driving) have not been incorporated into the statistical mechanics framework" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-entropy-maximization-x-income-distribution.yaml" }, { "id": "u-financial-contagion-epidemic-threshold-mapping", "title": "Which epidemic-theoretic quantities (thresholds, outbreak probability) remain identifiable for financial contagion when exposures are partially observed and strategies are endogenous?", "status": "open", "domain": "economics", "systematic_gaps": [ "Latent bilateral exposures confound network reconstruction.", "Behavioral responses can change topology during crises, violating static graph assumptions." ], "suggested_hypotheses": [ "h-interbank-default-cascades-exhibit-epidemic-thresholds" ], "file": "unknowns-catalog/economics/u-financial-contagion-epidemic-threshold-mapping.yaml" }, { "id": "u-financial-contagion-network-topology", "title": "How does the network topology of interbank lending and asset holdings determine systemic risk, and can pre-crisis network measures predict contagion?", "status": "open", "domain": "economics", "systematic_gaps": [ "The specific network topology (core-periphery vs distributed) that maximises systemic stability is theoretically disputed.", "Real-time interbank network data is not available to regulators; mapping network exposures requires major data infrastructure.", "The threshold at which network topology transitions from robust-yet-fragile to unstable has not been identified empirically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-financial-contagion-network-topology.yaml" }, { "id": "u-financial-lyapunov-time-versus-policy-interventions", "title": "When, if ever, is a finite “Lyapunov-like” divergence timescale for payment-system stress a robust early warning metric versus a misleading artifact of low-dimensional reductions?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Sparse public microdata on intraday withdrawal propagation suitable for dynamical fits.", "Regime shifts from policy announcements violate stationarity assumed in many chaos estimators." ], "suggested_hypotheses": [ "h-bank-run-lyapunov-time-shrinks-with-public-information-leaks" ], "file": "unknowns-catalog/economics/u-financial-lyapunov-time-versus-policy-interventions.yaml" }, { "id": "u-financialisation-real-economy-effects", "title": "Has the growth of the financial sector relative to GDP produced net economic benefits, or has financialisation harmed real economy investment and growth?", "status": "open", "domain": "economics", "systematic_gaps": [ "The threshold at which financial deepening turns from growth-enhancing to growth-retarding is estimated inconsistently across studies.", "Distinguishing productive from rent-seeking financial activity empirically has not been done at the transaction level.", "The effect of shareholder value maximisation norms (accelerated by financialisation) on long-term corporate investment has not been causally identified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-financialisation-real-economy-effects.yaml" }, { "id": "u-fluctuation-dissipation-stationary-market-assumption-breakdown", "title": "Under what empirical conditions do sum-rule or fluctuation–dissipation-style integrals over return correlations stabilize enough to be informative, and when do structural breaks invalidate them entirely?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Lack of shared datasets with millisecond trades and identified macro news shocks for controlled breaks.", "Nonlinear leverage effects couple mean and variance unlike equilibrium linear response." ], "suggested_hypotheses": [ "h-volatility-autocorrelation-satisfies-effective-fd-response" ], "file": "unknowns-catalog/economics/u-fluctuation-dissipation-stationary-market-assumption-breakdown.yaml" }, { "id": "u-game-theory-x-cryptography", "title": "Under what conditions does rational cryptography (game-theoretic security) coincide with or diverge from standard computational security definitions?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "A general theorem characterizing when computational security implies game-theoretic security (and vice versa) for arbitrary protocol classes has not been proved", "The game-theoretic security of real blockchain protocols (Ethereum, Bitcoin) under rational miner models with complete information has not been formally analyzed with modern equilibrium concepts", "The design space of cryptographic protocols that are simultaneously computationally secure AND Nash equilibria for rational parties has not been systematically characterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-game-theory-x-cryptography.yaml" }, { "id": "u-gig-economy-welfare-effects", "title": "What are the net welfare effects of gig economy platforms on workers, consumers, and incumbent industries, and how do regulatory regimes affect these?", "status": "open", "domain": "economics", "systematic_gaps": [ "Income volatility among gig workers is documented but its welfare cost relative to the value of flexibility is not measured.", "The effect of gig platforms on incumbent industry wages (taxi drivers, hotel workers) is estimated with inconsistent methods.", "Regulatory treatments (California AB5, UK Supreme Court ruling, EU Platform Work Directive) vary widely; their comparative welfare effects are not evaluated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-gig-economy-welfare-effects.yaml" }, { "id": "u-global-trade-leontief-systemic-shock-threshold", "title": "Is there a percolation-like threshold in global production networks (measured by Leontief input-output tables) below which local shocks remain local, and above which they cascade globally?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Leontief models are static; dynamic propagation (time-to-failure, recovery) is not captured", "World input-output tables have 1-2 year lag; near-real-time network data is unavailable", "Percolation threshold has not been formally computed for WIOD under realistic shock distributions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-global-trade-leontief-systemic-shock-threshold.yaml" }, { "id": "u-healthcare-cost-spiral-mechanisms", "title": "What mechanisms drive persistently rising healthcare costs in high-income countries, and which healthcare system structures most effectively contain them?", "status": "open", "domain": "economics", "systematic_gaps": [ "The decomposition of healthcare cost growth into technological change, price inflation, and volume growth is methodologically contested.", "Cross-national comparison of healthcare system performance is confounded by measurement differences and case-mix variation.", "The long-run effects of cost containment policies (DRG payment, global budgets, reference pricing) on innovation and access are not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-healthcare-cost-spiral-mechanisms.yaml" }, { "id": "u-housing-affordability-structural-causes", "title": "What are the primary structural causes of the housing affordability crisis in high-income cities, and which policy interventions are most effective?", "status": "open", "domain": "economics", "systematic_gaps": [ "Natural experiments on zoning reform show heterogeneous effects that are not explained by current supply models.", "The effect of institutional investor purchasing on housing affordability is estimated inconsistently across studies.", "Rent control effects on long-run housing supply are contested between economists; empirical estimates span a wide range." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-housing-affordability-structural-causes.yaml" }, { "id": "u-inequality-growth-relationship", "title": "Does economic inequality promote or retard long-run economic growth, and at what level of inequality does the net effect change sign?", "status": "open", "domain": "economics", "systematic_gaps": [ "Cross-country growth regressions with inequality suffer from severe endogeneity and omitted variable problems.", "The non-linear relationship (inverted U or threshold effect) has been claimed but not robustly established.", "The distributional position of inequality (bottom vs middle vs top share growth) matters for growth effects but models treat inequality as a single measure." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-inequality-growth-relationship.yaml" }, { "id": "u-inequality-health-phase-transition-threshold", "title": "Is there a critical Gini coefficient threshold above which population health outcomes undergo a discontinuous phase transition, and what is the mechanism?", "status": "open", "domain": "economics", "systematic_gaps": [ "Cross-national health-inequality correlations are well-documented but have not been analyzed for bifurcation structure", "The psychosocial stress pathway (chronic cortisol elevation, allostatic load) has been invoked but never modeled as a phase transition", "Causal direction between inequality and health is debated; bifurcation analysis requires longitudinal data with quasi-experimental variation", "The Ising social coupling model has been applied to opinion dynamics but not validated against health outcome distributions" ], "suggested_hypotheses": [ "Plotting mortality Gini vs income Gini across US counties will reveal an inflection point near Gini=0.40 consistent with a saddle-node bifurcation in the health-inequality system", "Social capital (measured by trust surveys) mediates the health-inequality relationship as the effective coupling constant J in a social Ising model" ], "file": "unknowns-catalog/economics/u-inequality-health-phase-transition-threshold.yaml" }, { "id": "u-innovation-diffusion-s-curve", "title": "Why do some innovations follow S-curve diffusion while others plateau or fail, and can early adoption patterns predict long-run diffusion outcomes?", "status": "open", "domain": "economics", "systematic_gaps": [ "Early adoption pattern metrics that reliably predict final market penetration have not been validated across technology domains.", "The relationship between network effects strength and diffusion ceiling is theoretically predicted but empirically heterogeneous.", "Why some technologies (electric vehicles, solar panels) suddenly accelerate after decades of slow adoption is not predicted by standard diffusion models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-innovation-diffusion-s-curve.yaml" }, { "id": "u-market-microstructure-price-formation", "title": "What determines the speed and efficiency of price discovery in financial markets, and how does high-frequency trading affect market quality?", "status": "open", "domain": "economics", "systematic_gaps": [ "The welfare effects of HFT on institutional and retail investors require counterfactual markets that do not exist.", "The relationship between HFT and market fragility (flash crashes) is not causally established.", "Cross-market contagion through HFT arbitrage strategies is theoretically predicted but empirically difficult to measure." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-market-microstructure-price-formation.yaml" }, { "id": "u-mechanism-design-algorithmic-markets", "title": "Can mechanism design DSIC guarantees be maintained in algorithmic markets where agents use learned bidding strategies, and does the revelation principle hold when agents are adaptive ML-based algorithms?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Revelation principle not extended to adaptive/learning agents with belief updates", "DSIC violations by ML bidding algorithms in repeated auctions not systematically measured", "Game-theoretic stability of VCG and Myerson mechanisms not proven for non-Bayesian agents" ], "suggested_hypotheses": [ "h-mechanism-design-algorithmic-markets" ], "file": "unknowns-catalog/economics/u-mechanism-design-algorithmic-markets.yaml" }, { "id": "u-minority-game-x-market-microstructure", "title": "Does the minority game phase transition at α_c correspond to a measurable threshold in real financial markets (e.g., the number of algorithmic traders per traded asset), and can the transition be detected empirically from order book microstructure data?", "status": "open", "domain": "economics", "systematic_gaps": [ "The minority game order parameter (attendance fluctuation) has no direct observable analogue in real market data", "α_c in real markets is confounded by trader heterogeneity and strategy space dimensionality differences", "No controlled experiment varying α (trader count with fixed strategy complexity) has been conducted in financial markets" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-minority-game-x-market-microstructure.yaml" }, { "id": "u-multiplier-fiscal-policy", "title": "What is the fiscal multiplier under different economic conditions, and when does government spending crowd out versus crowd in private investment?", "status": "open", "domain": "economics", "systematic_gaps": [ "Identification of fiscal multipliers from observational data requires instruments for government spending that are difficult to construct.", "The multiplier varies by spending type (infrastructure, transfers, government consumption) but these are not consistently distinguished in empirical estimates.", "Heterogeneous agent models predict different multipliers for different income groups receiving transfers; aggregate estimates miss this heterogeneity." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-multiplier-fiscal-policy.yaml" }, { "id": "u-natural-experiment-validity-economics", "title": "How valid are natural experiment and instrumental variable methods for causal identification in economics, and what are the threats to their external validity?", "status": "open", "domain": "economics", "systematic_gaps": [ "The external validity of findings from natural experiments to other settings, time periods, and populations is not systematically assessed.", "Weak instrument bias can be severe in many published IV studies; correction methods are not uniformly applied.", "The exclusion restriction in instrumental variables is untestable and often asserted without compelling justification." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-natural-experiment-validity-economics.yaml" }, { "id": "u-pareto-exponent-redistribution-mechanism", "title": "Is the Pareto exponent α of wealth/income distributions quantitatively determined by the ratio of redistribution rate to multiplicative growth rate as predicted by the Bouchaud-Mezard model, and what mechanism generates the crossover from Boltzmann-Gibbs (lower income) to Pareto (upper income) distributions?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No cross-country test of Bouchaud-Mezard formula α = 1 + r/(g-r) with independently measured redistribution and growth rates from OECD data", "The income level marking the Gibbs-to-Pareto crossover has not been systematically measured across countries and time, preventing identification of its determinants", "Non-equilibrium statistical mechanics tools (master equations, Jarzynski equality) have not been applied to model wealth dynamics during economic crises" ], "suggested_hypotheses": [ "The Pareto exponent α across OECD countries from 1990-2020 satisfies α ≈ 1 + r/(g-r) with r = tax-and-transfer fraction of GDP and g = top-1% income growth rate, with a goodness-of-fit better than linear regression on r alone (testing the specific functional form of the Bouchaud-Mezard model)" ], "file": "unknowns-catalog/economics/u-pareto-exponent-redistribution-mechanism.yaml" }, { "id": "u-pension-demographic-stress", "title": "How will demographic aging affect defined-benefit pension systems, and which reform strategies are fiscally sustainable and politically feasible?", "status": "open", "domain": "economics", "systematic_gaps": [ "Long-run demographic projections are sensitive to fertility and immigration assumptions that are inherently uncertain.", "The political economy of pension reform (who bears costs determines feasibility) is modelled separately from fiscal sustainability.", "The welfare effects of moving from defined benefit to defined contribution systems on worker lifetime consumption are not established across income groups." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-pension-demographic-stress.yaml" }, { "id": "u-platform-monopoly-welfare-effects", "title": "Do digital platform monopolies impose net welfare costs on consumers, and what is the appropriate regulatory framework for two-sided markets?", "status": "open", "domain": "economics", "systematic_gaps": [ "Measuring consumer surplus from digital platforms is methodologically contested; revealed preference approaches and contingent valuation diverge widely.", "Whether killer acquisitions (buying potential competitors) are systematically harmful has not been established; the counterfactual is unobservable.", "The appropriate market definition for digital platforms is disputed; definitions determine whether market power exists." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-platform-monopoly-welfare-effects.yaml" }, { "id": "u-post-scarcity-economics-feasibility", "title": "Can advanced technology enable post-scarcity economics, and what economic institutions are needed when marginal costs approach zero?", "status": "open", "domain": "economics", "systematic_gaps": [ "No economic model of post-scarcity transitions includes both the supply-side (falling marginal costs) and demand-side (evolving preferences) simultaneously.", "The transition path from market economies to post-scarcity distribution is not modelled for any specific sector.", "Intellectual property frameworks assume scarcity that is being undermined by digital goods and open-source production; replacement frameworks are not agreed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-post-scarcity-economics-feasibility.yaml" }, { "id": "u-predator-prey-market-oscillations", "title": "Do real commodity and technology markets exhibit quasi-periodic oscillations consistent with Lotka-Volterra predator-prey dynamics, and if so, can LV parameters be calibrated from empirical time series to generate useful forecasts of boom-bust cycles?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Long time series of firm-level market shares at the resolution needed for LV fitting are proprietary and rarely available for research", "Most econophysics studies use aggregate indices (stock market) not competitive market-share dynamics between specific firms", "No published study has done formal LV model selection against alternative dynamical models (delay-differential equation cobweb, SIR-type diffusion) using information criteria" ], "suggested_hypotheses": [ "h-lotka-volterra-semiconductor-capex-cycle" ], "file": "unknowns-catalog/economics/u-predator-prey-market-oscillations.yaml" }, { "id": "u-rational-inattention-x-entropy", "title": "What is the empirically measurable cognitive channel capacity of individual economic agents, and how does capacity heterogeneity across agents shape aggregate price dynamics?", "status": "open", "domain": "economics", "systematic_gaps": [ "Direct measurement of attention capacity in economic experiments is not standard; most evidence is indirect (moments of price distributions)", "The Shannon mutual information cost function is assumed not derived; alternatives have not been systematically tested", "Rational inattention models typically assume Gaussian signals; non-Gaussian returns in financial markets are not well handled" ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-rational-inattention-x-entropy.yaml" }, { "id": "u-shapley-value-practical-coalition-stability", "title": "When is the Shapley value a stable and behaviorally predictive allocation in real-world cooperative problems, and what institutional mechanisms enforce core stability when the core is empty?", "status": "open", "domain": "economics", "systematic_gaps": [ "Large-scale empirical tests of whether the Shapley value predicts actual allocation outcomes in real multi-party negotiations (trade agreements, water rights allocations) are rare.", "Mechanisms for enforcing stability in empty-core games (side payments, repeated games, reputation) are not well understood in applied institutional settings.", "The behavior of nucleolus and Shapley value under strategic misrepresentation of the characteristic function (when players can lie about coalition values) is understudied." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-shapley-value-practical-coalition-stability.yaml" }, { "id": "u-slutsky-vs-mechanical-reciprocity-operational-mapping", "title": "Under what coupled economic–physical models can Jacobian symmetry properties of demand systems be rigorously aligned with elastic reciprocity relations—if ever—without forcing unrealistic preferences?", "status": "open", "domain": "economics", "systematic_gaps": [ "Peer-reviewed theorems on structural symmetry alignment beyond trivial scalar Marshallian cases", "Empirical studies falsifying naive tensor-identification claims in applied IO" ], "suggested_hypotheses": [ "h-local-equilibrium-jacobian-best-conditioned-axis-aligns-with-principal-strain-demo-only" ], "file": "unknowns-catalog/economics/u-slutsky-vs-mechanical-reciprocity-operational-mapping.yaml" }, { "id": "u-social-cost-carbon-discount-rate", "title": "What is the appropriate social discount rate for computing the social cost of carbon (SCC), and how should the Ramsey framework handle ethical disagreements about intergenerational equity, uncertainty about long-run growth, and fat-tailed climate catastrophe risk?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "No consensus method for aggregating heterogeneous national discount rates into a global SCC in multi-region IAMs (RICE model)", "Empirical measurement of η (elasticity of marginal utility) from consumption data gives wide range (1.0-3.0) with different methods", "Palaeoclimate data on tipping points (PETM, Heinrich events) has not been systematically incorporated into IAM damage function calibration", "Behavioural evidence on how people actually discount future climate impacts (from experimental economics) is rarely used in normative SCC calculations" ], "suggested_hypotheses": [ "h-ramsey-optimal-carbon-price-tipping-points" ], "file": "unknowns-catalog/economics/u-social-cost-carbon-discount-rate.yaml" }, { "id": "u-sovereign-debt-sustainability", "title": "What determines sovereign debt sustainability thresholds, and how can debt crises be predicted before they occur?", "status": "open", "domain": "economics", "systematic_gaps": [ "Debt sustainability analyses by IMF and World Bank have consistently failed to predict crises in advance.", "The interest-growth differential (r minus g) is the theoretical driver of debt sustainability, but its future path is not predictable.", "The distinction between illiquidity-driven and insolvency-driven sovereign crises is diagnostically difficult but determines appropriate policy response." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-sovereign-debt-sustainability.yaml" }, { "id": "u-supply-chain-correlated-failure-calibration", "title": "How correlated are supplier-edge failures empirically across automotive and semiconductor tiers — and which correlated percolation ensembles fit procurement telemetry better than IID bond deletion baselines?", "status": "open", "domain": "economics", "systematic_gaps": [ "Anonymized multi-tier procurement graphs released with correlated disruption events labeled by disaster classes (earthquake, pandemic, geopolitical)", "Statistical tests comparing IPS disruption catalogs against correlated percolation simulations matched on degree sequences and clustering coefficients" ], "suggested_hypotheses": [ "h-supply-chain-network-x-bond-percolation-disruption" ], "file": "unknowns-catalog/economics/u-supply-chain-correlated-failure-calibration.yaml" }, { "id": "u-supply-chain-resilience-efficiency", "title": "What is the optimal tradeoff between supply chain efficiency and resilience, and how has COVID-19 revealed the limits of just-in-time production?", "status": "open", "domain": "economics", "systematic_gaps": [ "The systemic risk premium required to justify supply chain resilience investments is not calculated from empirical disruption data.", "Whether supply chain reshoring improves national economic security at acceptable cost is not established; estimates span a wide range.", "Dynamic capabilities models of supply chain adaptation are theoretically developed but empirically tested only in specific industries." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-supply-chain-resilience-efficiency.yaml" }, { "id": "u-trade-war-equilibrium", "title": "What is the long-term equilibrium outcome of escalating trade wars, and under what conditions do countries converge to cooperation versus persistent protection?", "status": "open", "domain": "economics", "systematic_gaps": [ "The welfare effects of the US-China trade war are estimated with inconsistent methods across studies.", "Long-run supply chain restructuring responses to tariffs have not been empirically tracked at the sectoral level.", "The conditions under which trade war escalation de-escalates (negotiated versus unilateral) are not established from historical cases." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-trade-war-equilibrium.yaml" }, { "id": "u-universal-basic-income-macro-effects", "title": "What are the macroeconomic effects of universal basic income on labour supply, inflation, innovation, and wellbeing at scale?", "status": "open", "domain": "economics", "systematic_gaps": [ "Pilot programs are too small and short to capture general equilibrium price and wage effects.", "The labour supply elasticity at the extensive (work vs not work) margin at UBI-level income is not known from any real-world implementation.", "Financing mechanisms (wealth tax, VAT, LVT) have different distributional and macroeconomic consequences not jointly modelled with UBI." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-universal-basic-income-macro-effects.yaml" }, { "id": "u-vaccination-game-equilibrium-gaps-versus-measured-coverage", "title": "In middle-income countries with partial vaccine financing, how large is the gap between Nash-equilibrium voluntary uptake predicted by calibrated payoff matrices and realized childhood vaccine coverage after accounting for administrative logistics, parental beliefs, and healthcare access barriers?\n", "status": "open", "domain": "economics", "systematic_gaps": [ "Harmonized datasets pairing stated-preference games with administrative vaccine registers longitudinally", "Structural estimation separating price incentives from trust shocks" ], "suggested_hypotheses": [ "h-price-subsidy-closes-nash-herd-gap-in-agent-based-metapopulations" ], "file": "unknowns-catalog/economics/u-vaccination-game-equilibrium-gaps-versus-measured-coverage.yaml" }, { "id": "u-vcg-combinatorial-auction-scalability", "title": "Can VCG-style incentive-compatible mechanisms scale to combinatorial auctions with thousands of items while remaining computationally tractable, and what is the revenue-complexity tradeoff?", "status": "open", "domain": "economics", "systematic_gaps": [ "Best approximation ratio for polytime incentive-compatible combinatorial auctions unknown", "Whether machine learning approaches can learn near-VCG mechanisms is open", "Revenue guarantees for approximate VCG under strategic bidding are not established" ], "suggested_hypotheses": [ "Neural network-based mechanism design (RegretNet) can learn near-VCG outcomes for combinatorial settings at polynomial computational cost" ], "file": "unknowns-catalog/economics/u-vcg-combinatorial-auction-scalability.yaml" }, { "id": "u-walrasian-tatonnement-convergence-without-gs", "title": "Under what conditions weaker than gross substitutability does tâtonnement converge to a Walrasian equilibrium, and are these conditions satisfied by empirically observed demand systems?\n", "status": "open", "domain": "economics", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-walrasian-tatonnement-convergence-without-gs.yaml" }, { "id": "u-wealth-distribution-universality", "title": "Is the Boltzmann-Gibbs / Pareto form of wealth distribution universal across economies, and what policy interventions correspond to changing the effective temperature or diffusion coefficient?", "status": "open", "domain": "economics", "systematic_gaps": [ "Cross-country comparison of the exponential-to-Pareto crossover point as a function of economic institutions is lacking.", "The Bouchaud-Mézard model has not been fit to time-series wealth data to extract model parameters and test dynamic predictions.", "The correspondence between specific redistributive policies and changes in the kinetic model parameters has not been derived analytically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/economics/u-wealth-distribution-universality.yaml" }, { "id": "u-econophysics-pareto-index-cross-national-variation", "title": "What drives systematic cross-national variation in the Pareto wealth exponent α (ranging from ~1.1 in highly unequal societies to ~2.5 in Nordic countries), and can the Bouchaud-Mézard multiplicative noise model quantitatively predict α from measurable parameters (capital return variance σ², mean growth g, redistribution rate τ)?\n", "status": "open", "domain": "econophysics", "systematic_gaps": [ "No systematic cross-national test of the Bouchaud-Mézard quantitative prediction α = f(ρ, σ², redistribution) using calibrated macro-financial data for σ² and ρ.", "Offshore wealth (Tax Justice Network estimates ~8% of global wealth) biases all top-wealth estimates; correction methods are ad hoc.", "Post-COVID asset price inflation (2020–2022) represents a natural experiment for multiplicative noise with high σ²; the predicted temporary reduction in α has not been tested." ], "suggested_hypotheses": [ "The Pareto exponent α for net wealth follows α = 1 + (r − g)/σ²_r across OECD countries (r = capital return, g = growth rate, σ²_r = variance of capital returns), with a redistribution correction −τ/σ²_r for effective capital tax rate τ. This predicts that Nordic countries (high τ, low σ²_r) achieve α > 2 while US/Brazil (low τ, high σ²_r) show α ≈ 1.2–1.5.\n" ], "file": "unknowns-catalog/econophysics/u-econophysics-pareto-index-cross-national-variation.yaml" }, { "id": "u-financial-market-impact-model-universal-mechanism", "title": "What is the mechanistic origin of the square root market impact law (ΔP ~ sqrt(Q/V)), and is it a universal non-equilibrium property of all continuous double auction markets or a consequence of specific agent behaviour (herding, information arrival, order-splitting strategies)?\n", "status": "open", "domain": "econophysics", "systematic_gaps": [ "Natural experiments in market microstructure (tick size changes, venue fragmentation, high-frequency trading regulations) have not been used to causally test whether the sqrt(Q) law exponent changes with microstructure parameters.", "A unified model deriving the sqrt(Q) law from first principles (order book dynamics + order splitting + information asymmetry) that matches all observed deviations (time-of-day effects, asset class differences) has not been constructed.", "The relationship between the propagator (autocorrelation of order flow imbalance) and the square root impact law has not been derived without assuming specific functional forms for the propagator decay." ], "suggested_hypotheses": [ "The market impact exponent alpha in ΔP ~ Q^alpha varies from 0.45 to 0.55 across assets and venues as a function of the order book resilience parameter (mean time to fill at best quote), with alpha → 0.5 in the limit of fast order book replenishment — testable using Level 2 order book data across multiple exchanges and tick-size regimes.\n" ], "file": "unknowns-catalog/econophysics/u-financial-market-impact-model-universal-mechanism.yaml" }, { "id": "u-order-book-flash-crash-phase-transition-mechanism", "title": "Is the limit order book near a self-organised critical point in normal market conditions — and does a flash crash correspond to a first-order phase transition (sudden LOB drain) or a second-order transition (diverging susceptibility with correlated HFT cancellations), and can early warning signals predict it?\n", "status": "open", "domain": "econophysics", "systematic_gaps": [ "No statistical test distinguishing first- vs. second-order flash crash has been applied to the 2010 or 2013 data with sufficient resolution.", "Early warning signals (variance, autocorrelation of LOB mid-price) have not been validated in a prospective real-time test on actual markets.", "The correlation structure of HFT order cancellations leading to flash crashes has not been reconstructed from exchange audit trail data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/econophysics/u-order-book-flash-crash-phase-transition-mechanism.yaml" }, { "id": "u-epsilon-near-zero-loss-radiation-q-tradeoff", "title": "For epsilon-near-zero resonances in finite-thickness films, how do material loss tangent, radiation leakage, and substrate coupling partition measured Q — and which term dominates at optical versus GHz engineering scales?\n", "status": "open", "domain": "electromagnetism", "systematic_gaps": [ "Few cross-frequency benchmarks using identical dispersion extraction workflows (ellipsometry vs VNA).", "Thermal and nonlinear saturation near field hotspots alter ε(ω) during operation." ], "suggested_hypotheses": [ "h-enz-crossover-curvature-predicts-local-q-maximum-thin-film-cavity" ], "file": "unknowns-catalog/electromagnetism/u-epsilon-near-zero-loss-radiation-q-tradeoff.yaml" }, { "id": "u-floquet-metamaterial-isolation-bandwidth-loss-tradeoff", "title": "For magnet-free isolators built from time-modulated metamaterial cells, what closed-form scaling laws link modulation frequency, harmonic leakage, insertion loss, and isolation bandwidth when semiconductor switches are bandwidth-limited?\n", "status": "open", "domain": "electromagnetism", "systematic_gaps": [ "Temperature drift of switch timing versus isolation stability under environmental vibration is rarely quantified.", "EMC certification pathways for time-modulated structures remain immature relative to ferrite circulators." ], "suggested_hypotheses": [ "h-staggered-commutation-frequency-threshold-for-target-isolation-db" ], "file": "unknowns-catalog/electromagnetism/u-floquet-metamaterial-isolation-bandwidth-loss-tradeoff.yaml" }, { "id": "u-3d-printed-metal-fatigue", "title": "How do process-induced defects in laser powder bed fusion parts govern fatigue life, and can fatigue properties of AM metals match wrought counterparts?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The relationship between defect size distribution (measured by CT) and fatigue life scatter has not been validated across the range of defect types generated by L-PBF.", "Whether fatigue initiation in AM metals always originates from the largest defect (as extreme value theory predicts) or from defect clusters is not established for all relevant alloys.", "The effectiveness of HIP in closing lack-of-fusion voids (which are irregular and may have oxide-contaminated surfaces) is material and process dependent but not systematically characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-3d-printed-metal-fatigue.yaml" }, { "id": "u-advanced-fission-proliferation", "title": "Do advanced fission reactor designs (molten salt, fast spectrum, small modular reactors) present materially different nuclear proliferation risks than light-water reactors?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The U-233 diversion risk from thorium cycle reactors has not been assessed under realistic material accounting conditions for online reprocessing designs.", "Whether SMR fuel (higher enrichment ~20% LEU) increases enrichment facility incentives or whether the small fuel volume per reactor reduces risk is not settled.", "The detection capability of existing IAEA safeguards instruments in non-LWR reactor geometries has not been fully characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-advanced-fission-proliferation.yaml" }, { "id": "u-aeroelastic-hopf-normal-form-transfer-limits", "title": "When do reduced-order Hopf-bifurcation normal forms quantitatively predict aeroelastic flutter and galloping onset in experiments with three-dimensional stall, structural hysteresis, and unsteady vortex shedding?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Paired wind-tunnel / numerical continuation datasets that report uncertainty on stall models and structural damping.", "Community benchmarks distinguishing galloping (low DOF) from fully coupled flutter instabilities in the same notation." ], "suggested_hypotheses": [ "h-hopf-reduced-order-predicts-galloping-onset-threshold" ], "file": "unknowns-catalog/engineering/u-aeroelastic-hopf-normal-form-transfer-limits.yaml" }, { "id": "u-autonomous-vehicle-edge-cases", "title": "How frequent are truly novel edge cases for autonomous vehicles in real-world deployment, and can safety guarantees be established without exhaustive real-world testing?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The statistical distribution of edge case frequency in real-world driving across diverse geographies and conditions has not been characterized from the AV fleet data that exists.", "Formal safety verification methods for neural network-based perception systems are computationally intractable for production systems.", "The coverage gap between logged simulation scenarios and real-world edge case diversity cannot currently be measured." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-autonomous-vehicle-edge-cases.yaml" }, { "id": "u-betz-limit-exceeded-unsteady-flow", "title": "Can wind turbines extract more than the Betz limit power fraction in highly turbulent or unsteady inflow conditions by exploiting unsteady aerodynamic effects, and if so by how much?\n", "status": "open", "domain": "engineering", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-betz-limit-exceeded-unsteady-flow.yaml" }, { "id": "u-biodegradable-electronics", "title": "Can biodegradable or transient electronics achieve the electrical performance and environmental lifetime control needed for implantable and disposable devices?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The mechanism of ion transport through degrading PLGA matrices (relevant to bioresorbable battery lifetime) has not been fully characterized.", "Long-term biocompatibility of transient electronics degradation products in soft tissue has been tested in animals but not in humans.", "Programmable degradation rates (variable lifetime in the same material system) have not been demonstrated without external triggering." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-biodegradable-electronics.yaml" }, { "id": "u-bode-waterbed-multi-loop-multi-objective-tradeoffs", "title": "What are the sharpest known MIMO extensions and non-minimum-phase relaxations of Bode-type sensitivity integrals for multi-loop cyber-physical systems with decentralized sensing?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Decentralized control lacks a single S; integral identities split across agents in ways not always taught.", "Hard nonlinearities break linear integral identities but lack equally crisp replacements." ], "suggested_hypotheses": [ "h-minimum-phase-plants-attain-tighter-bode-bounds" ], "file": "unknowns-catalog/engineering/u-bode-waterbed-multi-loop-multi-objective-tradeoffs.yaml" }, { "id": "u-carbon-capture-regeneration", "title": "What is the minimum thermodynamic energy penalty for CO2 capture and sorbent regeneration, and how close do current materials come to this limit?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Pilot-scale testing of solid sorbent systems (temperature or vacuum swing adsorption) at representative flue gas conditions is sparse, and degradation rates over thousands of cycles are poorly characterized.", "The interplay between sorbent kinetics (fast capture desired), thermodynamics (low regeneration energy desired), and mass transfer (reactor design) creates multi-objective optimization problems without known Pareto fronts.", "Electrochemical CO2 separation approaches (faradaic electro-swing) have not been demonstrated beyond lab scale; efficiency at industrial CO2 partial pressures is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-carbon-capture-regeneration.yaml" }, { "id": "u-cascade-threshold-infrastructure", "title": "What are the critical coupling thresholds between interdependent infrastructure networks (power, water, transport, communications) that trigger catastrophic cascade failures?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Empirical coupling topology between US critical infrastructure systems is not publicly available for research.", "Dynamic models including repair and restoration crews show different critical thresholds than static percolation models, but have not been validated.", "The interaction between cascade dynamics and human decision-making (operators disconnecting nodes to prevent further cascades) is not modeled." ], "suggested_hypotheses": [ "h-interdependency-drives-first-order-failure" ], "file": "unknowns-catalog/engineering/u-cascade-threshold-infrastructure.yaml" }, { "id": "u-chaos-transition-engineering-systems", "title": "What are the precise bifurcation boundaries for chaos onset in common engineering feedback systems, and how do they depend on delay and nonlinearity?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Bifurcation maps (Hopf boundaries in parameter space) for standard PID-controlled second and third-order plants with time delay have been partially computed but not systematically catalogued for engineering use.", "Real-time Lyapunov exponent estimation for power grid dynamics at the operational timescales needed for early warning is computationally impractical with current methods.", "The universality class of the chaos transition in delay-differential control systems (is it always the Feigenbaum logistic universality class, or do other routes occur?) is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-chaos-transition-engineering-systems.yaml" }, { "id": "u-cryo-em-resolution-limit-radiation-damage-versus-detector-efficiency", "title": "What is the fundamental resolution limit of single-particle cryo-EM — specifically, is it set by radiation damage (maximum electron dose before structural damage) or by the quantum efficiency of direct electron detectors, and can phase plates or new detector technologies push cryo-EM reliably below 1 Å resolution for small proteins?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Rigorous information-theoretic analysis of the maximum achievable resolution given a fixed total electron dose and the dose-response curve of radiation damage for different molecule types has not been published.", "The relationship between particle size, symmetry, and achievable resolution (at a given particle number) has been empirically characterised but not derived from first principles information theory.", "New detector designs (event-driven detectors, 4D-STEM pixelated detectors for ptychography) have not been systematically compared to direct detectors for single-particle cryo-EM in terms of achievable resolution per unit dose.", "Cryo-EM at 300 kV vs. 100 kV — lower voltage increases scattering cross-section (more contrast) but increases radiation damage; the optimal voltage for sub-1 Å cryo-EM has not been determined." ], "suggested_hypotheses": [ "h-cryo-em-membrane-protein-structures-without-detergent-native-lipid-bilayer" ], "file": "unknowns-catalog/engineering/u-cryo-em-resolution-limit-radiation-damage-versus-detector-efficiency.yaml" }, { "id": "u-droplet-splitting-variance-biology-alignment", "title": "Under what experimental conditions do microfluidic droplet-splitting statistics align with simple branching-process models used for cell lineage division — and when does physics-dominated pinch-off invalidate biological metaphors?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Time-resolved datasets linking split-ratio variance to operating points (Ca, Re, geometry) with biological replication controls absent.", "Joint statistical tests comparing microfluidic splitting histograms to microbial lineage CV using identical estimators." ], "suggested_hypotheses": [ "h-droplet-split-binomial-partition-fission-alignment" ], "file": "unknowns-catalog/engineering/u-droplet-splitting-variance-biology-alignment.yaml" }, { "id": "u-em-skin-depth-financial-firewall-mapping-limits", "title": "Under what empirical conditions can layered financial firewalls be calibrated to an exponential-attenuation model analogous to skin-depth shielding without misleading regulators about correlated tail risk?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "No standard dataset maps legal entity perimeter thickness to an equivalent attenuation length across shock frequencies.", "Correlated defaults violate independence assumptions implicit in simple exponential stacking metaphors." ], "suggested_hypotheses": [ "h-layered-em-shielding-financial-firewall-depth-ratio-analogy" ], "file": "unknowns-catalog/engineering/u-em-skin-depth-financial-firewall-mapping-limits.yaml" }, { "id": "u-fem-dec-mixed-form-equivalence-limits", "title": "For industrial-scale nonlinear elasticity and contact, when do DEC meshes match mixed FEM accuracy at equal cost, and where do nonlinear constitutive maps break commuting diagrams?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Software ecosystem fragmentation between DEC research codes and mainstream FEM suites.", "Time-dependent problems need symplectic or structure-preserving time integration paired with spatial FEEC." ], "suggested_hypotheses": [ "h-mixed-fem-for-hodge-laplace-matches-dec-upwind-schemes" ], "file": "unknowns-catalog/engineering/u-fem-dec-mixed-form-equivalence-limits.yaml" }, { "id": "u-finite-depth-kelvin-wake-angle-design-transfer", "title": "When do finite depth, hull geometry, and near-field effects dominate over the ideal Kelvin wake angle in design-relevant ship-wave predictions?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Open wake-image datasets with hull speed, bathymetry, and geometry metadata.", "Comparative errors for analytic, CFD, and empirical wake-angle predictions." ], "suggested_hypotheses": [ "h-dispersion-aware-wake-visualization-improves-hull-wave-interpretation" ], "file": "unknowns-catalog/engineering/u-finite-depth-kelvin-wake-angle-design-transfer.yaml" }, { "id": "u-floquet-metamaterial-nonreciprocity-passivity-limit", "title": "What passive-loss and modulation-depth limits bound magnet-free nonreciprocal performance in Floquet metamaterials?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Comparable benchmark protocols across frequency bands and modulation schemes are lacking.", "Large-signal linearity and intermodulation distortion are underreported.", "Passivity-consistent bounds linking isolation targets to required modulation depth remain incomplete." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-floquet-metamaterial-nonreciprocity-passivity-limit.yaml" }, { "id": "u-fusion-plasma-stability", "title": "What are the remaining plasma instability and confinement barriers to sustained net-energy-gain nuclear fusion at commercial scale?", "status": "open", "domain": "engineering", "systematic_gaps": [ "ELM suppression methods (RMP coils, pellet injection) developed at existing tokamaks may not scale to ITER without additional research.", "The tritium permeation rate through tungsten at reactor-relevant fluence and temperature has not been measured at scale.", "The economic feasibility of fusion depends on whether confinement scales as H-mode empirical laws predict, but no device operates in the relevant parameter regime." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-fusion-plasma-stability.yaml" }, { "id": "u-geothermal-subsidence", "title": "What controls surface subsidence and induced seismicity from enhanced geothermal systems, and can they be predicted and mitigated in pre-development assessment?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The stress state of mid-crustal faults at EGS depths (3–8 km) cannot be directly measured; only indirect estimates from borehole breakouts and seismic focal mechanisms are available.", "The relationship between injection volume, pressure, and induced seismicity magnitude follows no universally validated scaling law.", "Whether EGS can operate safely at commercially relevant injection rates in crystalline basement rock without significant seismic risk has not been demonstrated at the requisite scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-geothermal-subsidence.yaml" }, { "id": "u-graph-spectral-leakage-pmu-event-localization", "title": "How much graph spectral leakage limits disturbance localization accuracy in sparse-PMU power grids?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-graph-wavelet-energy-localizes-pmu-grid-disturbances-better-than-scada" ], "file": "unknowns-catalog/engineering/u-graph-spectral-leakage-pmu-event-localization.yaml" }, { "id": "u-graph-transformer-grid-contingency-false-negative-risk", "title": "What false-negative risk do graph-transformer contingency screeners incur under stressed grid conditions?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-graph-transformer-improves-grid-contingency-screening-recall" ], "file": "unknowns-catalog/engineering/u-graph-transformer-grid-contingency-false-negative-risk.yaml" }, { "id": "u-green-hydrogen-electrolysis", "title": "What is the fundamental efficiency ceiling for water electrolysis for green hydrogen production, and what electrode degradation mechanisms limit durability?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The degradation mechanism of IrO2 under dynamic (intermittent renewable) operation differs from steady-state and is not adequately captured by existing lifetime models.", "Alkaline anion exchange membrane (AEM) electrolyzers could avoid iridium but membrane hydroxide conductivity and stability limits are not understood from first principles.", "The efficiency gain from integrating electrolyzers with waste heat recovery (thermoelectrochemistry) has not been demonstrated at system scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-green-hydrogen-electrolysis.yaml" }, { "id": "u-hypersonic-thermal-protection", "title": "What material systems can provide reliable, reusable thermal protection for hypersonic vehicles at Mach 10–25 over multiple flights?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Oxidation behavior of UHTC composites at relevant oxygen partial pressures and high heat fluxes (>1 MW/m²) has not been characterized beyond 1,000 seconds.", "Thermal shock resistance of hypersonic TPS under repeated transient heating cycles (Mach 15+ entry) has been tested only for a handful of missions.", "The interaction between aerothermal heating, boundary layer transition, and surface roughness from ablation/oxidation creates a coupled fluid-solid problem without validated simulation tools." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-hypersonic-thermal-protection.yaml" }, { "id": "u-interdependent-network-early-warning-cascade", "title": "Are there measurable early-warning signals (critical slowing down, variance increase, autocorrelation rise) that precede catastrophic cascade failures in interdependent infrastructure networks, enabling real-time detection of approach to the discontinuous percolation threshold before collapse?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Whether real power-grid/internet interdependency structure produces a truly discontinuous transition or a smoothed near-discontinuous one (due to partial interdependence, geographic heterogeneity) has not been determined from empirical network data.", "PMU (phasor measurement unit) data from the 2003 blackout and subsequent events has not been re-analysed for early-warning signals using complex network metrics.", "Theoretical early-warning indicators for first-order network transitions have not been derived from the percolation formalism and compared to continuous-transition indicators." ], "suggested_hypotheses": [ "In partially interdependent networks (fraction q < 1 of nodes depend on the other network), the percolation transition smooths from first-order to continuous below a critical interdependency fraction q_c; above q_c, variance-based early-warning signals fail. Empirical power-grid topologies have q < q_c due to geographic redundancy, meaning real-time variance monitoring of grid frequency deviation should provide ~10-minute early warning of cascade onset.\n" ], "file": "unknowns-catalog/engineering/u-interdependent-network-early-warning-cascade.yaml" }, { "id": "u-lidar-scene-reconstruction-nonuniqueness", "title": "What are certifiable uncertainty bounds for reconstructed urban façades from airborne LiDAR under realistic occlusion and multi-return statistics?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Few public datasets with ground-truth 3D error fields tied to beam divergence and registration.", "Non-Gaussian heavy-tailed clutter violates textbook regularization analyses." ], "suggested_hypotheses": [ "h-sparsity-priors-stabilize-lidar-surface-recovery" ], "file": "unknowns-catalog/engineering/u-lidar-scene-reconstruction-nonuniqueness.yaml" }, { "id": "u-lie-group-nonholonomic-robot-optimality", "title": "What is the optimal control law for a nonholonomic robot (e.g. wheeled vehicle, snake robot) on curved configuration spaces (Lie groups), and when does a geometric controller outperform a Euclidean approximation?", "status": "open", "domain": "engineering", "systematic_gaps": [ "No closed-form optimal control law exists for SE(3) with obstacles", "The performance gap between geometric and Euclidean control as a function of curvature is not characterised", "Real-time implementation of Lie group optimal control on embedded hardware is unsolved" ], "suggested_hypotheses": [ "Geometric controllers on SO(3) outperform quaternion-based methods by > 20% in large-angle attitude maneuvers (> 90°) due to topological structure preservation" ], "file": "unknowns-catalog/engineering/u-lie-group-nonholonomic-robot-optimality.yaml" }, { "id": "u-lyapunov-function-discovery-automation", "title": "Can Lyapunov functions for arbitrary nonlinear dynamical systems be discovered automatically, and what is the computational complexity boundary of the stability verification problem?", "status": "open", "domain": "engineering", "systematic_gaps": [ "No algorithm is known that solves the Lyapunov function existence problem for arbitrary polynomial ODEs — whether such an algorithm exists is open.", "Neural Lyapunov methods lack formal verification guarantees; certified approaches (verified arithmetic) are computationally prohibitive at scale.", "The connection between Lyapunov stability and information-theoretic complexity of the system's attractors has not been formalised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-lyapunov-function-discovery-automation.yaml" }, { "id": "u-metamaterial-acoustic-cloaking", "title": "Can acoustic metamaterial cloaks achieve broadband, three-dimensional sound cloaking at practical scales, or are fundamental bandwidth-thickness trade-offs prohibitive?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The Kramers-Kronig-derived bandwidth-thickness trade-off for passive acoustic cloaks has not been formally proven analogous to the electromagnetic Rozanov bound.", "3D acoustic cloaks have been demonstrated only in water-tank conditions at narrow frequency bands; atmospheric acoustic cloaking at engineering scales has no experimental demonstration.", "Whether active acoustic cloaking (sensing and re-radiating) can circumvent the passive bandwidth limit while remaining stable is theoretically open." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-metamaterial-acoustic-cloaking.yaml" }, { "id": "u-microplastic-filtration", "title": "What physical and chemical mechanisms enable efficient removal of nanoplastics and microplastics from drinking water and wastewater at scale?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Standard analytical methods for nanoplastics in complex matrices are not yet validated or standardized, making removal efficiency comparisons unreliable.", "The fouling mechanism of microplastic-laden water on membranes differs from conventional fouling but has not been modeled predictively.", "Whether agglomeration of nanoplastics with natural organic matter can be engineered to improve conventional treatment removal is untested at scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-microplastic-filtration.yaml" }, { "id": "u-molecular-motor-efficiency-limit-biological", "title": "What sets the upper bound on mechanochemical efficiency of biological molecular motors, why does ATP synthase approach 100% efficiency while myosin and kinesin are limited to 25-40%, and can the Jarzynski equality be used to engineer artificial nanomotors approaching the biological limit?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Detailed kinetic measurements distinguishing power stroke from diffusive components", "Quantitative theory of conformational irreversibility in motor cycles", "Artificial nanomotor designs tested against Jarzynski equality predictions", "Stochastic thermodynamics framework for multi-step motor cycles" ], "suggested_hypotheses": [ "h-molecular-motor-near-equilibrium-operation" ], "file": "unknowns-catalog/engineering/u-molecular-motor-efficiency-limit-biological.yaml" }, { "id": "u-multi-coil-wpt-array-grating-lobes-cross-talk", "title": "In roadway or factory-scale multi-coil wireless power installations, how severe are unintended high-field lobes (array analogs of grating lobes) versus simple pairwise leakage models — and how should spacing standards incorporate full-wave results?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Regulatory stray-field limits historically derived from single-coil assumptions.", "Dynamic steering during vehicle motion adds time-varying exposure not captured by static SN curves." ], "suggested_hypotheses": [ "h-half-wavelength-coil-spacing-bound-suppresses-near-field-grating-analogs" ], "file": "unknowns-catalog/engineering/u-multi-coil-wpt-array-grating-lobes-cross-talk.yaml" }, { "id": "u-nanotechnology-self-assembly-yield", "title": "What limits the yield and complexity of DNA origami and molecular self-assembly, and how can hierarchical nanostructures be built with near-unity yield?", "status": "open", "domain": "engineering", "systematic_gaps": [ "A quantitative model of how individual strand incorporation probability combines to give final structure yield has not been experimentally validated for large origami.", "The contribution of oxidative damage to DNA during long annealing ramps to yield losses has not been systematically characterized.", "Hierarchical assembly (origami of origami) yield has not been optimized beyond 3–4 levels; whether 10+ level hierarchies are accessible is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-nanotechnology-self-assembly-yield.yaml" }, { "id": "u-neuromorphic-energy-efficiency", "title": "What are the fundamental energy efficiency limits of neuromorphic computing, and how do they compare to biological neural computation?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Benchmarking energy efficiency of neuromorphic systems against GPUs requires task-comparable workloads; no standardized benchmark set exists.", "The contribution of membrane time constants and leak currents to energy efficiency in biological neurons has not been fully modeled at the circuit level.", "Whether 3D integration of CMOS neuromorphic systems can approach the connection density of cortex (10^9 synapses/cm³) is a fabrication challenge without a clear engineering path." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-neuromorphic-energy-efficiency.yaml" }, { "id": "u-offshore-wind-fatigue", "title": "What are the accurate fatigue life models for offshore wind turbine monopile foundations under combined stochastic wave, wind, and ice loading?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Long-term fatigue crack propagation data in welded steel at seawater temperatures under representative loading spectra are sparse.", "Soil stiffness degradation under cyclic lateral loading changes foundation resonance frequency over years; long-term monitoring data sufficient to validate models are not yet available.", "The interaction between turbine control strategies (individual pitch control, passive load shedding) and structural fatigue life has not been characterized across turbine classes." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-offshore-wind-fatigue.yaml" }, { "id": "u-organ-chip-vascularization-long-term-viability", "title": "How can organ-on-a-chip devices maintain functional vascularized 3D tissue architectures for weeks-to-months timescales to enable chronic disease modeling and long-term drug toxicity testing?", "status": "open", "domain": "engineering", "systematic_gaps": [ "No OoC platform has demonstrated stable, physiologically realistic vascular perfusion for more than 4 weeks with multiple organ-relevant cell types.", "The Reynolds number and shear stress requirements for stable self-assembled microvasculature in OoC devices have not been systematically characterized.", "Integration of peristaltic pump mechanics with vascularized tissue to avoid flow-induced endothelial damage over chronic timescales is unsolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-organ-chip-vascularization-long-term-viability.yaml" }, { "id": "u-quantum-error-correction-overhead", "title": "What is the minimum physical qubit overhead required for fault-tolerant quantum computation at error rates achievable in near-term hardware?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The threshold error rate for promising new LDPC quantum codes has been computed in idealized noise models but not in realistic hardware noise environments.", "The classical decoding overhead (real-time classical computation for syndrome processing) may become a bottleneck before the physical qubit count becomes practical.", "Whether coherence times can be extended sufficiently (>10 ms for transmons) to reduce error rates below the LDPC code threshold is not guaranteed by current physics." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-quantum-error-correction-overhead.yaml" }, { "id": "u-quantum-linewidth-vs-leeson-corner-crossover-measurement-protocol", "title": "Can bench protocols harmonize laser linewidth measurements with microwave oscillator phase-noise spectra such that Schawlow–Townes quantum floors and Leeson corners appear on comparable normalized frequency-axis plots without misleading unit conversions?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Round-robin interlaboratory exercises bridging stabilized diode lasers and ultra-low-noise OCXOs using identical spectrum analyzers and impulse-response deconvolution kernels", "Published uncertainty budgets translating photon-number fluctuations into offset-frequency-dependent noise parity plots" ], "suggested_hypotheses": [ "h-identical-analyzer-method-noise-floor-dominated-regimes-match-at-mm-wave-carriers" ], "file": "unknowns-catalog/engineering/u-quantum-linewidth-vs-leeson-corner-crossover-measurement-protocol.yaml" }, { "id": "u-rate-distortion-optimal-neural-codes", "title": "Do sensory neural codes in the brain operate near the Shannon rate-distortion limit for natural stimuli, and if so, what distortion metric do biological neural circuits implicitly optimize?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Empirical measurement of I(X;X̂) for V1, V4, IT responses to natural images at sufficient neural population scale", "Principled derivation of the perceptual distortion metric D from psychophysics", "Whether the distortion metric changes across cortical hierarchy (V1 low-level vs. IT categorical)", "Whether the neural code is closer to R(D) for evolutionarily ancient (olfactory, auditory) vs. newer (visual) sensory systems" ], "suggested_hypotheses": [ "h-shannon-optimal-compression-biological-codes" ], "file": "unknowns-catalog/engineering/u-rate-distortion-optimal-neural-codes.yaml" }, { "id": "u-reusable-rocket-precision", "title": "What are the guidance and control limits for precision propulsive rocket landing, and what failure modes bound reusability turnaround times?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The statistical relationship between landing conditions (velocity, attitude, fuel remaining) and leg structural fatigue accumulation has not been publicly characterized.", "Guidance algorithms for propulsive landing near physical constraints (fuel minimum, gimbal limits) have been demonstrated empirically but not formally verified for all failure modes.", "Starship's full-stack catch maneuver (mechanical arms catching a falling booster) has no published failure mode and effects analysis in peer-reviewed literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-reusable-rocket-precision.yaml" }, { "id": "u-reversible-em-logic-gate-design", "title": "What physically realizable gate set embeds classical reversible computation (Toffoli/Fredkin-class) into microwave or RF cavity modes using non-helical resonator circuits?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "No standard library of reversible RF primitives analogous to CMOS adiabatic families.", "Cross-talk and finite bandwidth break ideal bijectivity unless expanded Hilbert space with ancillas is engineered.", "Verification methods for logical reversibility under finite-Q modes have not converged." ], "suggested_hypotheses": [ "h-nonhelical-resonator-adiabatic-quantum-memory" ], "file": "unknowns-catalog/engineering/u-reversible-em-logic-gate-design.yaml" }, { "id": "u-rf-noise-figure-two-port-correlation-matrix-room-temperature", "title": "When mutual coupling or shared substrate paths correlate noise between RF ports, how should noise figure and noise temperature be defined beyond scalar Friis cascade formulas while staying tied to Johnson–Nyquist equilibrium references?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Few published multi-port NF datasets that separate correlated Johnson noise from active device 1/f corners.", "Standards documents historically optimized for two-port scalar NF complicate regulatory wording for arrays." ], "suggested_hypotheses": [ "h-correlated-port-noise-matrix-lowers-effective-nf-two-port" ], "file": "unknowns-catalog/engineering/u-rf-noise-figure-two-port-correlation-matrix-room-temperature.yaml" }, { "id": "u-slip-model-biological-accuracy-multi-legged-running", "title": "How accurately does the spring-loaded inverted pendulum (SLIP) model predict energy storage and metabolic cost across different running speeds, gradients, and body morphologies, and does it generalise to multi-legged gaits beyond bipedal and quadrupedal running?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The effective spring constant k_leg for hexapodal locomotion (cockroach, ant) has not been measured in the same standardised way as bipedal/quadrupedal k_leg, making cross-taxon SLIP comparisons incomplete.", "Metabolic cost of transport predictions from SLIP theory for non-flat terrain have not been systematically validated against calorimetric measurements.", "The SLIP model assumes massless legs; for robotic systems with heavy leg segments, the deviation from SLIP predictions as a function of leg-to-body mass ratio is not characterised." ], "suggested_hypotheses": [ "The effective spring constant of the SLIP model is a conserved function of body mass (k ∝ m^0.67) across all running animals, providing a universal biomechanical scaling law that also predicts optimal leg stiffness for robots of any mass." ], "file": "unknowns-catalog/engineering/u-slip-model-biological-accuracy-multi-legged-running.yaml" }, { "id": "u-smart-grid-stability", "title": "How can electrical grid stability be maintained at high variable renewable energy penetration without fossil fuel synchronous generators providing inertia?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Real-time stability assessment at millisecond timescales for 100% inverter-dominated grids is computationally infeasible with current state-estimation methods.", "The optimal mix and placement of grid-forming inverters, synchronous condensers, and storage to maintain stability is not characterized for diverse grid topologies.", "Protection systems (relay coordination) designed for synchronous machine behavior may fail in inverter-dominated grids; wholesale redesign has not been completed for any large grid." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-smart-grid-stability.yaml" }, { "id": "u-soft-robotics-actuator-lifespan", "title": "What limits the fatigue life of soft pneumatic and hydraulic actuators, and can they achieve the 10^7+ cycle durability required for practical service robots?", "status": "open", "domain": "engineering", "systematic_gaps": [ "No standardized fatigue testing protocol exists for soft pneumatic actuators; published cycle-to-failure data are not comparable across labs.", "The stress concentration factor at air channel corners in soft actuators depends on hyperelastic geometry in ways that linear elastic fracture mechanics does not capture.", "Self-healing elastomers have been proposed to extend cycle life, but their fatigue behavior under repeated damage-healing cycles has not been characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-soft-robotics-actuator-lifespan.yaml" }, { "id": "u-soft-robotics-hyperelastic-inverse-design", "title": "Can hyperelastic inverse design reliably prescribe soft actuator geometry and fiber architecture to achieve a target force-displacement trajectory, and how does material uncertainty propagate to actuation performance?\n", "status": "open", "domain": "engineering", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-soft-robotics-hyperelastic-inverse-design.yaml" }, { "id": "u-solid-state-battery-failure", "title": "What are the dominant failure modes in solid-state lithium batteries, and can lithium dendrite penetration of solid electrolytes be prevented at high current densities?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The nucleation mechanism of Li dendrites at solid electrolyte grain boundaries vs. surface defects has not been resolved in operando.", "Whether electronic conductivity in sulfide solid electrolytes drives dendrite nucleation differently from oxide electrolytes is not established.", "The pressure required to suppress dendrite growth is incompatible with thin-film cell architectures; alternative suppression strategies lack experimental validation." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-solid-state-battery-failure.yaml" }, { "id": "u-space-debris-removal", "title": "What active debris removal approaches are technically feasible at scale to prevent Kessler syndrome in low Earth orbit?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Rendezvous and capture of a tumbling 1–8 rpm non-cooperative object (e.g., Envisat) has not been demonstrated; the dynamics of capture from untethered approach are incompletely modeled.", "The cost per removed object required to make ADR commercially viable is not achieved by any demonstrated approach.", "The liability framework for accidental collision during ADR operations (touching another country's satellite) has not been established under international space law." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-space-debris-removal.yaml" }, { "id": "u-spider-silk-recombinant-production-mechanical-parity", "title": "Why does recombinant spider silk produced in bacteria or yeast consistently underperform native spider silk in toughness and tensile strength, and what spinning process parameters close this gap?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The critical molecular weight threshold above which recombinant silk achieves native-equivalent toughness has not been determined.", "The relative contributions of spinning duct pH gradient, ion exchange, and extensional flow rate to beta-sheet nanocrystal alignment have not been independently varied in a systematic factorial experiment.", "Whether native silk toughness requires the full-length spidroin sequence or only specific domain arrangements has not been determined by domain-deletion mutagenesis." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-spider-silk-recombinant-production-mechanical-parity.yaml" }, { "id": "u-stigmergy-optimality-gap-real-environments", "title": "How large is the optimality gap between stigmergic swarm routing and global-optimal paths in real-world dynamic environments with noise and non-stationary costs?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "No tight bounds exist for ACO convergence speed vs. environment change rate in dynamic graphs.", "The trade-off between evaporation rate ρ and adaptability to route failures is not optimised in closed form.", "Empirical comparisons between stigmergic swarm robots and centralised planners in rescue/mapping scenarios are sparse." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-stigmergy-optimality-gap-real-environments.yaml" }, { "id": "u-tissue-engineering-vascularization-thick-constructs", "title": "How can functional vascular networks be engineered into thick (>1 cm) tissue constructs to overcome the oxygen diffusion bottleneck — and what is the minimum vascular network geometry required to sustain cell viability at physiological metabolic rates?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "No engineered tissue construct thicker than ~3 mm has achieved sustained cell viability (>80%) throughout the construct without external perfusion during culture.", "The VEGF gradient profile required to guide capillary sprouting from a printed macrovascular channel into the surrounding tissue space has not been determined or controlled in 3D.", "The minimum functional vascular network topology (fractal branching, inter-capillary spacing) for specific tissue types (cardiac, hepatic, renal) has not been computationally derived and experimentally validated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-tissue-engineering-vascularization-thick-constructs.yaml" }, { "id": "u-topoelectrical-circuit-disorder-robustness-limit", "title": "What quantitative disorder threshold causes topological boundary-mode signatures in topoelectrical circuits to lose practical robustness under component tolerances and loss?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "No shared benchmark defining acceptable edge-mode survival across resistor/capacitor/inductor tolerance distributions.", "Comparisons across labs use incompatible metrics (peak height, Q-factor, localization length).", "Finite-size, boundary-condition, and drive-frequency effects are often conflated with true disorder-induced phase change." ], "suggested_hypotheses": [ "h-topoelectrical-circuit-edge-mode-disorder-threshold" ], "file": "unknowns-catalog/engineering/u-topoelectrical-circuit-disorder-robustness-limit.yaml" }, { "id": "u-traffic-phantom-jam-nucleation-mechanism", "title": "What microscopic mechanism nucleates phantom traffic jams (stop-and-go waves without bottlenecks), and can their formation be predicted and suppressed by autonomous vehicle coordination?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Natural phantom jam experiments with controlled initial conditions have not been conducted at scale", "The Bando optimal velocity model predicts instability but its parameters have large uncertainty", "CAV jam-suppression experiments (Stern et al. 2018) used only 1 AV in 22 vehicles; scaling is unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-traffic-phantom-jam-nucleation-mechanism.yaml" }, { "id": "u-traffic-shock-microscopic-validation", "title": "Do microscopic car-following laws aggregate quantitatively to macroscopic LWR shocks calibrated independently — without systematic parameter drift across highways versus arterials?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Large-scale paired datasets linking synchronized trajectory telemetry with overhead density estimation validating Rankine–Hugoniot speeds lane-by-lane", "Uncertainty propagation from heterogeneous autonomous vehicle spacing algorithms into emergent shock speeds" ], "suggested_hypotheses": [ "h-compressible-shock-x-traffic-shock-wave" ], "file": "unknowns-catalog/engineering/u-traffic-shock-microscopic-validation.yaml" }, { "id": "u-turbulent-drag-reduction-limit", "title": "Is there a fundamental physical limit to turbulent drag reduction in pipe and channel flows, and does the maximum drag reduction (MDR) asymptote represent a true physical bound?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The turbulence structure near the MDR asymptote has not been fully characterized by DNS at high Reynolds numbers.", "The mechanism by which polymer extensional viscosity suppresses turbulence energy cascade (vs. near-wall cycle disruption) is disputed.", "Whether the MDR asymptote is the same for all additives or whether it varies with polymer stiffness and concentration is not settled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-turbulent-drag-reduction-limit.yaml" }, { "id": "u-urban-air-mobility-noise", "title": "What are the fundamental acoustic limits of electric vertical-takeoff-and-landing (eVTOL) aircraft, and can they achieve community-acceptable noise levels in urban environments?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Blade-vortex interaction noise during descent at urban approach angles has not been measured for multi-rotor eVTOL configurations.", "Psychoacoustic annoyance of eVTOL noise (tonal vs. broadband character) at equal A-weighted levels has not been fully characterized against community response.", "The interaction of eVTOL noise with urban canyon propagation creates hot spots that simple single-number metrics do not capture." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-urban-air-mobility-noise.yaml" }, { "id": "u-water-desalination-energy", "title": "How close to the thermodynamic minimum can seawater desalination approach, and what membrane and process innovations are needed to close the gap?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Concentration polarization at the membrane surface increases the effective feed concentration above bulk; the magnitude under real operating conditions is difficult to measure.", "Brine management for hypersaline desalination (zero liquid discharge) has no low-energy solution; the energy minimum for brine crystallizers is known but unachieved in practice.", "Biomimetic membranes (aquaporin-based) have demonstrated high water permeance in lab but not durability or selectivity at industrial scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-water-desalination-energy.yaml" }, { "id": "u-wireless-power-transfer-limit", "title": "What are the fundamental efficiency and range limits of resonant inductive and far-field wireless power transfer, and how does Friis transmission compare to near-field coupling?", "status": "open", "domain": "engineering", "systematic_gaps": [ "The optimal frequency, coil geometry, and impedance matching for near-field systems in the presence of metallic and biological material is not fully characterized by Floquet analysis.", "Space solar power rectenna efficiency at relevant microwave power densities (GHz frequencies, kW/m²) has not been validated in a complete prototype.", "Safety-efficiency trade-offs for far-field power delivery through the human body (medical implants) have not been formally Pareto-optimized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-wireless-power-transfer-limit.yaml" }, { "id": "u-wireless-power-transfer-q-bandwidth-coupling-limit", "title": "What are the practical Pareto limits between coupling, Q, bandwidth, and closed-loop retuning in resonant wireless power transfer?", "status": "open", "domain": "engineering", "systematic_gaps": [ "Most benchmarks report steady-state efficiency but not dynamic retuning latency under realistic motion profiles.", "Comparative datasets that jointly vary coil geometry, ferrite shielding, and controller architecture are sparse.", "Safety, EMC constraints, and magnetic exposure limits are rarely integrated into optimization objectives." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering/u-wireless-power-transfer-q-bandwidth-coupling-limit.yaml" }, { "id": "u-wpt-narrowband-q-bandwidth-multi-standard-coexistence", "title": "What joint constraints do resonator Q and coupling bandwidth impose on operating multiple wireless power standards or carriers through shared coils without unacceptable efficiency loss or EMI?\n", "status": "open", "domain": "engineering", "systematic_gaps": [ "Lack of published multi-carrier WPT datasets that separate resonator bandwidth limits from inverter slew-rate limits.", "Regulatory EMI templates rarely expose worst-case cases when two resonant links detune each other through stray coupling." ], "suggested_hypotheses": [ "h-wpt-coexistence-requires-q-bandwidth-renegotiation-per-standard" ], "file": "unknowns-catalog/engineering/u-wpt-narrowband-q-bandwidth-multi-standard-coexistence.yaml" }, { "id": "u-2d-material-fet-contact-resistance-scaling-below-1nm", "title": "What is the physical lower bound on contact resistance for 2D material (MoS₂, WSe₂) field-effect transistors, and can semimetal contacts (Bi, In) or phase- engineered metallic contacts achieve contact resistivity below the IRDS target of 10 Ω·µm to enable competitive ON-current for sub-1nm node devices?\n", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "Systematic Schottky barrier height measurement vs. metal work function for all 2D materials at technologically relevant thicknesses (1-5 monolayers).", "Transmission electron microscopy + EELS characterization of the atomistic contact structure for lowest-resistance contacts achieved.", "Theoretical NEGF simulation of contact transmission for realistic (disordered, non-ideal) 2D material / metal interfaces.", "Experimental comparison of semimetal vs. phase-engineered vs. graphene bridge contacts on the same 2D material/substrate system." ], "suggested_hypotheses": [ "Phase-engineered 1T'-MoS₂ contacts (achieved by K-intercalation or electrostatic carrier injection) will achieve contact resistivity <50 Ω·µm on 2H-MoS₂ channel devices at room temperature, limited by phonon scattering at the 1T'/2H interface rather than Schottky barriers — reducing the contact problem from a barrier problem to a phonon engineering problem.\n" ], "file": "unknowns-catalog/engineering-physics/u-2d-material-fet-contact-resistance-scaling-below-1nm.yaml" }, { "id": "u-h-infinity-nonlinear-systems-computational-tractability", "title": "Can H∞-optimal robust control be extended to nonlinear systems with guaranteed computational tractability — specifically, can sum-of-squares (SOS) or neural-network- based Lyapunov function approximations provide scalable robust stability certificates beyond the linear matrix inequality framework?\n", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "SOS H∞ synthesis has been demonstrated only for low-dimensional polynomial systems (n<10); scaling to aerospace-relevant dimensions (n>50) has not been demonstrated.", "Neural Lyapunov certificates have been shown to fail in adversarial cases; formal SMT-based verification of learned Lyapunov functions at scale (n>20) has not been demonstrated with completeness guarantees.", "The gap between worst-case HJI-optimal γ and LMI-optimal γ for nonlinear systems has not been quantified empirically across a benchmark suite of control problems." ], "suggested_hypotheses": [ "For polynomial nonlinear systems of degree ≤ 4 and dimension ≤ 20, the SOS hierarchy converges to the globally optimal H∞ performance index γ* within 5% at degree d=6 of the SOS relaxation; for dimension >50, neural Lyapunov methods achieve γ within 20% of γ* while requiring 100× less computation than SOS, establishing a practical size threshold for each method.\n" ], "file": "unknowns-catalog/engineering-physics/u-h-infinity-nonlinear-systems-computational-tractability.yaml" }, { "id": "u-heat-pipe-limit-miniaturization", "title": "What are the physical limits to heat pipe miniaturization for sub-millimeter electronics cooling, and can vapor chamber technology be extended to chip-scale integration?", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "Validated models of wick meniscus stability under high heat flux in miniaturized heat pipes at the capillary-to-boiling limit transition are lacking.", "The coupling between microstructured wick geometry (sintered powder, mesh, micro-pillar) and the effective capillary limit in sub-millimeter heat pipes has not been systematically characterized.", "Integration of two-phase cooling structures directly into silicon die (on-chip cooling) faces thermal stress, chemical compatibility, and manufacturing yield barriers not addressed in current literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/engineering-physics/u-heat-pipe-limit-miniaturization.yaml" }, { "id": "u-plasma-turbulence-transport-barrier-formation-mechanism", "title": "What is the complete physical mechanism by which edge transport barriers (H-mode pedestal) spontaneously form in tokamaks — specifically, what drives the L-H transition and sustains the pedestal pressure gradient — and can this mechanism be predictively modelled for ITER-scale plasmas?\n", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "The L-H power threshold P_LH scales poorly with plasma size — empirical scaling laws (Martin et al. 2008) disagree with first-principles predictions by factors of 2-5.", "The relative roles of ion heat flux, electron heat flux, density, and impurity content in triggering the L-H transition are not established.", "Gyrokinetic simulations cannot yet simulate a full L-H transition due to the extreme scale separation between turbulence (~mm) and pedestal (~cm).", "ELM suppression by resonant magnetic perturbations (RMPs) works empirically in DIII-D and AUG but the physics mechanism (field-line stochastization vs. flow drive) is contested." ], "suggested_hypotheses": [ "h-iter-q10-ignition-margin-sufficient-commercial-fusion" ], "file": "unknowns-catalog/engineering-physics/u-plasma-turbulence-transport-barrier-formation-mechanism.yaml" }, { "id": "u-skin-friction-scaling-across-roughness-regimes", "title": "Can a universal roughness function map measured micron-scale topography to u_τ shifts without full DNS for engineering tolerances?", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "Pressure-gradient effects couple to roughness in ways not captured by channel-flow calibrations.", "Three-dimensional anisotropic roughness lacks a complete parameter reduction." ], "suggested_hypotheses": [ "h-law-of-wall-predicts-local-skin-friction-when-roughness-scaled" ], "file": "unknowns-catalog/engineering-physics/u-skin-friction-scaling-across-roughness-regimes.yaml" }, { "id": "u-wpt-efficiency-biological-tissue-interaction", "title": "Whether resonant wireless power transfer at MHz frequencies interacts with biological tissue in ways that limit safe power delivery to implanted medical devices, and what the fundamental safety-efficiency trade-off is for in-body WPT\n", "status": "open", "domain": "engineering-physics", "systematic_gaps": [ "Specific absorption rate (SAR) limits in biological tissue constrain WPT to implantable devices, but the coupling between near-field resonant WPT and tissue heterogeneity (muscle, fat, bone) is not fully characterised.", "Frequency selection for in-body WPT involves trade-offs between tissue absorption (lower at low f) and coil size/Q factor (higher at high f); the Pareto-optimal frequency has not been established for arbitrary implant depths.", "Thermal effects of WPT near neural tissue (cochlear implants, retinal prostheses, brain-computer interfaces) are incompletely modelled for chronic exposure." ], "suggested_hypotheses": [ "h-resonant-wpt-ev-charging-grid-integration" ], "file": "unknowns-catalog/engineering-physics/u-wpt-efficiency-biological-tissue-interaction.yaml" }, { "id": "u-cultural-transmission-network-effects", "title": "How does the topology of social interaction networks (degree heterogeneity, community structure, homophily) modify the effective R_0 and final adoption fraction of cultural innovations relative to homogeneous-mixing SIR predictions, and can these network corrections be captured by a single network-epidemic summary statistic?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Longitudinal social network data with co-registered adoption timing for specific cultural practices are rare", "Distinguishing independent adoption from social contagion (complex contagion effects requiring multi-contact exposure) is statistically difficult", "Cultural abandonment (removal from I to R) may be reversible unlike disease recovery, violating SIR assumptions in ways not systematically quantified" ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-cultural-transmission-network-effects.yaml" }, { "id": "u-dispersion-shrinkage-stability-under-clinical-batch-effects", "title": "When do batch effects invalidate `b-deseq2-shrinkage-estimation-x-low-count-clinical-biomarker-surveillance` assumptions?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Operational surveillance datasets with explicit batch metadata are limited.", "Alerting policies rarely encode posterior uncertainty from shrinkage models." ], "suggested_hypotheses": [ "h-deseq2-style-shrinkage-reduces-false-alerts-in-low-count-clinical-monitoring" ], "file": "unknowns-catalog/epidemiology/u-dispersion-shrinkage-stability-under-clinical-batch-effects.yaml" }, { "id": "u-drift-robust-sprt-thresholding-for-streaming-pathogen-variant-alerts", "title": "What validation boundary conditions determine when `b-sequential-probability-ratio-test-x-pathogen-genomic-surveillance` remains decision-useful?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-adaptive-sprt-alerting-detects-concerning-pathogen-variants-earlier-than-fixed-window-rules" ], "file": "unknowns-catalog/epidemiology/u-drift-robust-sprt-thresholding-for-streaming-pathogen-variant-alerts.yaml" }, { "id": "u-epidemic-kalman-filter", "title": "What is the optimal state-space model structure for real-time epidemic forecasting that balances transmission heterogeneity, reporting delays, and non-Gaussian observation noise while remaining computationally tractable?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No systematic comparison of EnKF, UKF, particle filter, and EpiEstim for real-time Rt estimation across synthetic and real epidemic scenarios (influenza, COVID-19, RSV) with controlled ground truth.", "Observation models accounting for reporting delays, under-ascertainment, and day-of-week effects are not standardized across national surveillance systems.", "Ensemble forecast calibration (reliability diagrams, continuous ranked probability score) for epidemic filters has not been assessed in operational forecasting contexts." ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-epidemic-kalman-filter.yaml" }, { "id": "u-epidemic-mpc-next-generation-matrix-robustness", "title": "How robust are NGM-constrained model predictive control policies to surveillance delay and contact-network misspecification?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Comparative out-of-sample evaluations across multiple outbreaks with policy latency constraints are limited.", "Uncertainty sets for behavior-driven contact rewiring are weakly validated.", "Policy feasibility under socioeconomic compliance constraints is not consistently modeled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-epidemic-mpc-next-generation-matrix-robustness.yaml" }, { "id": "u-epidemiological-demographic-transition-timing", "title": "What determines the delay between mortality decline and fertility decline in the demographic transition, and can epidemiological models of infectious disease control predict the pace and timing of demographic transitions in low-income countries currently undergoing rapid disease burden shifts?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Country-level time series data linking infectious disease burden to fertility rates are confounded by simultaneous economic development", "Age-structured models require age-specific fertility and mortality data that are unavailable in many low-income countries", "The role of women's agency and education as mediating variables cannot be disentangled from mortality effects alone" ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-epidemiological-demographic-transition-timing.yaml" }, { "id": "u-federated-epidemic-model-drift-across-sites", "title": "How should federated epidemic forecasters adapt when local transmission dynamics diverge strongly across sites?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No standard benchmark for federated epidemic forecasting under policy and mobility shifts.", "Sparse reporting of subgroup calibration and fairness across regions.", "Insufficient guidance on fallback to local-only models during drift episodes." ], "suggested_hypotheses": [ "h-federated-ensembles-improve-cross-site-epidemic-generalization" ], "file": "unknowns-catalog/epidemiology/u-federated-epidemic-model-drift-across-sites.yaml" }, { "id": "u-floquet-instability-thresholds-seasonal-epidemic-control", "title": "Can Floquet-derived instability thresholds reliably define timing windows for seasonal epidemic interventions across pathogen classes?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-floquet-instability-metrics-improve-seasonal-epi-intervention-timing" ], "file": "unknowns-catalog/epidemiology/u-floquet-instability-thresholds-seasonal-epidemic-control.yaml" }, { "id": "u-memory-kernel-identifiability-from-case-time-series", "title": "Can epidemic memory kernels be identified robustly from routine case-time-series data alone?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Few identifiability studies under realistic reporting delay and under-ascertainment noise.", "No standard regularization protocol for stable kernel estimation in public-health practice." ], "suggested_hypotheses": [ "h-memory-augmented-seir-improves-forecast-turning-points" ], "file": "unknowns-catalog/epidemiology/u-memory-kernel-identifiability-from-case-time-series.yaml" }, { "id": "u-metapopulation-epidemic-threshold-fragmented-landscape", "title": "How does landscape fragmentation shift the epidemic persistence threshold R₀_eff in spatially structured host populations, and can metapopulation patch-occupancy theory predict cross-species spillover risk in fragmented habitats from landscape connectivity metrics alone?\n", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No empirical studies have simultaneously estimated Levins metapopulation parameters and SIR transmission parameters for the same host-pathogen system to test the quantitative equivalence prediction.", "Landscape genomics and phylogeographic data could distinguish patch-occupancy from epidemic-spread signatures but have not been systematically applied to test the bridge.", "The effect of habitat fragmentation on pathogen persistence (rescue effect vs. reduced patch carrying capacity) is contested; metapopulation theory predicts opposite outcomes depending on extinction-colonization balance." ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-metapopulation-epidemic-threshold-fragmented-landscape.yaml" }, { "id": "u-network-epidemic-threshold-heterogeneity", "title": "How does contact network heterogeneity (temporal dynamics, multi-layer structure, and spatial embedding) modify the epidemic threshold and final outbreak size beyond the static mean-field network approximation?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Exact epidemic threshold for arbitrary temporal contact networks is unknown; only bounds and approximations exist.", "The order of the percolation transition (continuous vs. first-order) in multi-layer temporal networks has not been fully characterized.", "The effect of spatial embedding on the percolation universality class for epidemics has not been rigorously established.", "Whether targeted vaccination strategies derived from static network theory remain optimal for temporal networks is not known." ], "suggested_hypotheses": [ "The epidemic threshold on temporal networks is bounded between the static threshold and the annealed (mean-field) threshold, with burstiness determining position within this range." ], "file": "unknowns-catalog/epidemiology/u-network-epidemic-threshold-heterogeneity.yaml" }, { "id": "u-network-fragmentation-thresholds-for-combination-antibiotic-coverage", "title": "What failure boundaries determine when `b-percolation-thresholds-x-antimicrobial-combination-therapy-networks` remains decision-useful?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-percolation-aware-combination-selection-delays-resistance-network-percolation" ], "file": "unknowns-catalog/epidemiology/u-network-fragmentation-thresholds-for-combination-antibiotic-coverage.yaml" }, { "id": "u-network-threshold-epidemic-spread", "title": "Can the epidemic threshold of a novel pathogen be estimated from contact network topology alone before transmission parameters are measured, and does the percolation-epidemic equivalence quantitatively predict superspreading event frequency from the contact degree distribution?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No prospective test of percolation-derived epidemic threshold predictions using contact network data", "No measurement of the degree distribution in real human contact networks at the scale needed for percolation threshold calculation", "Theoretical predictions of hub-targeted vaccination advantages not tested in controlled outbreak settings" ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-network-threshold-epidemic-spread.yaml" }, { "id": "u-pandemic-intervention-timing-optimal-uncertainty", "title": "How should optimal epidemic intervention timing be modified when the reproduction number R0, case ascertainment fraction, and NPI effectiveness are all uncertain, and can Bayesian optimal stopping provide robust real-time guidance?", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "Retrospective analyses of COVID-19 intervention timing have not been cast in a formal optimal stopping framework", "The speed of Bayesian R0 estimation in early outbreaks (< 50 confirmed cases) is insufficient for timely optimal stopping", "Political and behavioral constraints on NPI implementation are not captured in mathematical optimal stopping models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/epidemiology/u-pandemic-intervention-timing-optimal-uncertainty.yaml" }, { "id": "u-percolation-herd-immunity-heterogeneous-networks", "title": "Does the percolation-epidemic equivalence hold quantitatively on empirically measured human contact networks with heterogeneous degree distributions, and does it predict herd immunity thresholds more accurately than the classic 1 - 1/R0 formula?\n", "status": "open", "domain": "epidemiology", "systematic_gaps": [ "No systematic comparison of percolation threshold predictions vs classic HIT on POLYMOD-type data", "Heterogeneous degree distribution effects on critical threshold not validated against outbreak data", "Bond vs site percolation difference for vaccination vs natural immunity not empirically resolved" ], "suggested_hypotheses": [ "h-percolation-herd-immunity-heterogeneous-networks" ], "file": "unknowns-catalog/epidemiology/u-percolation-herd-immunity-heterogeneous-networks.yaml" }, { "id": "u-ptm-crosstalk-code-histone-combinatorial-regulation", "title": "What is the combinatorial logic of the histone PTM code — which combinations of marks are truly synergistic or antagonistic, and can a quantitative model predict gene expression from histone modification patterns genome-wide?\n", "status": "open", "domain": "epigenetics", "systematic_gaps": [ "Systematic double- and triple-PTM domain binding specificity (combinatorial binding) has not been measured for most reader domains; data is largely for single PTMs.", "Quantitative models predicting gene expression levels from histone mark patterns genome-wide perform modestly (R² ~ 0.5-0.7); the missing variance source is unknown.", "The causal directionality (does PTM pattern cause gene expression change, or does transcription cause the PTM change?) is poorly established for most marks." ], "suggested_hypotheses": [], "file": "unknowns-catalog/epigenetics/u-ptm-crosstalk-code-histone-combinatorial-regulation.yaml" }, { "id": "u-channel-capacity-evolution-rate", "title": "Does Shannon channel capacity bound the maximum rate of adaptive evolution, and can this bound be empirically measured from mutation rates and population sizes in fast-evolving organisms?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "No validated mapping from population genetics parameters to Shannon channel capacity", "No empirical test of capacity bounds against LTEE or phage evolution fitness trajectories", "Relationship between mutational load and channel noise not quantitatively established" ], "suggested_hypotheses": [ "h-channel-capacity-evolution-rate" ], "file": "unknowns-catalog/evolutionary-biology/u-channel-capacity-evolution-rate.yaml" }, { "id": "u-cooperative-breeding-hamiltons-rule-limits", "title": "Does Hamilton's rule rB > C provide a complete and accurate quantitative prediction for the evolution of cooperative breeding across birds and mammals, or are there systematic deviations requiring reciprocity, group augmentation, or direct benefit models?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "Molecular relatedness estimates exist for few cooperative breeding populations", "Helper effects on recruiter fitness are measured in fewer than 50 species", "Ecological constraints have been quantified in even fewer species" ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-cooperative-breeding-hamiltons-rule-limits.yaml" }, { "id": "u-cultural-group-selection-empirical-magnitude", "title": "How large is between-group selection on cultural traits relative to within-group selection in real human populations, and does the empirical magnitude of cultural group selection suffice to explain the origin of large-scale cooperative institutions?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "Price equation decomposition applied to longitudinal cultural transmission data is rare", "Intergroup competition fitness effects (warfare mortality, territory loss) are not compiled", "Simulation models of CGS lack empirically calibrated parameters" ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-cultural-group-selection-empirical-magnitude.yaml" }, { "id": "u-gene-culture-coevolution-rate-modern", "title": "How fast does gene-culture coevolution operate in modern industrialized populations, and which contemporary cultural practices are actively driving genetic selection?", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "No systematic genome-wide scan for selection signatures associated with documented cultural changes in the past 200 years has been published.", "The effective population size and strong drift in industrial populations may swamp weak cultural selection signals.", "Gene-culture coevolution models assume stable cultural practices over many generations; modern cultural change may be too rapid for genetic response." ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-gene-culture-coevolution-rate-modern.yaml" }, { "id": "u-handicap-principle-signal-cost-measurement", "title": "Can the cost function C(signal, quality) of animal honest signals be measured empirically to verify the single-crossing property required for handicap principle honesty, and under what ecological conditions do costly signals become evolutionarily unstable or replaced by intrinsic quality indicators?", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "Measuring individual condition continuously while simultaneously measuring signal production cost requires implanted metabolic sensors rarely available in field settings", "The theoretical ESS models assume constant environment, but seasonal and ecological variation means the cost function C(t,q) changes over time", "Digital ethology methods exist but have not been applied to systematically test single-crossing cost functions across populations" ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-handicap-principle-signal-cost-measurement.yaml" }, { "id": "u-horizontal-gene-transfer-rate-estimation", "title": "What are the rates of horizontal gene transfer between different prokaryotic species, and how do these rates vary with phylogenetic distance and ecological co-occurrence?", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "HGT rates measured in controlled laboratory conditions differ from rates inferred from comparative genomics; the 'true' environmental rate is unknown.", "The distribution of HGT rates across gene categories (metabolic, regulatory, structural) has not been systematically measured in wild microbiomes." ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-horizontal-gene-transfer-rate-estimation.yaml" }, { "id": "u-kin-selection-price-equation-unification", "title": "Does the Price equation provide a complete and unique decomposition of evolutionary change that fully unifies kin selection, group selection, and direct selection interpretations, or do these frameworks differ in empirical predictions that could be tested by manipulating relatedness and group structure independently?", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "Laboratory evolution experiments with controlled relatedness and group structure have been conducted mainly with bacteria and yeast, limiting generalization", "The distinction between \"direct\" and \"indirect\" fitness effects in inclusive fitness theory becomes ambiguous for traits with complex social interaction networks", "Theoretical analyses of Price equation limitations typically require idealized models; empirical tests with real organisms are rare" ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-kin-selection-price-equation-unification.yaml" }, { "id": "u-phenotypic-plasticity-adaptive-limits-speed", "title": "What are the evolutionary limits on the rate at which plasticity itself can evolve, and can populations track rapid environmental change faster through plasticity evolution than through allele frequency change?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-phenotypic-plasticity-adaptive-limits-speed.yaml" }, { "id": "u-phylogenetic-network-horizontal-transfer", "title": "How do horizontal gene transfer and hybridization events distort phylogenetic tree inference, and can network methods reliably detect and quantify them?", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "No scalable Bayesian method for phylogenetic network inference exists for >30 taxa.", "The statistical power to detect individual HGT events from comparative genomic data depends on unknown parameters (HGT rate, gene length, substitution model) in ways not well characterized.", "Whether the tree-like phylogenetic signal in protein-coding genes is sufficient to recover the species tree despite pervasive HGT in prokaryotes is actively debated." ], "suggested_hypotheses": [ "h-tree-topology-search-polynomial-approximation" ], "file": "unknowns-catalog/evolutionary-biology/u-phylogenetic-network-horizontal-transfer.yaml" }, { "id": "u-predator-vigilance-roc-optimal-threshold", "title": "Do prey animals set vigilance thresholds that maximise Bayesian fitness according to signal detection theory, and can ROC analysis quantify how natural selection tunes the sensitivity-specificity trade-off?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "Simultaneous measurement of sensory discrimination and predation mortality in field populations is rare", "Most vigilance models use threshold rules without fitting full ROC curves to behavioural data", "Collective signal detection in social animals has not been analysed with multi-observer SDT" ], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-predator-vigilance-roc-optimal-threshold.yaml" }, { "id": "u-red-queen-cycle-period-determinants", "title": "What determines the period and amplitude of Red Queen allele frequency cycles in natural host-parasite systems, and do these match the predictions of coevolutionary Lotka-Volterra models?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/evolutionary-biology/u-red-queen-cycle-period-determinants.yaml" }, { "id": "u-rmt-selective-sweep-detection-power", "title": "Does the random matrix theory Marchenko-Pastur null model provide higher statistical power for detecting selective sweeps in population genomics than standard Fst-based tests, particularly in admixed populations?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "No power comparison of RMT eigenvalue tests vs iHS/XP-EHH on matched simulated data", "Free probability corrections for admixture not applied to selective sweep detection", "RMT null model not validated against known sweeps in admixed African-European populations" ], "suggested_hypotheses": [ "h-rmt-selective-sweep-detection-power" ], "file": "unknowns-catalog/evolutionary-biology/u-rmt-selective-sweep-detection-power.yaml" }, { "id": "u-zahavi-handicap-mechanism-multimodal", "title": "Do multimodal signals (combining acoustic, visual, and chemical components) satisfy Zahavian honesty conditions as a composite costly signal, or do individual modalities independently satisfy single-crossing conditions — and can this be tested across taxa using phylogenetic comparative methods?\n", "status": "open", "domain": "evolutionary-biology", "systematic_gaps": [ "No cross-species phylogenetic comparative test of Zahavian single-crossing conditions for multimodal signals", "Whether composite quality (multiple immune, parasite, developmental dimensions) predicts multimodal display complexity", "Experimental test: does experimentally handicapping one signal modality cause compensatory increase in another?", "Receiver decision rules for multimodal signals (additive vs. multiplicative vs. threshold integration)" ], "suggested_hypotheses": [ "h-zahavi-handicap-single-crossing-stable-honest" ], "file": "unknowns-catalog/evolutionary-biology/u-zahavi-handicap-mechanism-multimodal.yaml" }, { "id": "u-fiber-nonlinearity-capacity-limit-shannon", "title": "What is the true Shannon capacity of the optical fiber channel including Kerr nonlinearity, and can nonlinear Fourier transform (NFT) based transmission systems approach this capacity limit in practical deployments?\n", "status": "open", "domain": "fiber-optics", "systematic_gaps": [ "The exact Shannon capacity of the optical fiber nonlinear channel (integrating over all launch powers, modulation formats, and DSP algorithms) has not been rigorously computed.", "NFT-based transmission has been demonstrated in short-haul laboratory experiments; extension to transoceanic multi-span systems with amplifier noise has not been achieved.", "Whether the NFT approach degrades gracefully with realistic fiber parameters (dispersion maps, amplifier noise, PMD) is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/fiber-optics/u-fiber-nonlinearity-capacity-limit-shannon.yaml" }, { "id": "u-market-microstructure-hawkes-calibration", "title": "Can a non-stationary multivariate Hawkes process with time-varying kernel parameters provide real-time early-warning indicators of flash-crash risk, and what is the minimum data window needed for reliable branching-ratio estimation on a live order book?", "status": "open", "domain": "finance", "systematic_gaps": [ "Proprietary order-book data at millisecond resolution is not publicly available for systematic model comparison", "Non-stationary Hawkes estimation methods are computationally expensive; real-time inference algorithms are not mature", "Empirical evidence that branching ratio eta is a leading indicator of flash crashes (rather than a coincident one) is weak" ], "suggested_hypotheses": [], "file": "unknowns-catalog/finance/u-market-microstructure-hawkes-calibration.yaml" }, { "id": "u-spin-glass-rmt-factor-clustering-limits", "title": "Beyond Marchenko–Pastur bulk cleaning, when does spin-glass replica-symmetry-breaking imagery add falsifiable predictions for hierarchical factor structure in empirical covariance matrices — versus storytelling without out-of-sample gains?\n", "status": "open", "domain": "finance", "systematic_gaps": [ "Pre-registered forecasts comparing RSB-motivated hierarchical clustering vs shrinkage-only baselines under identical transaction costs.", "Null simulations distinguishing weak hierarchical structure from estimation noise under realistic heavy tails." ], "suggested_hypotheses": [ "h-replica-sparsity-predicts-factor-eigenvalue-noise-bulk" ], "file": "unknowns-catalog/finance/u-spin-glass-rmt-factor-clustering-limits.yaml" }, { "id": "u-rmt-noise-signal-separation-finance", "title": "How can random matrix theory reliably separate true correlation signal from sampling noise in financial covariance matrices with non-stationary returns?", "status": "open", "domain": "finance-mathematics", "systematic_gaps": [ "No universally accepted method for Marchenko-Pastur threshold correction under non-Gaussian, non-stationary returns.", "Dynamic (time-varying) covariance estimation using RMT principles lacks theoretical convergence guarantees.", "The appropriate RMT ensemble for financial correlations (Wishart, beta-ensemble, other) has not been empirically determined." ], "suggested_hypotheses": [ "h-eigenvalue-cleaning-portfolio-performance" ], "file": "unknowns-catalog/finance-mathematics/u-rmt-noise-signal-separation-finance.yaml" }, { "id": "u-earthquake-soc-predictability", "title": "Is earthquake occurrence genuinely unpredictable (true SOC, exponential distribution of recurrence times) or does the approach to criticality produce detectable precursors (critical slowing down, power-law fluctuations)?", "status": "open", "domain": "geology", "systematic_gaps": [ "Distinguishing true SOC (perpetual criticality) from near-critical approach (intermittent criticality) using catalog statistics has not been achieved with current catalog completeness.", "Prospective tests of critical-slowing-down indicators for earthquake forecasting have not been conducted at sufficient scale and blind evaluation.", "The relationship between geodetic strain accumulation (GPS) and seismic criticality indicators has not been systematically quantified.", "Whether b-value decreases before major earthquakes are statistically significant (vs. catalog artifacts) remains contested." ], "suggested_hypotheses": [ "Fault segments within 10 years of a M≥7 rupture exhibit statistically significant increases in seismic correlation length, measurable in catalog data with completeness magnitude ≤ 2." ], "file": "unknowns-catalog/geology/u-earthquake-soc-predictability.yaml" }, { "id": "u-magma-fragmentation-rheology-threshold", "title": "What determines the critical Deborah number and strain rate at which silicate melt transitions from viscous to brittle fragmentation during volcanic ascent, and how do dissolved water content, crystal fraction, and bubble nucleation rate interact to set the fragmentation threshold?", "status": "open", "domain": "geology", "systematic_gaps": [ "High-pressure, high-strain-rate deformation experiments on natural magma compositions are technically challenging", "Seismic velocity changes in the shallow conduit that could indicate brittle-ductile transition are not resolvable with current networks", "Coupling between bubble growth, dissolved gas exsolution, and melt viscosity during rapid decompression is poorly parameterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geology/u-magma-fragmentation-rheology-threshold.yaml" }, { "id": "u-rock-magnetism-paleomagnetic-reversal-mechanism", "title": "What is the geophysical mechanism triggering polarity reversals of Earth's magnetic field, and can micromagnetic domain theory applied to natural remanence-recording minerals provide paleointensity records during reversals with sufficient temporal resolution to distinguish rapid vs. gradual field collapse?", "status": "open", "domain": "geology", "systematic_gaps": [ "Multi-domain magnetite paleointensity correction remains empirically calibrated rather than derived from micromagnetic first principles", "Sedimentary paleointensity records from lock-in depth and compaction effects are poorly constrained", "DFT calculations of magnetite K1 anisotropy constant at high temperature are not routinely used in paleomagnetic interpretation" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geology/u-rock-magnetism-paleomagnetic-reversal-mechanism.yaml" }, { "id": "u-seismic-tomography-null-space-resolution", "title": "What is the minimum resolvable length scale and depth extent of mantle structures in global P-wave tomography, and how do null-space contamination and regularization artifacts mimic real geodynamic features?", "status": "open", "domain": "geology", "systematic_gaps": [ "A probabilistic uncertainty quantification framework for global tomography models (providing pixel-wise confidence intervals rather than single deterministic models) does not exist at global scale — the posterior distribution over velocity models is too high-dimensional for current MCMC methods.", "The non-uniqueness of seismic tomography (infinitely many velocity models fit the data within noise) has not been systematically explored; existing \"different\" tomography models (TX2008, LLSVP_Garnero, SEMUCB-WM1) are not samples from the posterior but products of different regularization choices.", "Distinguishing thermal from compositional velocity anomalies (both change P-wave speed but in different ratios of Vp/Vs) requires joint P+S tomography with mineral physics constraints — current joint inversions disagree on LLSVP composition." ], "suggested_hypotheses": [ "Bayesian ensemble tomography using 100+ independent regularization parameter choices produces a posterior ensemble for lower mantle velocity anomalies in which the LLSVPs have probability >0.95 of being real (not artifacts), while proposed plume conduits below Hawaii and Iceland have probability <0.5 at 1000 km depth." ], "file": "unknowns-catalog/geology/u-seismic-tomography-null-space-resolution.yaml" }, { "id": "u-silicate-weathering-temperature-sensitivity-field", "title": "What is the effective temperature sensitivity of silicate weathering at watershed scales, and does it match laboratory kinetic measurements or show systematic deviation due to biological and physical factors?\n", "status": "open", "domain": "geology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/geology/u-silicate-weathering-temperature-sensitivity-field.yaml" }, { "id": "u-tectonic-coulomb-failure", "title": "What friction coefficient and pore pressure model best explains Coulomb failure function predictions for aftershock sequences, and why do ~20-30% of aftershocks fall in ΔCFF < 0 regions?", "status": "open", "domain": "geology", "systematic_gaps": [ "The effective friction coefficient μ' is rarely measured independently — it is typically fit to aftershock data, creating circularity.", "Dynamic Coulomb stress changes from passing seismic waves are not included in standard static ΔCFF maps but may dominate for distant triggered earthquakes.", "High-resolution 3D fault geometry is unavailable for most faults, making receiver fault orientation a dominant uncertainty." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geology/u-tectonic-coulomb-failure.yaml" }, { "id": "u-adjoint-seismic-backprop-gradient-stability", "title": "How stable are adjoint-derived gradients under realistic seismic noise and model mismatch?", "status": "open", "domain": "geophysics", "systematic_gaps": [ "No standardized cross-domain benchmark for gradient variance in PDE-constrained inversion.", "Limited evidence on when gradient clipping or trust-region steps outperform line search in production seismic workflows." ], "suggested_hypotheses": [ "h-adjoint-preconditioning-improves-seismic-inversion-convergence" ], "file": "unknowns-catalog/geophysics/u-adjoint-seismic-backprop-gradient-stability.yaml" }, { "id": "u-biogeochemical-multistability-empirical-identification", "title": "Which paleoclimate proxies decisively distinguish genuine attractor hysteresis in marine carbon cycle models from model artifact multiplicity absent robust field validation?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Independent replication of hysteresis loops across coupled climate–carbon models differing in ocean circulation fidelity", "Proxy networks resolving rate-dependent transitions versus measurement aliasing under chronological uncertainty" ], "suggested_hypotheses": [ "h-biogeochemical-box-models-x-attractor-stability" ], "file": "unknowns-catalog/geoscience/u-biogeochemical-multistability-empirical-identification.yaml" }, { "id": "u-braided-river-scaling-criticality-test", "title": "What finite-size scaling collapse with pre-registered exponents would elevate braided-river heavy-tail statistics beyond plausible heavy-tailed multiplicative-noise null models — potentially supporting SOC-like narratives currently speculative?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Multi-decadal lidar stacks with controlled hydrologic boundary conditions suitable for finite-size scaling collapses analogous to sandpile numerics", "Null simulators embedding correlated rainfall without critical phase transitions matched variance-for-variance to observations" ], "suggested_hypotheses": [ "h-river-braiding-x-soc-like-morphodynamics" ], "file": "unknowns-catalog/geoscience/u-braided-river-scaling-criticality-test.yaml" }, { "id": "u-coastline-roughness-effective-surface-tension", "title": "Which coastline datasets support universal roughening exponents predicted by simplified stochastic interface models, and where do human armoring and lithology dominate?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Sparse coupled records of waves, sediment supply, and shoreline response at the same resolution.", "Non-stationary climate forcing violates assumptions of scaling analyses." ], "suggested_hypotheses": [ "h-diffusive-interface-models-predict-shoreline-roughening-exponents" ], "file": "unknowns-catalog/geoscience/u-coastline-roughness-effective-surface-tension.yaml" }, { "id": "u-continental-drift-initiation", "title": "What initiated plate tectonics on early Earth, and did it operate continuously or episodically in the Archean?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The zircon geochemical signatures claimed as evidence for early subduction are non-unique and can be produced by other melting environments.", "Numerical models of early Earth do not reproduce the exact heat flow conditions that would favor plate tectonic initiation vs. stagnant lid.", "The rock record before 3.8 Ga is too fragmentary to test tectonic regime hypotheses directly." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-continental-drift-initiation.yaml" }, { "id": "u-cratonic-root-stability", "title": "Why are Archean cratonic keels stable for billions of years, and what conditions cause their sudden removal?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The water content of cratonic lithospheric mantle, which controls viscosity and stability, is poorly constrained.", "The trigger for North China Craton keel destruction (flat slab subduction? plume? inherited weakness?) is contested.", "Whether keel removal is rapid (millions of years) or gradual (hundreds of millions) cannot be resolved from the geological record." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-cratonic-root-stability.yaml" }, { "id": "u-crustal-delamination", "title": "When and how does lower crustal delamination occur, and what are its topographic, geochemical, and volcanic consequences?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Active delamination has not been imaged in real time; all evidence is post-hoc.", "The rheological conditions (viscosity, density contrast) that permit delamination vs. convective drip are poorly constrained.", "The chemical signature of delamination-derived magmas overlaps with other high-Mg mafic sources, limiting fingerprinting." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-crustal-delamination.yaml" }, { "id": "u-deep-carbon-storage", "title": "How much carbon is stored in Earth's deep interior, and what controls the long-term geologic carbon cycle between mantle, crust, and atmosphere?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The total carbon flux from mid-ocean ridge volcanism is estimated from sparse sampling; the ridge system is globally undersampled.", "How much subducted carbonate survives to reach the deep mantle vs. being decarbonated in the arc is uncertain by 50%.", "The speciation of carbon in the lower mantle (diamond, carbonate, metallic carbon) affects its geochemical behavior but cannot be probed directly." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-deep-carbon-storage.yaml" }, { "id": "u-deep-earth-water-cycle", "title": "How much water is stored in Earth's mantle and lower crust, and what are the fluxes that govern the deep water cycle?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The water content of the lower mantle (below 660 km) cannot be directly sampled; only seismic proxies exist.", "Subduction zone water budgets are poorly constrained because slab dehydration depth and efficiency vary with thermal structure.", "The water storage capacity of post-perovskite in the D'' layer is experimentally unconstrained at relevant pressures." ], "suggested_hypotheses": [ "The mantle currently contains 2–4 ocean masses of water, and subduction returns water faster than arc volcanism releases it, implying secular mantle hydration." ], "file": "unknowns-catalog/geoscience/u-deep-earth-water-cycle.yaml" }, { "id": "u-delta-avulsion-prediction", "title": "Can river delta avulsion timing and pathfinding be predicted, and what are the dominant controls on avulsion frequency?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Avulsion timing prediction requires knowledge of subsurface stratigraphy and compaction rates that are only coarsely known for most large deltas.", "Whether avulsions are purely geomorphic threshold phenomena or are triggered by external forcing (floods, earthquakes) is unresolved.", "The fate of abandoned lobes (how quickly they subside and erode) affects sea-level and coastal hazard projections for tens of millions of delta inhabitants." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-delta-avulsion-prediction.yaml" }, { "id": "u-diamond-inclusion-dating", "title": "How reliably do diamond inclusion ages record ancient mantle events, and what biases affect inclusions as windows into deep Earth history?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Re-Os dating of sulfide inclusions assumes closed-system behavior, but sulfides are reactive and may have partially re-equilibrated.", "The growth history of a single diamond (multiple growth zones separated in time by hundreds of millions of years) is now documented but the frequency is unknown.", "Nitrogen aggregation thermometry provides thermal history but requires assumptions about mantle residence time and temperature that are circular." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-diamond-inclusion-dating.yaml" }, { "id": "u-earthquake-early-warning-bayesian-latency-magnitude-error", "title": "How rapidly do Bayesian / sequential magnitude estimates for earthquake early warning converge to within one magnitude unit of final catalogs as station count increases, and how does geographic aperture interact with rupture directivity under finite rupture velocity?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Limited open comparisons that isolate algorithmic posterior contraction from scenario-dependent population exposure.", "Large-event catalogs sparse relative to noise-like microearthquake statistics used for offline tuning." ], "suggested_hypotheses": [ "h-eew-kalman-style-updates-tighten-magnitude-posterior-faster-with-dense-networks" ], "file": "unknowns-catalog/geoscience/u-earthquake-early-warning-bayesian-latency-magnitude-error.yaml" }, { "id": "u-earthquake-nucleation", "title": "What are the physical processes governing earthquake nucleation, and can they be detected before rupture propagates?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The spatial scale of the nucleation zone (meters to kilometers) is below the resolution of most seismic networks.", "Whether nucleation is deterministic (predictable from initial conditions) or stochastic is unresolved.", "The role of fluids in triggering nucleation vs. static stress transfer is poorly constrained for most fault settings." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-earthquake-nucleation.yaml" }, { "id": "u-earthquake-soc-universality-class", "title": "Which universality class does the earthquake fault network belong to — BTW sandpile (τ = 3/2), directed percolation, interface depinning, or a distinct geophysical class — and does the Gutenberg-Richter b-value directly measure the SOC critical exponent?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The empirical τ ≈ 1.67 does not clearly distinguish between BTW sandpile, directed percolation, and interface depinning universality classes.", "Laboratory rock fracture experiments span 6 orders of magnitude in energy but do not replicate crustal-scale geometry or driving rates.", "The b-value varies by ±0.3 across tectonic settings; whether this reflects genuine universality class variation or geometrical effects is unknown.", "Finite-size effects: smaller fault networks (smaller plates) should show larger deviations from power law; this prediction has not been systematically tested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-earthquake-soc-universality-class.yaml" }, { "id": "u-earthquake-swarm-migration", "title": "What physical process drives the spatiotemporal migration of earthquake swarms, and can migration patterns forecast mainshock occurrence?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The relative contributions of fluid pressure and aseismic slip to swarm migration cannot be separated seismologically in most cases.", "The relationship between swarm migration and subsequent mainshock nucleation (if any) has not been established statistically across a global catalog.", "Induced seismicity migration after wastewater injection shows similar patterns but the triggering pore pressure diffusivity differs from natural swarms by orders of magnitude." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-earthquake-swarm-migration.yaml" }, { "id": "u-ensemble-kalman-assimilation-nonlinear-localization-errors", "title": "How large are systematic biases from localization and inflation in EnKF for mesoscale weather extremes relative to tangent-linear 4D-Var when models are strongly nonlinear during rapidly developing storms?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Limited open publication of full-rank diagnostics at convective scales due to operational sensitivity.", "Coupled Earth-system increments complicate single-framework error accounting." ], "suggested_hypotheses": [ "h-adaptive-inflation-ensemble-kalman-corrects-extreme-events" ], "file": "unknowns-catalog/geoscience/u-ensemble-kalman-assimilation-nonlinear-localization-errors.yaml" }, { "id": "u-flood-basalt-trigger", "title": "What triggers large igneous province (flood basalt) eruptions, and why do they correlate with mass extinctions?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Whether mantle plumes initiate LIPs or are consequences of rifting is disputed.", "The relative contribution of climate cooling (volcanic winter) vs. warming (CO2) to extinction is unquantified.", "The timing lag between eruption onset and extinction varies across events, suggesting multiple kill mechanisms." ], "suggested_hypotheses": [ "Mercury anomalies in the rock record precisely fingerprint LIP volcanism and will show that the kill mechanism is primarily ozone destruction from halogen emissions rather than climate change." ], "file": "unknowns-catalog/geoscience/u-flood-basalt-trigger.yaml" }, { "id": "u-geomagnetic-excursion-climate", "title": "Do geomagnetic excursions and reversals affect climate by modulating cosmic ray flux and ozone production?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The duration of minimum field strength during excursions is constrained to only a few thousand years by paleomagnetic records, insufficient to distinguish transient from sustained climate forcing.", "No radiative forcing calculation exists for the cosmic ray enhancement during the Laschamps excursion at the resolution needed to compare with ice core records.", "The correlation between 10Be (cosmic ray proxy) and climate records during excursions has multiple alternative explanations." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-geomagnetic-excursion-climate.yaml" }, { "id": "u-geomagnetic-reversal-prediction", "title": "Can geomagnetic field reversals be predicted, and what controls their frequency and duration?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The duration of current field weakening is within the range of known geomagnetic excursions that did not culminate in reversal.", "Numerical geodynamo simulations have achieved reversals but at parameter regimes far from Earth's (much higher Ekman number).", "The boundary conditions (CMB heat flux heterogeneity) that bias reversal frequency are unconstrained by direct observation." ], "suggested_hypotheses": [ "The current South Atlantic Anomaly growth rate is below the threshold distinguishing excursions from reversals, making a reversal within 1,000 years unlikely based on paleomagnetic base rates." ], "file": "unknowns-catalog/geoscience/u-geomagnetic-reversal-prediction.yaml" }, { "id": "u-geomagnetic-reversal-trigger-mechanism", "title": "What triggers geomagnetic reversals — internal MHD fluctuations, mantle thermal anomalies, or inner core heterogeneities — and can reversal timing be predicted from current geomagnetic field observations?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Geodynamo simulations are far from Earth's parameter regime (Pm, Ek too large)", "Paleomagnetic precursor signatures before reversals are debated and differ between reversals", "The role of inner core growth in geodynamo evolution over geological time is not constrained" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-geomagnetic-reversal-trigger-mechanism.yaml" }, { "id": "u-hydrothermal-vent-biodiversity", "title": "What determines species richness and biogeographic connectivity patterns at deep-sea hydrothermal vents?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Larval dispersal of vent fauna between ridge segments cannot be tracked directly; only genetic methods provide indirect evidence.", "The lifetime of individual vent fields (years to centuries) relative to ecological succession timescales is poorly constrained.", "The role of fluid chemistry in filtering colonists has not been tested with controlled experiments at realistic deep-sea conditions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-hydrothermal-vent-biodiversity.yaml" }, { "id": "u-ice-sheet-basal-melting", "title": "What controls basal melting rates beneath the Antarctic and Greenland ice sheets, and how do subglacial hydrology and geothermal flux affect ice dynamics?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The Antarctic geothermal heat flux map has resolution of ~500 km, far too coarse to constrain basal melt.", "Subglacial hydrological networks route meltwater through unknown pathways, creating episodic lubrication events that current models cannot reproduce.", "Whether Thwaites has crossed the marine ice sheet instability threshold is contested by the 2023–2025 observational campaigns." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-ice-sheet-basal-melting.yaml" }, { "id": "u-inner-core-anisotropy-origin", "title": "What is the origin of seismic anisotropy in Earth's inner core, and does it record solidification texture or ongoing convection?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The stable phase of iron at inner core conditions (hcp vs. bcc vs. dhcp) is not experimentally confirmed.", "Whether the inner core rotates relative to the mantle faster or slower than claimed in early studies remains contested.", "The mechanism generating hemispherical asymmetry (differential solidification, inner core convection, or mantle heterogeneity) is unknown." ], "suggested_hypotheses": [ "The inner core anisotropy records a frozen solidification texture aligned with the paleomagnetic field axis, not ongoing convection, and its rotation rate matches the mantle within current measurement uncertainty." ], "file": "unknowns-catalog/geoscience/u-inner-core-anisotropy-origin.yaml" }, { "id": "u-karst-aquifer-connectivity", "title": "How are karst aquifer conduit networks organized, and can their connectivity and recharge dynamics be characterized without full cave exploration?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "No non-invasive method reliably maps conduit geometry at depth in covered karst.", "The transition between conduit-dominated and diffuse-flow-dominated recharge is abrupt but cannot be predicted from surface geology alone.", "Climate change impacts on karst spring discharge are poorly constrained because recharge-discharge lags (months to decades) are aquifer-specific." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-karst-aquifer-connectivity.yaml" }, { "id": "u-mantle-convection-plate-tectonic-onset", "title": "What physical and rheological conditions trigger the onset of plate tectonics from a stagnant-lid convection regime, and why does Earth have plate tectonics while Venus does not?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "No self-consistent mantle convection simulation has spontaneously initiated plate-tectonic-like behaviour from a stagnant lid without prescribed weakening zones.", "The relative importance of water content, impact history, and initial temperature in triggering plate tectonics is not quantified.", "Venus's interior structure is poorly constrained; surface topography data from Magellan is insufficient to detect active tectonism." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-mantle-convection-plate-tectonic-onset.yaml" }, { "id": "u-mantle-convection-transitions", "title": "What controls the transition between layered and whole-mantle convection, and can the pattern switch on geologic timescales?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The Clapeyron slope of the post-spinel transition at 660 km is disputed across experiments, affecting whether it promotes or resists slab penetration.", "Dynamic models cannot currently reproduce the observed regional variation in slab behavior simultaneously.", "The frequency and periodicity of mantle overturns in deep time cannot be extracted from the rock record." ], "suggested_hypotheses": [ "Slab stagnation at 660 km is controlled primarily by trench rollback velocity rather than slab buoyancy, predicting a critical rollback threshold observable in current subduction zones." ], "file": "unknowns-catalog/geoscience/u-mantle-convection-transitions.yaml" }, { "id": "u-mantle-horizontal-spectrum-versus-rb-wavelength-law", "title": "Can normalized horizontal power spectra of mantle convection in numerical dynamo-like spherical-shell simulations be mapped quantitatively onto classical Rayleigh-Bénard wavenumber-selection curves after accounting for temperature-dependent viscosity and internal heating — or does rheological splitting invalidate simple wavelength correspondence?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Community benchmarks exporting spherical harmonic spectra from mantle simulations with harmonized nondimensional groups", "Uncertainty quantification linking tomographic velocity spectra to true flow spectra" ], "suggested_hypotheses": [ "h-numerical-mantle-spectral-peaks-track-effective-rb-wavenumber-branches" ], "file": "unknowns-catalog/geoscience/u-mantle-horizontal-spectrum-versus-rb-wavelength-law.yaml" }, { "id": "u-mantle-rheology-x-viscoelasticity", "title": "Is Earth's lower mantle rheology best described by a Maxwell viscoelastic model, a Burgers model (elastic-viscous-viscous), or a power-law creep model, and what laboratory constraints on olivine deformation can distinguish these?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Glacial isostatic adjustment data constrain average mantle viscosity; lateral heterogeneity (subduction zones, plumes) is not resolved", "Laboratory deformation experiments on olivine are limited to strain rates > 10^-6 s^-1; natural deformation is at ~10^-14 s^-1; extrapolation spans 8 orders of magnitude", "Transient creep (Burgers body) has been identified in some GIA analyses but its depth distribution is not determined" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-mantle-rheology-x-viscoelasticity.yaml" }, { "id": "u-microseismic-acoustic-emission-b-value-failure", "title": "Can the b-value decrease observed in acoustic emission experiments before laboratory specimen failure be used as a reliable precursor metric for mine-scale and reservoir-scale microseismic failure, and what are the universal thresholds for warning?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Cross-scale calibration of b-value between lab specimens and field-scale rock masses is incomplete", "Lead time statistics for b-value precursors are not compiled across materials and field sites", "Effect of heterogeneity on false-positive rate of b-value precursors is unstudied" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-microseismic-acoustic-emission-b-value-failure.yaml" }, { "id": "u-mineral-nucleation-kinetics", "title": "What controls mineral nucleation kinetics in natural fluids, and why do classical nucleation theory predictions fail for many geological systems?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Direct observation of critical nuclei (sub-nanometer clusters) in natural solutions is still at the frontier of cryo-TEM and X-ray scattering techniques.", "The role of organic matter in templating mineral nucleation in sedimentary environments is poorly quantified.", "Multi-component natural solutions (with Mg, SO4, organic acids) have not been systematically tested against modified CNT frameworks." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-mineral-nucleation-kinetics.yaml" }, { "id": "u-neural-operator-generalization-groundwater-boundary-shift", "title": "How well do neural-operator groundwater surrogates generalize under boundary-condition and forcing shift?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-fourier-neural-operator-surrogates-accelerate-groundwater-inversion-with-calibrated-uncertainty" ], "file": "unknowns-catalog/geoscience/u-neural-operator-generalization-groundwater-boundary-shift.yaml" }, { "id": "u-nitrogen-cycle-jacobian-eigenstructure-versus-observed-anomalies", "title": "Do empirical decadal anomalies in ocean nitrate inventories and surface chlorophyll align with leading eigenmodes predicted by linearization of state-of-the-art coupled nitrogen–climate models around historical steady states?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Long observing-system records harmonized with ensemble model Jacobians at comparable spatial aggregation", "Attribution separating nitrogen-cycle eigenmodes from unrelated climate variability" ], "suggested_hypotheses": [ "h-linearized-n-cycle-models-predict-chlorophyll-mode-timescales" ], "file": "unknowns-catalog/geoscience/u-nitrogen-cycle-jacobian-eigenstructure-versus-observed-anomalies.yaml" }, { "id": "u-ocean-ultrasound-shared-inverse-regularizers", "title": "Can identical Bayesian regularizers (edge-preserving priors, sparsity transforms) achieve comparable reconstruction calibration errors when ported between basin-scale ocean acoustic tomography and clinical ultrasound transmission CT phantoms?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Paired publications applying identical MCMC uncertainty pipelines across modalities with harmonized discrepancy models", "Scale-aware calibration datasets bridging meter versus millimeter wavelengths without committing ecological fallacies" ], "suggested_hypotheses": [ "h-adjoint-base-resolution-operator-matches-ray-density-despite-scale-gap" ], "file": "unknowns-catalog/geoscience/u-ocean-ultrasound-shared-inverse-regularizers.yaml" }, { "id": "u-permafrost-thaw-subsidence", "title": "What are the rates, spatial patterns, and feedback mechanisms governing thermokarst formation and carbon release from thawing permafrost?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Remote sensing can detect thermokarst at 10–100 m scale but misses small features that may dominate total area.", "The lability of deep (Pleistocene-age) permafrost carbon is different from shallow layers but has been measured in only a few locations.", "Whether thermokarst lake drainage (methane source → carbon sink transition) accelerates or dampens the feedback is uncertain at landscape scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-permafrost-thaw-subsidence.yaml" }, { "id": "u-plate-boundary-fracture-scale-bridging", "title": "At what scale transitions from laboratory fracture toughness tests to fault-zone cohesive zones become predictive for macroscopic rupture energetics?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Integrated modeling pipelines coupling meter-scale lab friction experiments with dynamic rupture simulations under comparable strain rates", "Uncertainty quantification bridging cohesive lengths inferred from microstructures vs seismically inferred breakdown energies" ], "suggested_hypotheses": [ "h-plate-boundary-slip-x-fracture-mechanics" ], "file": "unknowns-catalog/geoscience/u-plate-boundary-fracture-scale-bridging.yaml" }, { "id": "u-plate-tectonics-x-convection", "title": "Why does Earth have plate tectonics while Venus and Mars do not, and what determines the transition between tectonic modes in planetary mantle convection?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The critical yield stress ratio (lithospheric strength / convective stress) for plate tectonics initiation has not been derived from first principles with realistic rheology", "Whether plate tectonics could occur without liquid water (anhydrous lithosphere) has not been determined from convection simulations at Earth-like Ra", "The tectonic history of early Earth (before 3.5 Ga) — whether it had plate tectonics or a different convection mode — is unresolved from geologic evidence" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-plate-tectonics-x-convection.yaml" }, { "id": "u-post-perovskite-implications", "title": "What are the dynamical and seismic implications of the post-perovskite phase transition in Earth's D'' layer?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The ppv stability field in a realistic pyrolite mantle composition is not well-constrained experimentally.", "Whether the D'' discontinuity is entirely explained by ppv or requires additional compositional layering is debated.", "The rheology of ppv and its contribution to D'' anisotropy are poorly constrained." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-post-perovskite-implications.yaml" }, { "id": "u-river-network-branching", "title": "Is river network branching geometry universal, and what physical principle selects Hack's law exponents and Horton ratios?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Analytic derivations of Hack's law exponent from erosion mechanics have not reproduced the empirical value (0.57–0.60) from first principles.", "Whether \"optimal channel networks\" correspond to actual physical minima or mathematical attractors of simplified models is unresolved.", "The influence of initial conditions (bedrock structure, initial topography) on final network geometry is difficult to disentangle from universal behavior." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-river-network-branching.yaml" }, { "id": "u-river-network-hacks-law-variability", "title": "Why does Hack's law exponent h vary systematically from 0.5 to 0.7 across different climate zones and lithologies, and what determines whether a drainage network converges to the OCN optimum or remains in a metastable suboptimal configuration?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Systematic compilation of h values with climate and lithology covariates across biomes is lacking", "OCN energy expenditure has not been computed for real networks to test minimisation", "Post-glacial network re-organisation timescales are poorly constrained" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-river-network-hacks-law-variability.yaml" }, { "id": "u-sea-level-fingerprint", "title": "How do sea-level fingerprints from individual ice mass changes allow attribution of observed sea-level trends to specific glacier and ice sheet sources?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "GIA models disagree by up to 1 mm/yr in sea-level equivalent, comparable to the fingerprint signals being detected.", "Terrestrial water storage changes (groundwater depletion, reservoir filling) contaminate the gravity signal used for fingerprinting.", "The sea-level fingerprint of the West Antarctic Ice Sheet cannot be separated from GIA in the instrumental record due to their similar spatial patterns." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-sea-level-fingerprint.yaml" }, { "id": "u-sediment-transport-nonlinearity", "title": "What are the nonlinear thresholds and stochastic dynamics governing sediment transport in rivers and their long-term geomorphic effects?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Sediment entrainment thresholds are empirically determined but lack a first-principles mechanical derivation for natural sediment mixtures.", "The contribution of rare catastrophic floods to long-term sediment flux vs. frequent moderate floods is poorly constrained in most field settings.", "Feedback between sediment supply, valley geometry, and transport capacity creates path-dependent landscape evolution that current models cannot capture." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-sediment-transport-nonlinearity.yaml" }, { "id": "u-seismic-wave-x-elastic-wave", "title": "Can full-waveform inversion (FWI) of seismic data recover the complete elastic tensor (anisotropic Cijkl) of the Earth's crust at 100m resolution, and what is the fundamental resolution limit imposed by seismic wavelengths and noise?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "FWI is non-convex with cycle-skipping local minima that prevent convergence without good initial models", "Full anisotropic tensor recovery requires complete azimuthal coverage not available in standard acquisition", "The information content of seismic data relative to the number of elastic parameters is not rigorously bounded" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-seismic-wave-x-elastic-wave.yaml" }, { "id": "u-serpentinization-hydrogen", "title": "What is the global flux of abiotic hydrogen produced by serpentinization, and can it support subsurface chemolithotrophs at ocean ridges and in continental settings?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "H2 flux measurements exist for only a handful of vent sites; interpolation to global ridge length is highly uncertain.", "The efficiency of H2 utilization by the subsurface biosphere at pressures >100 bar and temperatures >120°C is not well characterized.", "Whether continental serpentinization in ophiolites and cratonic cratons contributes significantly to the global H2 budget is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-serpentinization-hydrogen.yaml" }, { "id": "u-slow-slip-event-origin", "title": "What physical mechanism produces slow-slip events and episodic tremor-and-slip in subduction zones?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The rate-and-state friction parameters that produce SSE behavior (velocity-weakening at low slip rates?) have not been directly measured in deep megathrust rocks.", "Whether episodic SSEs are driven by fluid pressure waves propagating from depth or by frictional instability is unresolved.", "The stress transfer from SSE to the overlying locked zone cannot currently be modeled with sufficient resolution to assess hazard implications." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-slow-slip-event-origin.yaml" }, { "id": "u-snowball-earth-escape", "title": "How did Snowball Earth events end, and what prevented Earth from permanently freezing under high-albedo ice cover?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The CO2 concentration required to deglaciate depends on ice-albedo, cloud feedbacks, and dust deposition—all poorly constrained for a frozen Earth.", "Whether life could have persisted in equatorial open-water refugia under hard Snowball conditions is not settled by the fossil record.", "The duration of individual Snowball events (1–50 Myr) cannot be precisely determined from available radiometric dates." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-snowball-earth-escape.yaml" }, { "id": "u-soc-earthquake-precursor-detection", "title": "Do SOC early warning indicators (rising autocorrelation, variance divergence) in regional seismicity time series provide statistically significant precursors to large earthquakes (M > 6.5)?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "No systematic retrospective analysis of SOC indicators before all M > 6.5 events in a complete catalog", "False positive rate of SOC indicators not benchmarked against Poisson null model", "Spatial scale of precursor region not determined by SOC theory for realistic fault geometries" ], "suggested_hypotheses": [ "h-soc-earthquake-precursor-detection" ], "file": "unknowns-catalog/geoscience/u-soc-earthquake-precursor-detection.yaml" }, { "id": "u-soil-aggregate-fractal-dimension-stability-link", "title": "Does soil aggregate fractal dimension D_f provide a universal predictor of aggregate stability across soil types, management practices, and climates, and what is the causal mechanism linking fractal pore geometry to resistance against slaking and mechanical disruption?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Controlled experiments varying D_f independently of organic matter content are lacking", "D_f-stability relationships across climate zones and tillage systems are not compiled", "Non-destructive D_f measurement methods with field applicability are not established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-soil-aggregate-fractal-dimension-stability-link.yaml" }, { "id": "u-subduction-initiation", "title": "How does subduction initiation occur, and can it begin spontaneously from a passive margin without a pre-existing plate boundary?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "No modern analog for spontaneous subduction initiation has been confirmed.", "The stress thresholds for passive-margin conversion are unconstrained by direct observation.", "Numerical models disagree on whether water weakening of the lithosphere is required for initiation." ], "suggested_hypotheses": [ "Subduction cannot initiate spontaneously without pre-existing structural weakness (transform faults, fracture zones); all observed initiations are induced by external stress." ], "file": "unknowns-catalog/geoscience/u-subduction-initiation.yaml" }, { "id": "u-supervolcano-eruption-forecasting", "title": "What are the precursors and timescales of supereruption onset at caldera systems like Yellowstone and Campi Flegrei?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The proportion of eruptible melt vs. crystal mush in active caldera systems cannot be resolved by current seismic tomography.", "Ground deformation models for large calderas cannot distinguish magma intrusion from hydrothermal system pressurization.", "No supersystem has produced a VEI 8 eruption in the instrumental record; all forecasting relies on geological analogy." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-supervolcano-eruption-forecasting.yaml" }, { "id": "u-thermohaline-circulation-x-buoyancy-flow", "title": "Is the Atlantic Meridional Overturning Circulation (AMOC) currently approaching a saddle-node bifurcation tipping point, and what observational fingerprint would provide advance warning of an irreversible collapse?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "CMIP6 models underestimate AMOC sensitivity to freshwater forcing due to insufficient resolution of mesoscale eddies", "The freshwater budget of the South Atlantic (a key AMOC precursor region) has observational gaps of ±0.1 Sv", "No observational system can directly measure the distance to the saddle-node bifurcation point without knowing all model parameters" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-thermohaline-circulation-x-buoyancy-flow.yaml" }, { "id": "u-tsunami-dispersive-nonlinearity-regime-classification", "title": "Can operational tsunami forecast diagnostics classify approaching wave trains into bore-dominated versus dispersive-trailing-wave regimes early enough to improve inundation estimates beyond hydrostatic shallow-water defaults?\n", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Curated buoy datasets with concurrent bottom-pressure and coastal tide-gauge chains annotated by regime proxies (Ursell number, nonlinear parameter).", "Coupled-model validation exercises separating integrable toy limits from realistic-breaking fronts." ], "suggested_hypotheses": [ "h-tsunami-front-regime-classifier-nonlinear-dispersive-bore" ], "file": "unknowns-catalog/geoscience/u-tsunami-dispersive-nonlinearity-regime-classification.yaml" }, { "id": "u-tsunami-submarine-slides", "title": "What are the physics of tsunami generation by submarine landslides, and how does slide rheology control wave amplitude and runup?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Laboratory experiments on slide-generated waves use simplified geometries; scaling to oceanic bathymetry is unvalidated.", "Submarine landslide catalogs are incomplete because most submarine slopes have not been mapped at sufficient resolution.", "Whether climate change (warming oceans destabilizing gas hydrates) is currently increasing submarine slope instability is unquantified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-tsunami-submarine-slides.yaml" }, { "id": "u-unet-satellite-flood-generalization-under-cloud-noise", "title": "How well do U-Net flood-segmentation models generalize under cloud cover, sensor differences, and regional terrain shifts?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "Sparse benchmark coverage for extreme weather and persistent cloud conditions.", "Limited reporting of uncertainty calibration for flood-boundary predictions.", "Inconsistent label quality across agencies and regions." ], "suggested_hypotheses": [ "h-unet-domain-randomization-improves-flood-mapping-recall" ], "file": "unknowns-catalog/geoscience/u-unet-satellite-flood-generalization-under-cloud-noise.yaml" }, { "id": "u-xenolith-mantle-bias", "title": "To what extent do mantle xenoliths provide a representative sample of the lithospheric mantle, and what biases are introduced by entrainment and transport?", "status": "open", "domain": "geoscience", "systematic_gaps": [ "The depth from which xenoliths are sampled is estimated from thermobarometry but has systematic errors from retrograde re-equilibration.", "The chemical signature of kimberlite-mantle interaction (metasomatism) cannot always be separated from primary mantle signatures.", "The spatial coverage of xenolith localities is highly uneven; large portions of cratons have no xenolith samples." ], "suggested_hypotheses": [], "file": "unknowns-catalog/geoscience/u-xenolith-mantle-bias.yaml" }, { "id": "u-epigenetic-clock-causal-mechanism", "title": "Are DNA methylation epigenetic clocks a causal driver of aging or a downstream biomarker, and which specific CpG sites regulate aging-related gene expression versus merely correlate with it?", "status": "open", "domain": "geroscience", "systematic_gaps": [ "No experiment has demonstrated that reversing methylation at a subset of clock CpGs extends lifespan without full reprogramming", "The chromatin context of clock CpGs (enhancers, promoters, repeats) is catalogued but functional roles are not established", "Single-cell resolution shows high methylation heterogeneity within tissues; bulk clock measurements may obscure causal cell types" ], "suggested_hypotheses": [], "file": "unknowns-catalog/geroscience/u-epigenetic-clock-causal-mechanism.yaml" }, { "id": "u-glacier-basal-sliding-uncertainty", "title": "What is the correct sliding law relating basal velocity to effective pressure and bed roughness in glaciers, and why do different formulations produce order-of-magnitude differences in ice sheet projections?", "status": "open", "domain": "glaciology", "systematic_gaps": [ "No direct borehole measurements of sliding velocity with simultaneous bed characterization at outlet glacier scale", "Transition between Weertman and Coulomb regimes is poorly constrained by both theory and observation", "Subglacial hydrology (water pressure governing effective pressure) is highly dynamic and unobservable at relevant scales" ], "suggested_hypotheses": [], "file": "unknowns-catalog/glaciology/u-glacier-basal-sliding-uncertainty.yaml" }, { "id": "u-glacier-calving-crack-propagation-threshold", "title": "What stress intensity factor threshold governs full-depth crevasse propagation to the glacier bed, and how do basal water pressure, ice temperature, and crystal fabric anisotropy modulate the effective fracture toughness of Antarctic and Greenlandic outlet glaciers?", "status": "open", "domain": "glaciology", "systematic_gaps": [ "Direct measurement of ice fracture toughness K_Ic in situ at glacier termini under realistic confining pressure is rarely done", "Full-depth water pressure in crevasses on outlet glaciers is poorly constrained by remote sensing", "Coupling between tidal stress cycles and crack-tip fatigue has not been quantified for marine-terminating glaciers" ], "suggested_hypotheses": [], "file": "unknowns-catalog/glaciology/u-glacier-calving-crack-propagation-threshold.yaml" }, { "id": "u-black-hole-information-paradox-bulk-reconstruction", "title": "Does the island formula (quantum extremal surface prescription) provide a complete resolution of the black hole information paradox in full quantum gravity, or only within the semiclassical approximation where the bulk geometric saddle points are well-defined — and what is the mechanism by which bulk quantum fields reconstruct the interior from boundary data after the Page time?\n", "status": "open", "domain": "gravitational-physics", "systematic_gaps": [ "Island formula in 4D asymptotically flat black holes — Penington and Almheiri's derivations used 2D JT gravity or AdS/CFT; the 4D Schwarzschild case has not been derived from first principles.", "The explicit quantum error correcting code mapping bulk operators to boundary operators (entanglement wedge reconstruction) in dynamical evaporating geometries has not been constructed.", "Whether the Page curve is reproduced in de Sitter space (no boundary / observer- dependent horizon) using island formula is contested." ], "suggested_hypotheses": [ "The island formula in 4D flat-space black holes requires non-perturbative wormhole contributions that are suppressed by exp(−A/4G) — parametrically small in Planck units — and the replica wormhole saddle requires topology change in quantum gravity that is only well-defined in string theory or other UV-complete theories; semiclassical derivations that ignore UV completion miss O(1) corrections to the Page curve near the endpoint of evaporation.\n" ], "file": "unknowns-catalog/gravitational-physics/u-black-hole-information-paradox-bulk-reconstruction.yaml" }, { "id": "u-gauge-gravity-duality-mechanism", "title": "What is the precise mathematical mechanism by which AdS/CFT duality maps quantum gravity in anti-de Sitter space to conformal field theory on its boundary?", "status": "open", "domain": "gravitational-physics", "systematic_gaps": [ "No proof of AdS/CFT from string theory first principles exists; all checks are in specific limits (large N, strong coupling) where independent calculation is possible.", "The duality relies on supersymmetry; whether a non-supersymmetric version exists for realistic QCD-like theories is unresolved (holographic QCD is approximate)." ], "suggested_hypotheses": [], "file": "unknowns-catalog/gravitational-physics/u-gauge-gravity-duality-mechanism.yaml" }, { "id": "u-quantum-gravity-semiclassical-limit", "title": "How does quantum gravity reduce to general relativity in the semiclassical limit, and what observable corrections to GR does quantum gravity predict?", "status": "open", "domain": "gravitational-physics", "systematic_gaps": [ "No quantum gravity theory makes predictions at currently achievable energy scales that differ from GR + quantum field theory predictions.", "The black hole information paradox (Hawking radiation and unitarity violation) remains unresolved; proposed solutions (fuzzball, firewall, island formula) differ in predictions for specific observables." ], "suggested_hypotheses": [], "file": "unknowns-catalog/gravitational-physics/u-quantum-gravity-semiclassical-limit.yaml" }, { "id": "u-aging-interventions-translatability", "title": "The degree to which longevity and healthspan interventions validated in model organisms quantitatively predict human-relevant outcomes remains unsettled across intervention classes", "status": "open", "domain": "high-priority", "systematic_gaps": [ "Heterogeneous endpoints (survival vs molecular biomarkers) complicate cross-species comparison protocols." ], "suggested_hypotheses": [ "h-conserved-metabolic-bottlenecks-longevity" ], "file": "unknowns-catalog/high-priority/u-aging-interventions-translatability.yaml" }, { "id": "u-amyloid-progression-trajectory", "title": "What determines whether amyloid-beta accumulation in an individual brain follows a slow, decades-long trajectory versus rapid escalation to clinical Alzheimer's disease", "status": "open", "domain": "high-priority", "systematic_gaps": [ "Longitudinal amyloid PET studies show high inter-individual variability in progression rates; the biological factors that predict fast vs slow accumulation are not established.", "The relationship between amyloid load and tau propagation is probabilistic, not deterministic — some individuals show high amyloid burden with minimal tau spread and preserved cognition for years.", "Latent progression models (e.g. trajectory clustering from imaging data) identify distinct subgroups but cannot resolve whether differences arise from genetics, vascular co-pathology, synaptic resilience, or clearance rate variation.", "Glymphatic clearance efficiency (sleep-dependent CSF flow) is hypothesized as a modifiable rate-limiter, but causal evidence in humans is limited." ], "suggested_hypotheses": [ "h-glymphatic-amyloid-clearance-rate" ], "file": "unknowns-catalog/high-priority/u-amyloid-progression-trajectory.yaml" }, { "id": "u-brain-criticality-function", "title": "Whether the brain operates near a critical phase transition as a functional necessity, or whether criticality is an emergent side-effect of neural dynamics that serves no privileged computational role", "status": "open", "domain": "high-priority", "systematic_gaps": [ "Most evidence for criticality (power-law avalanche distributions, maximal dynamic range) is observational and correlational; causal interventions that push a system away from criticality and measure functional degradation are scarce.", "The definition of \"critical\" varies across studies (branching ratio, Lyapunov exponents, susceptibility peaks), making cross-study comparisons unreliable.", "Self-organized criticality models predict specific signatures that are difficult to distinguish from sub-critical or supercritical dynamics given realistic measurement noise.", "It is unclear whether criticality is a property of the whole brain, local circuits, or specific projection systems." ], "suggested_hypotheses": [ "h-criticality-conscious-integration" ], "file": "unknowns-catalog/high-priority/u-brain-criticality-function.yaml" }, { "id": "u-dark-matter-microphysics", "title": "The particle or field microphysics of galactic dark matter remains unidentified while cosmological and astrophysical evidence for its gravitational effects is strong", "status": "open", "domain": "high-priority", "systematic_gaps": [ "Direct detection and laboratory constraints narrowly bound some models but do not yet identify a unique microphysical explanation across scales." ], "suggested_hypotheses": [ "h-radio-axion-like-dm-constraints" ], "file": "unknowns-catalog/high-priority/u-dark-matter-microphysics.yaml" }, { "id": "u-borrelia-persister-cell-eradication", "title": "Why do Borrelia persister cells survive standard doxycycline treatment, and what combination antibiotic regimen or host-directed therapy can reliably eradicate them?\n", "status": "open", "domain": "immunology", "systematic_gaps": [ "No validated human biomarker or assay for detecting viable Borrelia persisters in post-treatment PTLDS patients (serology detects antibodies, not live bacteria; PCR misses low-burden persister-phase organisms)", "The triple combination (daptomycin + doxycycline + cefuroxime) from Feng et al. (2015) has not been tested in primate models with established post-treatment infection", "CNS penetration of daptomycin is insufficient for neuroborreliosis — an alternative membrane-disrupting agent with BBB penetration is needed for neuro-Lyme persister eradication", "The frequency of true persister cells in human PTLDS tissue (synovium, skin, CSF) is unknown; xenodiagnosis (tick feeding on PTLDS patients) studies have produced conflicting results", "Host-directed therapy approaches (e.g., enhancing macrophage phagocytosis of persister-form Borrelia) have not been investigated" ], "suggested_hypotheses": [ "h-borrelia-triple-combo-persister-eradication" ], "file": "unknowns-catalog/immunology/u-borrelia-persister-cell-eradication.yaml" }, { "id": "u-immune-escape-ess-predictions", "title": "Can evolutionary stable strategy theory from game theory quantitatively predict the equilibrium diversity of immune escape mutations maintained by frequency-dependent selection in chronic viral infections?", "status": "open", "domain": "immunology", "systematic_gaps": [ "The cross-reactivity matrix (payoff matrix) for immune responses to influenza has not been measured at sufficient resolution to parameterize ESS models.", "Quantitative tests of ESS diversity predictions for within-host HIV variant diversity are lacking in natural infection cohorts.", "Game-theoretic vaccine design (designing vaccines to shift the ESS to benign strains) has not been applied clinically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/immunology/u-immune-escape-ess-predictions.yaml" }, { "id": "u-immune-treg-pi-control-quantitative", "title": "Can the IL-2/Treg feedback loop be quantitatively characterized as a PI controller with measurable gain constants, and does controller theory predict observed autoimmune disease dynamics?", "status": "open", "domain": "immunology", "systematic_gaps": [ "Quantitative measurement of IL-2 sensitivity and Treg expansion kinetics (K_p, K_i) from in vivo data has not been done in a control-theoretic framework.", "The effective loop delay in the IL-2/Treg feedback loop has not been measured with sufficient resolution to predict oscillation frequency.", "Whether relapsing-remitting autoimmune disease oscillation frequencies match PI controller predictions has not been systematically tested.", "Personalized controller parameter estimation from clinical biomarkers has not been attempted." ], "suggested_hypotheses": [ "Patients with type 1 diabetes have reduced K_i (lower Treg expansion per unit IL-2) compared to healthy controls, quantifiable from blood IL-2 and Treg time-series data." ], "file": "unknowns-catalog/immunology/u-immune-treg-pi-control-quantitative.yaml" }, { "id": "u-lnp-tissue-targeting-mechanism", "title": "What molecular and biophysical mechanisms govern LNP organ selectivity, and can rational lipid design achieve reliable non-hepatic tissue targeting for mRNA therapeutics?", "status": "open", "domain": "immunology", "systematic_gaps": [ "The protein corona composition of organ-selective LNPs (and its dynamics in vivo) has not been systematically correlated with tissue biodistribution across a broad lipid chemical space.", "The biophysical mechanism by which the fifth (targeting) lipid in SORT-LNPs changes protein corona composition is unknown.", "Blood-brain barrier (BBB) penetration by LNPs is very low; whether any lipid formulation can achieve clinically relevant CNS mRNA delivery without direct CNS injection is unknown." ], "suggested_hypotheses": [ "The fifth lipid in SORT-LNP formulations alters LNP surface charge density, which determines the composition of the protein corona (ApoE vs ApoA1 vs other serum proteins), which in turn determines organ tropism." ], "file": "unknowns-catalog/immunology/u-lnp-tissue-targeting-mechanism.yaml" }, { "id": "u-tcr-foundation-model-ood-binding-generalization", "title": "Do TCR foundation models generalize binding predictions to out-of-distribution epitopes?", "status": "open", "domain": "immunology", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-tcr-foundation-pretraining-improves-antigen-specificity-recall" ], "file": "unknowns-catalog/immunology/u-tcr-foundation-model-ood-binding-generalization.yaml" }, { "id": "u-tcr-repertoire-pathogen-space-coverage", "title": "Does the ~10⁷ naive T-cell repertoire provide sufficient coverage of pathogen peptide-MHC space, and what is the quantitative relationship between repertoire diversity, thymic selection stringency, and resistance to novel pathogens?", "status": "open", "domain": "immunology", "systematic_gaps": [ "The dimensionality of TCR-pMHC shape space has not been empirically determined; theoretical estimates range from d=10 to d=64 (number of amino acids determining binding), dramatically changing the predicted minimum repertoire size.", "The cross-reactivity radius r (fraction of randomly sampled peptide-MHC that a given TCR can recognize) is estimated at 10^-5 to 10^-6 from experimental data but varies by 100-fold across studies, preventing a quantitative test of the covering theory.", "Whether TCR repertoire diversity (as measured by deep sequencing) correlates with breadth of antigen recognition in primary responses to novel pathogens has not been established in prospective cohort studies controlling for prior exposure history." ], "suggested_hypotheses": [ "The effective dimensionality of TCR-pMHC shape space is d=15±5 (determined by the contact residues of TCR CDR3 loops), and the observed ~10⁷ naive repertoire size corresponds to the percolation threshold for 99% pathogen coverage at the empirically measured cross-reactivity radius r≈10^-5." ], "file": "unknowns-catalog/immunology/u-tcr-repertoire-pathogen-space-coverage.yaml" }, { "id": "u-idiotypic-network-clinical-validation", "title": "Whether Jerne's idiotypic network theory can be validated using modern B-cell receptor (BCR) repertoire sequencing, and whether idiotypic network topology measurably differs between healthy individuals and those with autoimmune disease\n", "status": "open", "domain": "immunology-network-science", "systematic_gaps": [ "BCR-seq can now sequence millions of B-cell clonotypes per individual, but computational methods to reconstruct idiotypic connectivity (which antibody recognises which other) from sequence data alone are not established.", "Anti-idiotypic reactivity requires structural complementarity between antibody variable regions; predicting this from sequence without structural data requires validated computational tools that do not yet exist.", "Clinical studies comparing idiotypic network topology in autoimmune vs. healthy subjects are essentially absent; the theory predicts measurable differences but has not been operationalised for modern sequencing data.", "The idiotypic network in vivo may be far sparser than classical theory assumed; the fraction of antibody pairs with measurable anti-idiotypic reactivity is unknown at the repertoire scale." ], "suggested_hypotheses": [ "h-autoimmune-disease-idiotypic-attractor-bifurcation" ], "file": "unknowns-catalog/immunology-network-science/u-idiotypic-network-clinical-validation.yaml" }, { "id": "u-mae-cryo-em-prior-induced-hallucination-risk", "title": "Do masked-autoencoder priors introduce structural hallucination risk in low-SNR cryo-EM reconstruction?", "status": "open", "domain": "infectious-disease", "systematic_gaps": [ "Limited controlled benchmarks with known ground-truth structures at varying SNR levels.", "Inconsistent reporting of reconstruction confidence and hallucination diagnostics.", "Few studies test pretraining transfer across pathogen families." ], "suggested_hypotheses": [ "h-masked-autoencoder-pretraining-improves-cryo-em-low-snr-reconstruction" ], "file": "unknowns-catalog/infectious-disease/u-mae-cryo-em-prior-induced-hallucination-risk.yaml" }, { "id": "u-regret-aware-safety-constraints-for-antibiotic-de-escalation-bandits", "title": "What failure boundaries determine when `b-multi-armed-bandits-x-sepsis-antibiotic-de-escalation` remains decision-useful?", "status": "open", "domain": "infectious-disease", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-constrained-bandit-policies-reduce-sepsis-antibiotic-overtreatment-days" ], "file": "unknowns-catalog/infectious-disease/u-regret-aware-safety-constraints-for-antibiotic-de-escalation-bandits.yaml" }, { "id": "u-entropy-rate-nonstationary-language-data", "title": "How far below Shannon entropy-rate bounds can large language models push perplexity when corpora are demonstrably nonstationary across domains and eras?", "status": "open", "domain": "information-theory", "systematic_gaps": [ "Joint entropy-rate estimators on sliding corpora matched to LM evaluation splits by provenance and date", "Confidence intervals on perplexity deltas under correlated sequential datasets violating IID assumptions in classical entropic proofs" ], "suggested_hypotheses": [ "h-entropy-rate-x-language-model-perplexity" ], "file": "unknowns-catalog/information-theory/u-entropy-rate-nonstationary-language-data.yaml" }, { "id": "u-genetic-code-information-optimality", "title": "Whether the standard genetic code is globally optimal for error minimisation among all possible codon table assignments, and whether its optimality reflects historical contingency, selection pressure, or mathematical inevitability\n", "status": "open", "domain": "information-theory-genetics", "systematic_gaps": [ "Freeland & Hurst (1998) showed the standard code is better than ~1 in 10^6 random codes at minimising amino acid property change per substitution, but exhaustive optimisation over all 10^84 possible codes is computationally intractable.", "It is unclear whether the genetic code's optimality is a frozen accident (one of many near-optimal solutions) or a unique global optimum.", "The fitness function used to evaluate codes (amino acid physicochemical similarity) is debated; polar requirement, hydrophobicity, or chemical reactivity may be the relevant property.", "The co-evolution of the code with tRNA anticodons and aminoacyl-tRNA synthetases means optimality is constrained by biochemical reachability, not just combinatorics." ], "suggested_hypotheses": [ "h-genetic-code-error-correcting-design" ], "file": "unknowns-catalog/information-theory-genetics/u-genetic-code-information-optimality.yaml" }, { "id": "u-bilingual-cognitive-advantage-replication", "title": "Does bilingualism confer measurable cognitive advantages in executive function, and why have many key findings failed to replicate?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The definition of bilingualism (degree of proficiency, age of acquisition, language use frequency) varies so much across studies that comparison is difficult.", "Publication bias in favour of positive results severely inflates effect size estimates in meta-analyses.", "Laboratory executive function tasks may not reflect real-world cognitive performance differences." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-bilingual-cognitive-advantage-replication.yaml" }, { "id": "u-birdsong-syntax-generative-grammar-limits", "title": "Do any wild bird species produce vocal sequences that require context-sensitive (Type 1 Chomsky) grammar to describe, and what neural circuit architecture would be necessary to support the additional computational power beyond a pushdown automaton?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Playback experiments designed to test context-sensitive dependencies in birdsong have not been conducted for most species", "Neural recording during natural song production in wild birds is technically challenging, limiting mechanistic inference", "The statistical power of corpus-based grammar inference depends on song corpus size; most field studies are underpowered for Type 2 vs. Type 1 discrimination" ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-birdsong-syntax-generative-grammar-limits.yaml" }, { "id": "u-creole-genesis-mechanism", "title": "What grammatical and social mechanisms produce creole languages from contact situations, and is there a universal creole prototype?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The bioprogramme hypothesis predicts specific creole universals that are contested across cases.", "The role of adults versus children in creolisation has not been determined from historical records.", "Creole formation in contemporary signed language contact situations has not been fully studied." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-creole-genesis-mechanism.yaml" }, { "id": "u-creole-universals-origin", "title": "Why do creole languages independently converge on similar grammatical features, and does this reflect innate structure or contact dynamics?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Historical documentation of creole genesis situations is fragmentary for most creoles", "The bioprogramme makes specific predictions that are contested across creoles", "Universal second-language acquisition biases cannot be distinguished from innate structure", "The degree to which creole grammatical features are stable across generations is understudied" ], "suggested_hypotheses": [ "h-bioprogramme-tma-prediction", "h-creole-l2-convergence" ], "file": "unknowns-catalog/linguistics/u-creole-universals-origin.yaml" }, { "id": "u-dialect-contact-as-graph-diffusion", "title": "When does a pure diffusion model fail for dialect features because of identity-driven categorical switching, and how can mixtures be identified from atlas data?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Sparse temporal sampling in historical atlases limits dynamic fitting.", "Contact often involves bilingualism with code-switching not captured by single-feature diffusion." ], "suggested_hypotheses": [ "h-lexical-diffusion-on-geographic-graphs-predicts-isoglosses" ], "file": "unknowns-catalog/linguistics/u-dialect-contact-as-graph-diffusion.yaml" }, { "id": "u-endangered-language-documentation-priority", "title": "What documentation strategies best preserve endangered languages for future linguistic and cultural research, and how should priorities be set?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The relative value of different documentation types for future linguistic research versus community use are not empirically assessed.", "Digital preservation formats and archiving standards are not standardised across documentation projects, creating fragmentation.", "The effectiveness of documentation in supporting later revitalisation has not been systematically evaluated across projects." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-endangered-language-documentation-priority.yaml" }, { "id": "u-gesture-language-interface", "title": "What is the cognitive and neural relationship between gesture and speech, and does gesture play a constitutive role in language production and comprehension?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The neural regions integrating gesture and speech have been identified but the computational mechanisms of integration are not modelled.", "Whether gesturing facilitates thinking or merely indexes thinking is not experimentally distinguished in current paradigms.", "Cross-cultural variation in gesture use and its effects on comprehension are undercharacterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-gesture-language-interface.yaml" }, { "id": "u-historical-reconstruction-limit", "title": "What is the temporal limit of reliable linguistic reconstruction, and can proto-language families beyond 10,000 years be validly inferred?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No agreed statistical method distinguishes deep genealogical relationship from chance similarity at timescales beyond 10,000 years.", "Mass comparison (Greenberg) and the comparative method give different and incompatible results on the same language groupings.", "Archaeological and genetic evidence is inconsistent with some linguistic family groupings and cannot resolve the disputes." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-historical-reconstruction-limit.yaml" }, { "id": "u-language-acquisition-poverty-stimulus", "title": "Does the logical problem of language acquisition (poverty of the stimulus) require innate grammatical knowledge, or can it be solved by statistical learning?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The statistical information available to children for specific grammatical structures (e.g. subject-auxiliary inversion) has not been exhaustively computed from child-directed speech corpora.", "Large language models acquire apparently structure-dependent knowledge from text, but they receive vastly more input than children and lack embodied experience.", "The age at which specific grammatical structures are acquired cross-linguistically does not follow predictions of either strong nativist or strong empiricist models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-acquisition-poverty-stimulus.yaml" }, { "id": "u-language-contact-convergence-limit", "title": "What is the maximum degree of structural convergence possible between unrelated contact languages, and what constraints prevent full convergence?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "A typologically complete borrowability hierarchy for all structural features has not been established.", "The social conditions that facilitate versus resist structural borrowing are not generalised.", "Timescales required for structural convergence in different feature domains are not estimated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-contact-convergence-limit.yaml" }, { "id": "u-language-death-reversal-feasibility", "title": "Under what conditions can a dying language be successfully revitalised, and what are the cognitive and social prerequisites for sustainable reversal?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No validated predictive model identifies which endangered languages are most likely to benefit from intervention.", "The role of written tradition versus oral transmission in revitalisation success is not established across cases.", "Long-term outcomes of language nests and immersion education beyond 20 years have not been tracked." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-death-reversal-feasibility.yaml" }, { "id": "u-language-evolution-emergence", "title": "How and when did language evolve in the hominin lineage, and what were the anatomical, neural, and social preconditions?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "FOXP2 mutations affecting language in humans are present in Neandertals but FOXP2 alone does not determine language ability.", "The genetic basis of the full language apparatus spans hundreds of genes; evolutionary reconstruction is not possible from known variants.", "Archaeological proxies for language (symbolic behaviour, complex tools) may reflect other cognitive capacities rather than language specifically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-evolution-emergence.yaml" }, { "id": "u-language-evolution-selection-neutrality", "title": "Can linguistic change rates be decomposed into neutral drift and selection components, and which grammatical features are under positive, purifying, or balancing selection in human populations?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "A rigorous method for computing linguistic Tajima's D (neutral vs. selected change) from corpus data has not been developed.", "The effective population size for linguistic drift in different community types (isolated village, urban center, written tradition) has not been quantified.", "Whether grammaticalization is driven by selection for processing efficiency or by neutral functional reanalysis is not resolved.", "Cross-linguistic comparison of change rates with phylogenetic control, testing for selection signatures, has not been done at the level of morphological paradigms." ], "suggested_hypotheses": [ "Grammatical features encoding information-theoretically efficient distinctions (high UID — uniform information density) evolve under positive selection and show convergent evolution in unrelated language families." ], "file": "unknowns-catalog/linguistics/u-language-evolution-selection-neutrality.yaml" }, { "id": "u-language-model-meaning-vs-human", "title": "Do large language models have genuine semantic understanding of language meaning, or do they manipulate form without accessing meaning?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No agreed operationalisation of \"genuine understanding\" exists that would distinguish LLM competence from human competence.", "LLMs fail on systematic generalisation tasks in ways that human language users do not, but the nature of these failures is disputed.", "Whether grounding language in perception and action is necessary for semantic understanding or merely sufficient cannot be determined from current experiments." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-model-meaning-vs-human.yaml" }, { "id": "u-language-thought-causality", "title": "Does the grammar of a language causally shape non-linguistic cognition (strong Sapir-Whorf), or only correlate with it?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Most studies use correlational designs that cannot establish causal direction", "Color naming experiments conflate linguistic encoding with perceptual salience", "Artificial language learning paradigms alter many variables simultaneously", "Replication rates for Sapir-Whorf effects are low in pre-registered studies" ], "suggested_hypotheses": [ "h-weak-linguistic-relativity-spatial-frames" ], "file": "unknowns-catalog/linguistics/u-language-thought-causality.yaml" }, { "id": "u-language-thought-interface", "title": "Is language necessary for abstract thought, or can complex reasoning occur in pre-linguistic or non-linguistic representational formats?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Patients with severe aphasia who lose language production/comprehension sometimes retain complex reasoning abilities, but the extent is debated.", "Pre-linguistic infants demonstrate abstract numerical and causal reasoning, but whether this is linguistic is definitionally circular.", "The mentalese hypothesis (inner language of thought) is unfalsifiable in its strong form." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-thought-interface.yaml" }, { "id": "u-language-universals-typology", "title": "Which linguistic features are truly universal across all human languages, and what explains the implicational universals observed in typological surveys?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "WALS (World Atlas of Language Structures) covers only a fraction of languages and is biased toward documented, larger languages.", "The distinction between hard universals and strong tendencies has not been resolved due to insufficient typological coverage.", "Processing efficiency explanations for word order universals have been challenged by the existence of flexible word order languages that are also common." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-language-universals-typology.yaml" }, { "id": "u-linguistic-relativity-cognition", "title": "Does the language one speaks causally shape non-linguistic thought and perception, and to what degree does the Sapir-Whorf hypothesis hold?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Distinguishing linguistic from cultural effects in cross-linguistic studies is methodologically difficult.", "Color perception effects of linguistic categories have been replicated with different spatial patterns across studies.", "The neural mechanisms by which linguistic categories influence pre-linguistic perception are not known." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-linguistic-relativity-cognition.yaml" }, { "id": "u-linguistic-relativity-color-perception", "title": "Does the number and location of color term boundaries in a language causally affect the speed and accuracy of cross-category color discrimination?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Perceptual interference studies (where verbal interference reduces the color categorical perception effect) are not conclusive about whether the effect is pre-linguistic.", "Cross-cultural color categorisation studies rely on Munsell chips that may not be culturally neutral stimuli.", "The effect size of cross-linguistic color categorical perception differences is small and contested in meta-analyses." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-linguistic-relativity-color-perception.yaml" }, { "id": "u-metaphor-universality", "title": "Are conceptual metaphors universal across languages and cultures, or are they culturally specific constructions reflecting local experience?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Cross-linguistic corpus studies of conceptual metaphor are biased toward Indo-European languages.", "Distinguishing universal from widespread-but-not-universal metaphors requires very broad typological sampling not yet done.", "The relationship between linguistic metaphor and non-linguistic analogical reasoning is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-metaphor-universality.yaml" }, { "id": "u-natural-language-complexity-class", "title": "Does human natural language belong strictly to the mildly context-sensitive class, and can transformer language models generate or recognize all and only the languages in this class?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No rigorous experimental protocol exists to determine the complexity class of a natural language from corpus data — existing arguments rely on constructed examples (cross-serial dependencies) that are grammatical but may not be representative of actual usage frequency.", "The computational complexity of human language parsing is confounded with processing difficulty — theoretical grammar and performance grammar diverge in ways that make the complexity question empirically inaccessible from behavioral data alone.", "Transformer LMs' formal language recognition abilities have been tested on artificial grammars but not systematically on the full range of MCSL constructions; the precise boundary of what transformers can and cannot recognize is unknown." ], "suggested_hypotheses": [ "Transformers with unlimited depth and width recognize exactly the class of languages recognizable by O(n²)-space computation — strictly between context-free and context-sensitive — matching the mildly context-sensitive class that best characterizes human language." ], "file": "unknowns-catalog/linguistics/u-natural-language-complexity-class.yaml" }, { "id": "u-pragmatic-inference-neural-basis", "title": "What neural mechanisms support pragmatic inference (implicature, irony, indirect speech), and why are these mechanisms impaired in autism spectrum conditions?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The neural basis of scalar implicature (interpreting \"some\" as \"not all\") is disputed between left and right hemisphere theories.", "The relationship between pragmatic impairment in ASD and theory of mind deficit is correlational, not causal.", "Pragmatic inference in second language speakers recruits different neural circuits than in native speakers; the developmental trajectory is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-pragmatic-inference-neural-basis.yaml" }, { "id": "u-predictive-coding-grammar-neural-substrate", "title": "Which cortical layers and circuits implement the prediction vs. prediction-error hierarchy for syntactic processing, and does the same architecture that codes word-level surprisal also code phrase-structure violations at a higher hierarchical level?\n", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No laminar fMRI study has directly tested whether syntactic predictions originate in deep layers of IFG/temporal cortex and syntactic errors are encoded in superficial layers", "The quantitative relationship between word-level surprisal (Levy 2008 reading times) and N400 amplitude has been replicated but not extended to surprisal at the phrase and clause level with matched statistical controls", "Whether precision-weighting in syntactic processing corresponds to measurable attention effects (pupillometry, alpha-band desynchronization) at syntactic dependency boundaries has not been tested" ], "suggested_hypotheses": [ "N400 amplitude scales linearly with word surprisal (-log P(w|context)) even when controlling for semantic plausibility, word frequency, and phonological neighborhood density — a pure syntactic surprisal effect derivable from the predictive coding model" ], "file": "unknowns-catalog/linguistics/u-predictive-coding-grammar-neural-substrate.yaml" }, { "id": "u-prosodic-bootstrapping-acquisition", "title": "Does prosodic structure in infant-directed speech provide bootstrapping cues for syntactic acquisition, and how large is its contribution?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The specific syntactic information that can be inferred from prosodic patterns alone has not been formally delimited.", "Cross-linguistic infant studies on prosodic bootstrapping are biased toward English; rhythmically different languages have not been comparably studied.", "The interaction between prosodic bootstrapping and semantic or pragmatic bootstrapping has not been modelled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-prosodic-bootstrapping-acquisition.yaml" }, { "id": "u-prosody-meaning-interface", "title": "How do prosodic contours (pitch, rhythm) systematically modulate propositional meaning across languages?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The semantics of L+H* versus H* nuclear pitch accents is not cross-linguistically stable", "Interaction of lexical tone and intonation in tonal languages is incompletely modeled", "Psychophysical experiments on prosody interpretation have not produced a unified model", "Neural processing of prosodic meaning is poorly dissociated from syntactic parsing" ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-prosody-meaning-interface.yaml" }, { "id": "u-prosody-meaning-mapping", "title": "How are the acoustic properties of prosody (pitch, duration, rhythm) systematically mapped to meaning, and how is this mapping acquired?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "A unified formal account of prosody that handles both intonation phonology and pragmatic meaning in all language types does not exist.", "The acquisition timeline of prosody compared to segmental phonology has not been systematically cross-linguistically compared.", "Prosodic disambiguation in parsing (bracketing prosody) is modelled separately from information-structural prosody without unification." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-prosody-meaning-mapping.yaml" }, { "id": "u-recursion-uniquely-human", "title": "Is syntactic recursion uniquely human and essential for language, or do non-human animals possess recursive cognitive mechanisms?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The claim that Piraha lacks recursion is disputed by other linguists on grammatical grounds; the fieldwork has not been replicated by independent researchers.", "Animal grammar learning experiments cannot distinguish pattern memorisation from recursive rule learning with current methods.", "Whether recursion in language is the same cognitive capacity as recursion in mathematical and spatial reasoning is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-recursion-uniquely-human.yaml" }, { "id": "u-semantic-change-prediction", "title": "What mechanisms drive lexical semantic change over time, and can computational models predict which word meanings will shift?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No predictive model of semantic change achieves better than baseline accuracy on held-out data from historical corpora.", "The relative contribution of contact-driven versus internal structural pressures to semantic change is not quantified.", "Short-term semantic drift in internet language does not follow the same patterns as long-term historical change." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-semantic-change-prediction.yaml" }, { "id": "u-semantic-compositionality-limits", "title": "To what extent is natural language meaning compositional, and where do non-compositional constructions require fundamentally different processing?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Formal compositional semantics handles core syntax-semantics interface well but cannot account for conventional implicature, presupposition, and constructional meaning in a unified framework.", "Neural language models appear to handle non-compositional constructions but their internal representations are not compositional in the formal sense.", "The developmental trajectory of compositional versus construction-specific meaning acquisition in children is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-semantic-compositionality-limits.yaml" }, { "id": "u-semantic-shift-prediction", "title": "Can the semantic drift of a word over decades be predicted from its current distributional properties?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Distributional models conflate polysemy with semantic broadness", "Social and cultural factors driving meaning change are not encoded in text distributions alone", "Most diachronic models are validated on English; cross-linguistic generalization is untested", "Causal mechanisms of semantic shift are not distinguished from statistical correlates" ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-semantic-shift-prediction.yaml" }, { "id": "u-signed-language-neural-substrate", "title": "Do signed languages engage the same or different neural substrates as spoken languages, and what does this reveal about language universality?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The lateralisation of signed language in deaf versus hearing signers shows different patterns not fully explained by models of language lateralisation.", "The neural basis of cross-modal influence (speechreading modifying auditory processing in hearing signers) is not well understood.", "Deaf native signers and hearing L2 signers show different neural activation patterns whose interpretation is contested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-signed-language-neural-substrate.yaml" }, { "id": "u-syntax-innateness-evidence", "title": "Is there a genetically specified universal grammar, and what is the evidence for or against Chomsky's poverty of the stimulus argument?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "No specific UG principle has been identified in the genome or neural architecture.", "Modern large language models acquire complex grammar from statistical patterns, weakening the poverty of stimulus argument but not eliminating it.", "Cross-linguistic acquisition studies do not agree on whether construction-specific or abstract syntactic knowledge emerges first." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-syntax-innateness-evidence.yaml" }, { "id": "u-tonal-language-cognitive-effects", "title": "Does speaking a tonal language confer cognitive differences in pitch processing, and does this interact with absolute pitch ability?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "Studies of absolute pitch in tonal language musicians are subject to selection bias as tonal language communities have different musical training traditions.", "The developmental window during which tonal language exposure enhances pitch processing has not been established.", "Neurological basis of tone processing differences between tonal and non-tonal language speakers is undercharacterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-tonal-language-cognitive-effects.yaml" }, { "id": "u-universal-grammar-substrate", "title": "Is there a neurobiological substrate that implements universal grammar constraints, and what is its architecture?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "fMRI spatial resolution is insufficient to distinguish syntactic from lexical circuits", "Agrammatic aphasia studies do not cleanly dissociate syntactic from semantic deficits", "No animal model captures hierarchical recursive syntax", "Cross-linguistic universality of neural language regions has not been fully tested" ], "suggested_hypotheses": [ "h-merge-operation-frontal-cortex" ], "file": "unknowns-catalog/linguistics/u-universal-grammar-substrate.yaml" }, { "id": "u-writing-system-cognition-effects", "title": "Do different writing systems (alphabetic, syllabic, logographic) produce measurable differences in reading processes and cognitive architecture?", "status": "open", "domain": "linguistics", "systematic_gaps": [ "The neural basis of logographic versus alphabetic reading shows consistent differences in imaging studies, but their cognitive significance is not clear.", "Dyslexia manifests differently in different writing systems; whether it is one disorder or many remains unknown.", "The causal effect of writing system choice (e.g., Atatürk's romanisation of Turkish) on literacy rates and cognition has not been isolated from confounding factors." ], "suggested_hypotheses": [], "file": "unknowns-catalog/linguistics/u-writing-system-cognition-effects.yaml" }, { "id": "u-active-liquid-crystal-topology-flow-coupling", "title": "How do topological defects in active liquid crystals (bacterial suspensions, cytoskeletal networks) couple to spontaneous flow ΓÇö and can the defect-flow dynamics be controlled to direct active matter transport for synthetic biology or materials applications?\n", "status": "open", "domain": "liquid-crystals", "systematic_gaps": [ "Quantitative prediction of defect velocity from Frank elastic constants, active stress magnitude, and geometry has not been validated experimentally.", "Confinement-guided active LC transport has been demonstrated in simple geometries but the design rules for arbitrary channel geometries are not established.", "The role of thermal fluctuations vs. active noise in defect nucleation in biological active LCs (actin-myosin networks) has not been separated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/liquid-crystals/u-active-liquid-crystal-topology-flow-coupling.yaml" }, { "id": "u-liquid-crystals-frank-elasticity", "title": "Can Frank elastic constants K₁, K₂, K₃ be predicted from molecular structure alone (molecular dynamics + density functional theory) without fitting to experimental Freedericksz data?", "status": "open", "domain": "liquid-crystals", "systematic_gaps": [ "No QSAR model for Frank elastic constants has been validated on more than ~20 compounds; the molecular descriptors that best predict K₁ vs K₂ vs K₃ are unknown.", "Coarse-grained MD force fields for liquid crystals reproduce phase sequences but not quantitative elastic constants.", "The relative magnitudes of K₁:K₂:K₃ across different mesogen classes (calamitic, discotic, bent-core) have not been explained from first principles." ], "suggested_hypotheses": [], "file": "unknowns-catalog/liquid-crystals/u-liquid-crystals-frank-elasticity.yaml" }, { "id": "u-nematic-ordering-fluctuation-corrections-maier-saupe", "title": "How large are the fluctuation corrections to Maier-Saupe mean-field theory for the isotropic-nematic transition, and do they change the transition from first-order to continuous in confined or low-molecular-weight nematics?\n", "status": "open", "domain": "liquid-crystals", "systematic_gaps": [ "Renormalisation group analysis of the I-N transition beyond mean field is incomplete", "Confined nematic experiments in nanopores have ambiguous transition-order results", "Low-molecular-weight nematics with large fluctuations have not been systematically compared to Maier-Saupe" ], "suggested_hypotheses": [], "file": "unknowns-catalog/liquid-crystals/u-nematic-ordering-fluctuation-corrections-maier-saupe.yaml" }, { "id": "u-diffusion-models-x-stochastic-processes", "title": "What is the theoretical lower bound on the number of sampling steps required for a diffusion model to generate samples indistinguishable from the data distribution, and how does this depend on data geometry and the choice of SDE?", "status": "open", "domain": "machine-learning", "systematic_gaps": [ "Convergence analysis of diffusion samplers (DDPM, DDIM) is incomplete for non-Gaussian data; convergence rates depend on score estimation error", "The optimal choice of forward SDE (variance-exploding vs variance-preserving vs sub-VP) for a given data distribution is not theoretically justified", "Consistency models and distillation achieve fast sampling empirically but lack sample quality guarantees comparable to full DDPM" ], "suggested_hypotheses": [], "file": "unknowns-catalog/machine-learning/u-diffusion-models-x-stochastic-processes.yaml" }, { "id": "u-mean-field-theory-x-neural-networks", "title": "How do mean-field predictions for deep neural network initialization break down as network width decreases, and what is the minimum width at which finite-width corrections become significant for training?", "status": "open", "domain": "machine-learning", "systematic_gaps": [ "1/width corrections to NTK and NNGP have been computed to first order but higher-order terms are intractable", "Empirical comparison of mean-field predictions to finite-width networks is limited to smooth activations; ReLU networks have phase transitions at the origin", "The effect of residual connections and normalization layers on the mean-field phase diagram is only partially understood" ], "suggested_hypotheses": [], "file": "unknowns-catalog/machine-learning/u-mean-field-theory-x-neural-networks.yaml" }, { "id": "u-renormalization-group-ml-universality", "title": "Do deep residual networks belong to a specific renormalization group universality class, and if so, what class — and can this class membership be determined from small-model experiments without training at full scale?", "status": "open", "domain": "machine-learning", "systematic_gaps": [ "No systematic measurement of generalisation scaling exponents across ResNet depths and widths near the grokking transition", "No comparison of empirical scaling exponents with known 2D/3D Ising, percolation, and XY model exponents", "No finite-size scaling analysis applied to ResNet grokking to test the universality hypothesis" ], "suggested_hypotheses": [], "file": "unknowns-catalog/machine-learning/u-renormalization-group-ml-universality.yaml" }, { "id": "u-rg-ml-universality-classes", "title": "Do universality classes from the renormalization group predict generalization behavior in deep neural networks trained on different data distributions?\n", "status": "open", "domain": "machine-learning", "systematic_gaps": [ "No systematic measurement of generalisation scaling exponents across architectures near critical transitions", "No comparison of empirical scaling exponents with 2D/3D Ising, percolation, and XY model exponents", "No controlled study of networks trained on Ising-critical vs off-critical configurations" ], "suggested_hypotheses": [ "h-rg-ml-universality-classes" ], "file": "unknowns-catalog/machine-learning/u-rg-ml-universality-classes.yaml" }, { "id": "u-uap-stone-weierstrass-pedagogy-misconception-rate", "title": "Does teaching Stone-Weierstrass-style compact density before neural-network universal approximation reduce student misconceptions that approximation existence implies trainability or generalization?\n", "status": "open", "domain": "machine-learning", "systematic_gaps": [ "Controlled instructional comparisons with pre/post misconception instruments.", "Rubrics separating density, optimization, sample complexity, and extrapolation." ], "suggested_hypotheses": [ "h-compact-algebra-first-sequence-improves-uap-transfer" ], "file": "unknowns-catalog/machine-learning/u-uap-stone-weierstrass-pedagogy-misconception-rate.yaml" }, { "id": "u-fish-schooling-topological-interaction", "title": "Is topological interaction (fixed k nearest neighbors) vs. metric interaction (fixed radius r) a species-specific adaptation or a context-dependent switch, and what selective pressure drives the topology?", "status": "open", "domain": "marine-biology", "systematic_gaps": [ "3D tracking of natural open-water fish schools at sufficient resolution to measure individual interaction rules (metric vs. topological) has not been achieved for most species.", "The selective pressure determining the specific number of interacting neighbors (k ≈ 7 for starlings) has no theoretical explanation.", "Whether interaction topology switches dynamically (metric in calm conditions, topological under predation pressure) has not been tested.", "Hydrodynamic contribution to schooling (lateral line sensing of vortex wakes) vs. visual contribution has not been quantitatively partitioned." ], "suggested_hypotheses": [ "Fish species with higher predation risk in natural habitats use smaller k (fewer neighbors, faster decision propagation) than prey-poor species, as an evolutionarily optimized tradeoff between information accuracy and response speed." ], "file": "unknowns-catalog/marine-biology/u-fish-schooling-topological-interaction.yaml" }, { "id": "u-2d-material-defect-transport", "title": "How do point defects and grain boundaries in 2D materials limit carrier mobility?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Suspended graphene achieves near-ballistic transport", "Chalcogenide grain boundary scattering cross-sections unmeasured" ], "suggested_hypotheses": [ "Grain boundary tilt angle determines scattering cross-section, and specific tilt angles produce transmission resonances" ], "file": "unknowns-catalog/materials-science/u-2d-material-defect-transport.yaml" }, { "id": "u-active-learning-bias-in-alloy-discovery-loops", "title": "How much acquisition bias accumulates in Bayesian active-learning loops for alloy discovery?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-active-learning-bayesian-optimization-improves-alloy-hit-rate" ], "file": "unknowns-catalog/materials-science/u-active-learning-bias-in-alloy-discovery-loops.yaml" }, { "id": "u-amorphous-metal-fatigue-limit", "title": "Do metallic glasses have a fatigue limit, and if so what determines it?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Scatter in fatigue data for metallic glasses is an order of magnitude larger than for crystalline alloys", "The role of free volume vs. structural heterogeneity in shear band nucleation is debated", "No unified constitutive model exists for cyclic plasticity in metallic glasses", "Surface effects and residual stress from processing confound bulk fatigue measurements" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-amorphous-metal-fatigue-limit.yaml" }, { "id": "u-amorphous-metal-magnetism", "title": "What causes the anomalously high coercivity in some amorphous metallic glass compositions?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Structural disorder reduces exchange coupling on average", "Local atomic clusters that pin domain walls unresolved" ], "suggested_hypotheses": [ "Nanoscale chemical heterogeneity in as-quenched metallic glasses creates random magnetic anisotropy that sets coercivity" ], "file": "unknowns-catalog/materials-science/u-amorphous-metal-magnetism.yaml" }, { "id": "u-auxetic-materials-scalable-fabrication-3d", "title": "Can auxetic 3D metamaterial microgeometries be fabricated at millimeter scale and below with sufficient precision to achieve designed negative Poisson's ratios across multiple deformation axes?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-auxetic-materials-scalable-fabrication-3d.yaml" }, { "id": "u-battery-dendrite-nucleation", "title": "What determines the nucleation site and growth direction of lithium dendrites in battery anodes?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Surface heterogeneities identified as nucleation sites", "Predictive model linking surface chemistry to dendrite morphology lacking" ], "suggested_hypotheses": [ "Local current density hotspots from SEI heterogeneity determine dendrite nucleation, and uniform SEI formation suppresses dendrites" ], "file": "unknowns-catalog/materials-science/u-battery-dendrite-nucleation.yaml" }, { "id": "u-bic-metasurface-q-factor-radiative-disorder-limit", "title": "What disorder and finite-size mechanisms dominate Q-factor degradation in quasi-BIC dielectric metasurfaces?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Cross-fab datasets linking metrology features to Q degradation are limited.", "Finite-array effects are often confounded with local defect scattering in reported measurements.", "Robust process windows balancing target Q and fabrication yield are not standardized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-bic-metasurface-q-factor-radiative-disorder-limit.yaml" }, { "id": "u-biomineralisation-control", "title": "How do organisms control polymorph selection and crystallographic texture during biomineralisation?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Acidic proteins influence calcite vs aragonite selection", "Protein-mineral interaction at nucleation site unresolved atomistically" ], "suggested_hypotheses": [ "Specific amino acid sequences create epitaxial templates that select mineral polymorph through lattice matching" ], "file": "unknowns-catalog/materials-science/u-biomineralisation-control.yaml" }, { "id": "u-biomineralization-polymorph-control", "title": "How do biomineralizing organisms select specific crystal polymorphs (calcite vs. aragonite) during skeleton formation, and can this be replicated synthetically?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Atomic-resolution structures of protein-crystal interfaces during nucleation are not available (nucleating crystals are too transient for X-ray crystallography).", "The role of amorphous precursor phases (ACC — amorphous calcium carbonate) in polymorph selection is not quantitatively understood." ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-biomineralization-polymorph-control.yaml" }, { "id": "u-capillary-length-contact-line-hysteresis-unified-model", "title": "Can a single reduced model predict droplet morphology across the competition among capillary length, defect pinning distribution, and viscous spreading rate on engineered rough surfaces?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Limited open datasets pairing 3D surface topography with time-resolved contact-line velocity fields.", "Numerical contact-line regularizations obscure comparability across codes." ], "suggested_hypotheses": [ "h-capillary-wetting-pinning-length-universality-class" ], "file": "unknowns-catalog/materials-science/u-capillary-length-contact-line-hysteresis-unified-model.yaml" }, { "id": "u-classical-nucleation-theory-prefactor-discrepancy", "title": "Why does classical nucleation theory fail by 10-20 orders of magnitude for protein and ice nucleation, and what molecular-scale corrections are needed for quantitative prediction?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Interfacial free energy gamma for sub-nanometer clusters cannot be measured directly", "Two-step nucleation pathways (liquid-precursor route) are observed but not incorporated in standard CNT", "MD simulations of nucleation are limited to supersaturations > 10x beyond experiment" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-classical-nucleation-theory-prefactor-discrepancy.yaml" }, { "id": "u-corrosion-mechanism-passivation", "title": "What is the atomic-scale mechanism of passive film breakdown that initiates pitting corrosion?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Cl- adsorption identified as trigger in steels and aluminium", "Sub-nanometre film structure during breakdown unresolved" ], "suggested_hypotheses": [ "Halide-induced local dissolution creates nanoscale pits that self-accelerate once depth exceeds a critical threshold" ], "file": "unknowns-catalog/materials-science/u-corrosion-mechanism-passivation.yaml" }, { "id": "u-dislocation-avalanche-statistical-mechanics-plasticity", "title": "Do dislocation avalanches in plastically deforming metals belong to a universal criticality class (directed percolation, mean-field depinning), and can this universality class predict the statistics of fracture precursors?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "The universality class of dislocation avalanches has not been determined with sufficient precision to discriminate between mean-field depinning (τ=1.5), directed percolation (τ=1.75), and other candidates — existing data are consistent with multiple classes.", "Whether dislocation avalanche statistics change systematically as a material approaches fracture (analogous to critical slowing down) has not been established; existing acoustic emission studies focus on the stationary steady-state, not the approach to failure.", "The connection between the microscopic dislocation avalanche size distribution and macroscopic stress-strain curve features (Lüders bands, serrated flow) has not been derived from first-principles statistical mechanics." ], "suggested_hypotheses": [ "Dislocation avalanches in single crystals below the ductile-brittle transition belong to the mean-field depinning universality class (τ=1.5, z=2); polycrystals show a crossover to directed percolation universality (τ=1.75) due to grain boundary pinning, and this crossover is measurable via the acoustic emission exponent." ], "file": "unknowns-catalog/materials-science/u-dislocation-avalanche-statistical-mechanics-plasticity.yaml" }, { "id": "u-entropy-stabilized-ceramics", "title": "How does configurational entropy stabilise single-phase multi-principal-component oxides at room temperature?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Five-component high-entropy oxides synthesised at high temperature", "Thermodynamic stability window poorly defined" ], "suggested_hypotheses": [ "Entropy of mixing exceeds the sum of individual-oxide formation enthalpies above a critical compositional diversity threshold" ], "file": "unknowns-catalog/materials-science/u-entropy-stabilized-ceramics.yaml" }, { "id": "u-ferroelectric-fatigue-mechanism", "title": "What causes ferroelectric fatigue (loss of switchable polarisation) under repeated electric cycling?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Oxygen vacancy accumulation at electrodes identified", "Nucleation dynamics of reversed domains after fatigue unclear" ], "suggested_hypotheses": [ "Oxygen vacancy clustering at 180-degree domain walls pins domain nucleation and suppresses switchable polarisation" ], "file": "unknowns-catalog/materials-science/u-ferroelectric-fatigue-mechanism.yaml" }, { "id": "u-fisher-optimal-experiment-policy-shift-drift", "title": "How quickly do Fisher-optimal experiment policies degrade under drifting materials process conditions?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "No standard drift benchmark links process shift magnitude to Fisher-objective degradation.", "Limited side-by-side comparison of static versus adaptive design in autonomous labs." ], "suggested_hypotheses": [ "h-information-optimal-batching-accelerates-material-discovery" ], "file": "unknowns-catalog/materials-science/u-fisher-optimal-experiment-policy-shift-drift.yaml" }, { "id": "u-fracture-avalanche-universality-class", "title": "What is the exact universality class of acoustic emission avalanches in brittle fracture, and is the crackling-noise exponent τ ~ 1.5 universal across materials or material-specific?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Finite-size scaling analysis of AE avalanche distributions has not been performed on sufficiently large sample sets to distinguish universality classes.", "The role of material anisotropy and grain-size distribution on the τ exponent is not characterised.", "Comparison between acoustic emission and direct imaging of crack-front geometry has not been performed to validate the depinning model." ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-fracture-avalanche-universality-class.yaml" }, { "id": "u-grain-boundary-embrittlement-prediction", "title": "Can the embrittlement susceptibility of a grain boundary be predicted from its geometric and chemical parameters alone?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "DFT grain boundary calculations are limited to low-Σ special boundaries", "The role of grain boundary structural units vs. planar chemistry is unresolved", "No transferable interatomic potential captures both geometry and impurity effects reliably", "Machine-learning potentials have not been validated for rare embrittling configurations" ], "suggested_hypotheses": [ "h-grain-boundary-topology-embrittlement" ], "file": "unknowns-catalog/materials-science/u-grain-boundary-embrittlement-prediction.yaml" }, { "id": "u-grain-boundary-segregation", "title": "How does solute segregation to grain boundaries control polycrystalline material failure?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Atom probe tomography reveals segregant concentrations", "Segregation effect on fracture toughness poorly predicted from first principles" ], "suggested_hypotheses": [ "Grain boundary embrittlement is dominated by electronic charge transfer from segregants rather than volumetric strain effects" ], "file": "unknowns-catalog/materials-science/u-grain-boundary-segregation.yaml" }, { "id": "u-high-entropy-alloy-design-principles", "title": "What are the fundamental design principles governing phase selection and mechanical properties in high-entropy alloys?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "CALPHAD databases are unreliable for multi-principal-element systems", "Short-range order effects are invisible to standard DFT supercell approaches", "The contribution of sluggish diffusion to HEA phase stability is contested", "Composition-property relationships cannot currently be predicted for novel HEAs" ], "suggested_hypotheses": [ "h-hea-valence-electron-phase-predictor" ], "file": "unknowns-catalog/materials-science/u-high-entropy-alloy-design-principles.yaml" }, { "id": "u-high-entropy-alloy-phase-stability-prediction", "title": "Can CALPHAD-based thermodynamic models reliably predict the phase stability, mechanical properties, and oxidation resistance of high-entropy alloys with 5+ principal elements without extensive experimental validation?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "CALPHAD databases lack reliable higher-order interaction parameters (quaternary, quinary) for most HEA-relevant element combinations; extrapolation errors can exceed 10 kJ/mol, reversing phase stability predictions.", "The thermodynamic conditions for single-phase HEA formation vs. phase separation into multiple phases have not been mapped across composition space; the \"high entropy effect\" boundary conditions are undefined.", "Oxidation resistance in HEAs (critical for high-temperature applications) depends on selective oxidation of the most reactive element — a kinetic problem not captured by equilibrium CALPHAD, requiring coupled thermodynamic-kinetic models not yet available." ], "suggested_hypotheses": [ "Machine-learning interatomic potentials trained on DFT calculations for binary/ternary subsets can predict single-phase stability of quinary HEAs with <5% error in phase boundary temperatures when using a many-body equivariant architecture (NequIP/MACE)." ], "file": "unknowns-catalog/materials-science/u-high-entropy-alloy-phase-stability-prediction.yaml" }, { "id": "u-high-tc-superconductivity-mechanism", "title": "What is the pairing mechanism in cuprate high-temperature superconductors above 77 K?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Phonon-mediated pairing is insufficient at these temperatures", "RVB and stripe-phase models remain contested" ], "suggested_hypotheses": [ "Spin-fluctuation-mediated Cooper pairing explains the d-wave gap symmetry in cuprates" ], "file": "unknowns-catalog/materials-science/u-high-tc-superconductivity-mechanism.yaml" }, { "id": "u-hydrogel-fracture-toughness-network-structure", "title": "What polymer network architectural features (strand length distribution, topological defects, physical vs. chemical crosslinks) determine hydrogel fracture toughness, and can they be predicted from small-angle X-ray scattering measurements?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "SAXS measures network heterogeneity but cannot distinguish load-bearing from dangling strands", "Lake-Thomas theory underestimates Gc by 10-100x for tough hydrogels", "The role of viscoelastic dissipation vs. elastic energy storage in hydrogel toughness is not separated experimentally" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-hydrogel-fracture-toughness-network-structure.yaml" }, { "id": "u-hydrogen-embrittlement-pathway", "title": "What is the dominant mechanism of hydrogen embrittlement in high-strength steels?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Hydrogen-enhanced decohesion and localised plasticity are competing models", "In-situ atomistic observations during fracture lacking" ], "suggested_hypotheses": [ "Hydrogen localises at dislocations and reduces the Peierls barrier, causing premature plastic instability at crack tips" ], "file": "unknowns-catalog/materials-science/u-hydrogen-embrittlement-pathway.yaml" }, { "id": "u-lithium-dendrite-nucleation-control", "title": "What conditions deterministically prevent lithium dendrite nucleation in solid-state electrolytes?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Operando imaging of dendrite nucleation in solid electrolytes is technically limited", "Grain boundary chemistry varies with synthesis route and is not controllable at scale", "Theoretical models disagree on whether dendrites nucleate at surface defects or bulk flaws", "Stack pressure requirements are poorly specified across electrolyte families" ], "suggested_hypotheses": [ "h-solid-electrolyte-interlayer-dendrite-blocking" ], "file": "unknowns-catalog/materials-science/u-lithium-dendrite-nucleation-control.yaml" }, { "id": "u-metallic-glass-crystallisation", "title": "What determines the nucleation kinetics and crystallisation pathways in metallic glasses?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Differential scanning calorimetry captures onset temperatures", "Atomic-level nucleation sites remain unresolved" ], "suggested_hypotheses": [ "Icosahedral medium-range order suppresses crystallisation nucleation by raising the interfacial free energy" ], "file": "unknowns-catalog/materials-science/u-metallic-glass-crystallisation.yaml" }, { "id": "u-metamaterial-self-assembly-dynamics", "title": "Can metamaterial function (bandgap, effective medium response, scattering suppression) emerge from self-organized electromagnetic modes without globally imposed periodicity?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Limited experiments reporting spontaneous spatial modulation of eigenmodes independent of fabrication pitch.", "Missing statistical characterization of disorder sensitivity versus emergent periodicity.", "Unclear manufacturing pathways that preserve needed nonlinear saturation/bistability without dominating linear coupling." ], "suggested_hypotheses": [ "h-nonhelical-turing-cloaking-adaptation" ], "file": "unknowns-catalog/materials-science/u-metamaterial-self-assembly-dynamics.yaml" }, { "id": "u-metamaterial-wave-control", "title": "What physical limits govern negative-index metamaterials for sub-diffraction imaging at optical frequencies?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Microwave negative refraction demonstrated", "Losses at optical frequencies remain prohibitive" ], "suggested_hypotheses": [ "Gain-assisted optical metamaterials can overcome absorption losses and enable lossless sub-diffraction imaging" ], "file": "unknowns-catalog/materials-science/u-metamaterial-wave-control.yaml" }, { "id": "u-peridynamic-horizon-calibration-for-cortical-bone-microcrack-prediction", "title": "What validation boundary conditions determine when `b-peridynamics-nonlocal-fracture-x-bone-microdamage-remodeling` remains decision-useful?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-peridynamic-models-predict-bone-microdamage-hotspots-before-radiographic-failure" ], "file": "unknowns-catalog/materials-science/u-peridynamic-horizon-calibration-for-cortical-bone-microcrack-prediction.yaml" }, { "id": "u-perovskite-stability-degradation", "title": "What are the dominant degradation mechanisms limiting perovskite solar cell lifetime to under 20 years?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Ion migration under electric field identified as major pathway", "Role of grain boundaries vs bulk defects unresolved" ], "suggested_hypotheses": [ "Halide segregation at grain boundaries is the primary long-term degradation pathway in mixed-halide perovskites" ], "file": "unknowns-catalog/materials-science/u-perovskite-stability-degradation.yaml" }, { "id": "u-phonon-engineering-thermal", "title": "Can phonon dispersion be engineered to achieve near-zero thermal conductivity in crystalline materials?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Phononic crystals reduce conductivity but introduce new scattering channels", "Lower bound on minimum lattice thermal conductivity disputed" ], "suggested_hypotheses": [ "Resonant phonon scattering via rattler atoms in cage structures can approach the amorphous thermal conductivity limit" ], "file": "unknowns-catalog/materials-science/u-phonon-engineering-thermal.yaml" }, { "id": "u-phonon-mean-free-path-nanostructured-materials", "title": "How does the phonon mean-free-path spectrum change at interfaces and grain boundaries in nanostructured thermoelectric materials, and can interface engineering selectively scatter heat-carrying phonons without degrading electron transport?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Phonon-interface scattering models (diffuse mismatch, acoustic mismatch) systematically underestimate measured interface thermal resistance (Kapitza resistance).", "The cross-over from bulk to nano-scale phonon transport is not captured by the BTE with bulk scattering rates.", "The optimal grain-size distribution for maximum ZT in polycrystalline thermoelectrics is not derived from first principles." ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-phonon-mean-free-path-nanostructured-materials.yaml" }, { "id": "u-piezoelectric-biopolymers", "title": "Can biological polymers like collagen and cellulose be tuned to achieve technologically relevant piezoelectric coefficients?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Natural piezoelectricity in bone and wood measured", "Molecular origin of piezoelectric response in hierarchical structures unclear" ], "suggested_hypotheses": [ "Hierarchical fibril alignment optimised through processing achieves piezoelectric coefficients exceeding conventional ceramics in composite architectures" ], "file": "unknowns-catalog/materials-science/u-piezoelectric-biopolymers.yaml" }, { "id": "u-piezoelectricity-symmetry-breaking", "title": "Can high-throughput crystal structure prediction combined with group-theory symmetry screening discover novel lead-free piezoelectric materials with d_33 > 300 pC/N to replace PZT?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "First-principles DFT calculations of d_33 are accurate for single crystals but the polycrystalline averaging and domain contribution (d_33^soft) are not routinely included.", "The crystal structure prediction landscape for oxide perovskites and Aurivillius phases has not been systematically filtered for piezoelectric symmetry.", "High-throughput experimental validation pipelines for piezoelectric screening are not established beyond a few hundred compositions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-piezoelectricity-symmetry-breaking.yaml" }, { "id": "u-preisach-model-physical-interpretation-density", "title": "What microscopic physical mechanism determines the Preisach density rho(alpha,beta) in real ferromagnetic materials, and can rho be predicted from microstructural parameters without fitting to measured hysteresis loops?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "No first-principles calculation of Preisach density from grain size distribution has been validated against FORC measurements", "The effect of thermal activation on rate-independent Preisach operators is not well formulated", "Preisach model extensions to accommodate accommodation (gradual minor loop drift) are not standardized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-preisach-model-physical-interpretation-density.yaml" }, { "id": "u-protein-matrix-nucleation-control", "title": "How do organic protein matrices quantitatively control crystal polymorph selection and nucleation kinetics during biomineralization?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "No quantitative structure-activity relationship linking protein sequence features to nucleation rate constants for specific mineral polymorphs.", "The role of protein conformational dynamics (not just static structure) in presenting nucleation-active templates is unmeasured.", "Whether non-classical (two-step) nucleation is the rule or exception in biomineralization in vivo remains unclear." ], "suggested_hypotheses": [ "h-organic-template-lowers-nucleation-barrier" ], "file": "unknowns-catalog/materials-science/u-protein-matrix-nucleation-control.yaml" }, { "id": "u-quantum-dot-confinement-size-tunability", "title": "What are the upper bounds on quantum dot photoluminescence quantum yield and emission linewidth achievable with purely inorganic core-shell architectures, and at what size regime does the Brus particle-in-a-box approximation fail to predict emission energy within 5 meV due to surface reconstruction or many-body correlation effects?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Single-dot spectroscopy under controlled temperature and electric field is needed to separate homogeneous from inhomogeneous linewidth contributions", "Systematic comparison of Brus equation predictions vs. DFT vs. tight-binding across size series for non-CdSe dots is lacking", "Surface reconstruction effects on emission energy are not captured by any widely used analytical model" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-quantum-dot-confinement-size-tunability.yaml" }, { "id": "u-quasicrystal-stability-origin", "title": "What determines whether a quasicrystalline phase forms versus an approximant crystal in metallic alloys?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Hume-Rothery electron concentration rules partially explain stability", "Phason strain energy landscape poorly understood" ], "suggested_hypotheses": [ "Pseudogap deepening at the Fermi level by quasiperiodic diffraction is the dominant stabilising mechanism over competing approximants" ], "file": "unknowns-catalog/materials-science/u-quasicrystal-stability-origin.yaml" }, { "id": "u-radiation-damage-recovery", "title": "What atomic mechanisms drive radiation damage recovery in nuclear materials and can they be accelerated?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Frenkel pair annihilation measured by positron annihilation spectroscopy", "Role of grain boundaries as defect sinks poorly quantified" ], "suggested_hypotheses": [ "Grain boundaries act as unsaturable sinks for interstitials, and nanocrystalline metals with high boundary density show superior radiation tolerance" ], "file": "unknowns-catalog/materials-science/u-radiation-damage-recovery.yaml" }, { "id": "u-room-temperature-superconductivity-mechanism", "title": "What microscopic mechanism could stabilize superconductivity at room temperature and ambient pressure?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "No consensus on the pairing mechanism in high-Tc cuprates after 40 years", "Ambient-pressure hydrides destabilize rapidly without extreme confinement", "The role of electron-phonon coupling vs. strong correlations remains contested", "No first-principles method reliably predicts Tc above ~50 K" ], "suggested_hypotheses": [ "h-topological-phonon-superconductivity", "h-high-tc-flat-band-mechanism" ], "file": "unknowns-catalog/materials-science/u-room-temperature-superconductivity-mechanism.yaml" }, { "id": "u-room-temperature-superconductivity", "title": "What materials architecture would achieve ambient-pressure room-temperature superconductivity?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Hydrogen-rich compounds show Tc > 200 K at megabar pressures", "Stabilisation at ambient pressure remains unsolved" ], "suggested_hypotheses": [ "Covalent hydrogen cage structures stabilised by electron donation from heavy elements achieve Tc > 273 K at ambient pressure" ], "file": "unknowns-catalog/materials-science/u-room-temperature-superconductivity.yaml" }, { "id": "u-self-healing-polymer-mechanism", "title": "What is the molecular mechanism enabling autonomous self-healing in non-covalent polymer networks?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Hydrogen bond reformation characterised by spectroscopy", "Kinetics of macroscopic crack healing poorly quantified" ], "suggested_hypotheses": [ "Dynamic disulfide bond exchange rate sets the healing timescale independently of polymer backbone stiffness" ], "file": "unknowns-catalog/materials-science/u-self-healing-polymer-mechanism.yaml" }, { "id": "u-semiconductor-doping-fermi-level-pinning", "title": "What mechanisms cause Fermi level pinning at semiconductor surfaces and interfaces, and can chemical potential engineering of surface passivation overcome pinning to enable reliable band alignment control in heterojunction devices?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Quantitative relationship between surface chemistry (oxidation state) and pinning energy is not established", "MIGS theory gives rough predictions; ab initio chemical potential calculations of pinning are not routine", "2D semiconductor interfaces show anomalous pinning not explained by bulk models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-semiconductor-doping-fermi-level-pinning.yaml" }, { "id": "u-shape-memory-alloy-fatigue", "title": "What atomic-scale mechanisms drive functional fatigue in shape-memory alloys after repeated cycling?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Dislocation accumulation measured macroscopically", "Martensite interface pinning at nanoscale unresolved" ], "suggested_hypotheses": [ "Irreversible dislocation tangles at austenite-martensite interfaces accumulate with each cycle, raising transformation hysteresis" ], "file": "unknowns-catalog/materials-science/u-shape-memory-alloy-fatigue.yaml" }, { "id": "u-soft-ferrite-nonlinear-permeability-wpt-harmonic-loss", "title": "How do inverter-generated harmonics and spatial flux bias combine to shift soft-ferrite hysteresis losses in consumer wireless chargers beyond manufacturer Steinmetz curves calibrated under sinusoidal excitation?\n", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Few public datasets correlating thermal imaging of ferrite tiles with on-board harmonic spectra across brands.", "Temperature-dependent permeability feedback loops can cause thermal runaway under misalignment — poorly modeled." ], "suggested_hypotheses": [ "h-gapped-ferrite-bias-point-maximizes-wpt-q-under-saturation-margin" ], "file": "unknowns-catalog/materials-science/u-soft-ferrite-nonlinear-permeability-wpt-harmonic-loss.yaml" }, { "id": "u-solid-electrolyte-interface", "title": "What is the full chemical composition and ion-transport mechanism of the solid electrolyte interphase?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Cryo-TEM reveals layered SEI structure", "Species-resolved ion conductivity across layers unmeasured" ], "suggested_hypotheses": [ "Organic outer and inorganic inner SEI layers transport Li+ via distinct mechanisms whose relative resistance determines cycle life" ], "file": "unknowns-catalog/materials-science/u-solid-electrolyte-interface.yaml" }, { "id": "u-thermoelectric-zt-limit", "title": "Is there a fundamental upper limit to thermoelectric figure-of-merit zT and what materials approach it?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "zT > 3 achieved in some nanostructured materials", "Theoretical limit disputed because of coupled transport coefficients" ], "suggested_hypotheses": [ "Phonon-glass electron-crystal nanocomposites can decouple thermal and electrical conductivity to achieve zT > 4 at optimal temperatures" ], "file": "unknowns-catalog/materials-science/u-thermoelectric-zt-limit.yaml" }, { "id": "u-thermoelectric-zt-theoretical-limit", "title": "Is there a fundamental thermodynamic upper bound on the thermoelectric figure of merit zT beyond the Carnot efficiency argument, and what combination of electronic band structure features can approach this bound in a real material?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "First-principles prediction of lattice thermal conductivity kappa_L at high temperature requires anharmonic force constants that are expensive to compute accurately", "The Seebeck coefficient prediction from DFT Boltzmann transport is sensitive to band structure near the Fermi level; spin-orbit and correlation effects are often underestimated", "Experimental validation of theoretically predicted high-zT materials faces synthesis and single-crystal characterization bottlenecks" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science/u-thermoelectric-zt-theoretical-limit.yaml" }, { "id": "u-topological-insulator-surface-states", "title": "Why do topological insulator surface states remain robust under certain perturbations but not others?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Time-reversal symmetry protection is well characterised", "Disorder effects on Dirac cone lifetime are poorly constrained" ], "suggested_hypotheses": [ "Electron-electron interactions on TI surfaces create a symmetry-protected metal distinct from bulk predictions" ], "file": "unknowns-catalog/materials-science/u-topological-insulator-surface-states.yaml" }, { "id": "u-topological-signatures-microcrack-coalescence-transferability", "title": "Are persistent-homology microcrack signatures transferable across materials classes and loading regimes?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-persistent-h1-betti-curves-predict-material-failure-earlier-than-stress-thresholds" ], "file": "unknowns-catalog/materials-science/u-topological-signatures-microcrack-coalescence-transferability.yaml" }, { "id": "u-twistronics-moire-phases", "title": "What is the full phase diagram of moiré superlattices as a function of twist angle, pressure, and field?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Correlated insulator and superconductor phases identified at magic angle", "Phase boundaries for non-graphene systems unmapped" ], "suggested_hypotheses": [ "A universal topological Mott insulator phase exists at commensurate twist angles across all hexagonal van der Waals systems" ], "file": "unknowns-catalog/materials-science/u-twistronics-moire-phases.yaml" }, { "id": "u-vdw-heterostructure-emergent-phases", "title": "What emergent electronic phases arise in van der Waals heterostructures beyond graphene-hBN systems?", "status": "open", "domain": "materials-science", "systematic_gaps": [ "Magic-angle graphene superconductivity established", "Systematic phase diagram across twist angles incomplete" ], "suggested_hypotheses": [ "Twist-angle engineering in TMD bilayers produces a universal phase diagram with Mott, superconducting, and topological regions" ], "file": "unknowns-catalog/materials-science/u-vdw-heterostructure-emergent-phases.yaml" }, { "id": "u-dislocation-dynamics-alloy-high-entropy", "title": "What dislocation mechanisms produce the exceptional combination of high strength and high ductility observed in high-entropy alloys (HEAs), and can these be predicted from first principles?", "status": "open", "domain": "materials-science-mechanics", "systematic_gaps": [ "TEM characterization of dislocation cores in HEAs is technically limited; chemical mapping at atomic scale is emerging", "Multiscale dislocation dynamics simulations of HEAs are computationally expensive and require large-scale DFT training data", "The role of stacking fault energy (SFE) in controlling deformation mode (slip vs. twinning vs. transformation) in HEAs is incompletely characterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/materials-science-mechanics/u-dislocation-dynamics-alloy-high-entropy.yaml" }, { "id": "u-gauge-fields-as-bundle-connections-pedagogy", "title": "Which bundle-theoretic perspectives (connections, holonomy, characteristic classes) most improve predictive modeling literacy for early-career theorists without obscuring computability?", "status": "open", "domain": "mathematical-physics", "systematic_gaps": [ "Curricula rarely integrate lattice gauge theory labs with continuum bundle pictures.", "Students’ misconceptions about gauge fixing vs physical observables persist across both languages." ], "suggested_hypotheses": [ "h-gauge-fixing-parallels-coordinate-choice-in-models" ], "file": "unknowns-catalog/mathematical-physics/u-gauge-fields-as-bundle-connections-pedagogy.yaml" }, { "id": "u-non-abelian-aharonov-bohm-observable-consequences", "title": "What experimentally observable consequences distinguish the non-Abelian Aharonov-Bohm effect (SU(2) gauge holonomy) from the Abelian U(1) case, and can they be measured in condensed matter systems?", "status": "open", "domain": "mathematical-physics", "systematic_gaps": [ "No condensed matter experiment has unambiguously demonstrated non-Abelian AB holonomy (as opposed to other non-Abelian topological effects like braiding statistics).", "The relationship between non-Abelian AB phase and observable interference pattern in multi-path electron interferometers has not been computed for realistic device geometries.", "Whether topological quantum computing proposals based on non-Abelian anyons require the full non-Abelian AB effect or only non-Abelian braiding statistics has not been clarified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematical-physics/u-non-abelian-aharonov-bohm-observable-consequences.yaml" }, { "id": "u-ricci-flow-intuition-vs-rigorous-gr-correspondence", "title": "Where is Ricci flow (beyond heuristic metaphors) formally tied to renormalization-group flow or gravitational dynamics in physically predictive models rather than pedagogy alone?", "status": "open", "domain": "mathematical-physics", "systematic_gaps": [ "Curated comparison articles separating theorem-level Ricci flow from Wilsonian RG equations on statistical fields", "Lack of undergraduate pathways translating Ricci flow simulations into GR coursework labs beyond unrelated numerical GR codes" ], "suggested_hypotheses": [ "h-ricci-flow-x-geometrization-program" ], "file": "unknowns-catalog/mathematical-physics/u-ricci-flow-intuition-vs-rigorous-gr-correspondence.yaml" }, { "id": "u-stochastic-quantization-non-equilibrium-regimes", "title": "Can Parisi-Wu stochastic quantization be rigorously extended to non-equilibrium quantum field theories (finite-density QCD, Keldysh formalism, open quantum systems) where the equilibrium Boltzmann fixed point does not exist, and do SPDE regularity structures (Hairer) provide the convergence proofs needed for lattice stochastic quantization?\n", "status": "open", "domain": "mathematical-physics", "systematic_gaps": [ "Complex Langevin dynamics for finite-density QCD — convergence criteria and criteria distinguishing correct vs. incorrect fixpoints are not rigorously established; the Nishimura-Aarts correctness criterion is heuristic.", "Hairer regularity structures have not been applied to Yang-Mills-Langevin dynamics in 4D; the gauge-orbit quotient space introduces non-trivial geometric obstacles.", "Non-equilibrium stochastic quantization (Keldysh + Langevin hybrid) has not been formulated; it could provide a path to non-equilibrium QFT without real-time Monte Carlo sign problem." ], "suggested_hypotheses": [ "For gauge theories on the lattice, the Gribov copy ambiguity in Landau gauge fixation causes complex Langevin to converge to incorrect fixed points; Gribov copy-free stochastic gauges (stochastic gauge fixing) will fix the convergence problem and allow finite-density lattice QCD calculations at μ_B > T.\n" ], "file": "unknowns-catalog/mathematical-physics/u-stochastic-quantization-non-equilibrium-regimes.yaml" }, { "id": "u-symplectic-topology-classical-quantum-correspondence-limits", "title": "What is the precise mathematical relationship between Gromov's non-squeezing theorem for symplectic manifolds and the Heisenberg uncertainty principle, and can symplectic rigidity results (Gromov width, symplectic capacities) be derived from quantum mechanics in the hbar → 0 classical limit?\n", "status": "open", "domain": "mathematical-physics", "systematic_gaps": [ "The relationship between symplectic capacities (Ekeland-Hofer, Hofer-Zehnder, Gromov width) and quantum observables has been characterised only for special geometries; the general case is open.", "Whether Floer homology (symplectic topology invariant) has a direct quantum mechanical interpretation as a partition function or path integral over some quantum system has not been established rigorously.", "The Arnold diffusion (breakdown of KAM tori in near-integrable systems with n≥3 degrees of freedom) and its quantum analogue (quantum chaos, ergodicity transition) have not been connected via a unified semiclassical theory." ], "suggested_hypotheses": [ "Every Ekeland-Hofer symplectic capacity c_k(M,omega) of a star-shaped domain M equals (2k-1)pi*r² for k=1,2,... — the spectrum of a quantum harmonic oscillator on the corresponding quantum system — establishing a precise spectral-geometric dictionary between symplectic topology and quantum energy levels.\n" ], "file": "unknowns-catalog/mathematical-physics/u-symplectic-topology-classical-quantum-correspondence-limits.yaml" }, { "id": "u-3manifold-invariants-completeness", "title": "Are quantum invariants of 3-manifolds complete in the sense of distinguishing all non-homeomorphic 3-manifolds?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Jones polynomial and Witten-Reshetikhin-Turaev invariants distinguish many but not all pairs", "Whether any single quantum invariant is complete is unknown" ], "suggested_hypotheses": [ "The coloured Jones polynomial evaluated at all roots of unity is a complete invariant for prime 3-manifolds" ], "file": "unknowns-catalog/mathematics/u-3manifold-invariants-completeness.yaml" }, { "id": "u-abc-conjecture-verification", "title": "Is Mochizuki's proof of the abc conjecture correct and how can it be made verifiable by the community?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "IUT theory has been disputed by Scholze and Stix since 2018", "The gap in Corollary 3.12 has not been resolved to community consensus" ], "suggested_hypotheses": [ "A reformulation of IUT in classical scheme-theoretic language exists that would make the proof verifiable without understanding the full inter-universal Teichmuller theory" ], "file": "unknowns-catalog/mathematics/u-abc-conjecture-verification.yaml" }, { "id": "u-aesthetic-complexity-information-measure", "title": "Is there a universal, computable information-theoretic measure that predicts cross-cultural aesthetic preference for visual and auditory stimuli, and what is the neural implementation of the compression-progress reward signal that Schmidhuber's theory posits?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No systematic cross-cultural study using identical stimuli spanning the full complexity range (constant → random) across visual, auditory, and olfactory modalities.", "The neural correlate of \"compression progress\" (reduction in prediction error per unit time) has not been identified using real-time fMRI or EEG.", "The relationship between individual aesthetic preferences and individual differences in compression algorithm efficiency (as measured by cognitive tasks) has not been tested.", "Whether Pollock's D trajectory (1.12 → 1.72) reflects a conscious artistic strategy toward the aesthetic optimum or is a byproduct of physical drip dynamics is unresolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-aesthetic-complexity-information-measure.yaml" }, { "id": "u-banach-space-geometry", "title": "What is the geometry of the space of all Banach spaces under various equivalence relations on their structure?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Isomorphic classification of Banach spaces is far from complete", "Generic Banach spaces in the Baire-category sense have been studied but remain exotic" ], "suggested_hypotheses": [ "The Banach-Mazur compactum is infinite-dimensional with no isolated points, and the generic Banach space contains all separable Banach spaces as subspaces" ], "file": "unknowns-catalog/mathematics/u-banach-space-geometry.yaml" }, { "id": "u-black-scholes-heat-equation", "title": "What is the correct PDE generalization of Black-Scholes for markets with jumps, stochastic volatility, and transaction costs, and does it retain the heat-equation structure?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Analytical solutions to the Heston PDE under all parameter regimes (including Feller condition violation) are not fully classified.", "The connection between rough volatility models (Volterra fractional Brownian motion, H<1/2) and fractional PDEs has not been fully established.", "Whether a universal 'natural' PDE framework exists for option pricing under market microstructure noise is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-black-scholes-heat-equation.yaml" }, { "id": "u-category-theory-x-functional-programming", "title": "Can all practical programming language features be expressed as categorical universal constructions, and what new type system features does higher category theory predict?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The categorical semantics of algebraic effects and handlers (modern alternative to monads) is not fully established", "Whether homotopy type theory (HoTT) can be compiled to efficient machine code while preserving its categorical semantics is unknown", "The connection between dependent types and locally cartesian closed categories breaks for recursive types — no complete categorical model exists" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-category-theory-x-functional-programming.yaml" }, { "id": "u-causal-attribution-chain-rule-universality", "title": "Does a universal chain rule for causal attribution unify natural selection, Bayesian learning, economic rationality, and gradient descent as instances of the same mathematical process?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the causal chain rule framework generates all known attribution methods (Shapley values, integrated gradients, LIME, Taylor decompositions) as special cases has not been formally verified.", "The conditions under which the chain rule attribution is unique (vs. having multiple valid attributions) have not been characterized.", "Empirical tests comparing chain-rule attributions to human intuitive causal judgments have not been conducted." ], "suggested_hypotheses": [ "Every known attribution method in ML (Shapley values, LIME, integrated gradients, attention weights) corresponds to a specific symmetry constraint on the chain rule decomposition, providing a complete classification of attribution methods by their symmetry group." ], "file": "unknowns-catalog/mathematics/u-causal-attribution-chain-rule-universality.yaml" }, { "id": "u-chaos-x-ergodic-theory", "title": "Are physically relevant chaotic systems (turbulence, weather, neural dynamics) truly ergodic, and how does finite-time ergodicity breaking affect predictions?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The ergodicity breaking time scale for physically relevant chaotic attractors (Lorenz 96, primitive equation weather model) as a function of noise level has not been quantified", "Whether the Pesin theorem holds for stochastic differential equations (Brownian dynamics on attractors) in the limit of small noise has not been rigorously established", "The practical implication of ergodicity breaking for climate predictions — whether multi-decadal ensemble averaging is sufficient for ergodic sampling of the climate attractor — is unresolved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-chaos-x-ergodic-theory.yaml" }, { "id": "u-compressed-sensing-x-sparse-recovery", "title": "What are the fundamental limits of compressed sensing recovery for non-sparse but approximately sparse signals, and how do these limits change under adversarial or structured noise?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Tight information-theoretic lower bounds for compressed sensing with structured (non-i.i.d.) noise are not known", "Sample complexity of compressed sensing for group-sparse or low-rank matrix recovery with dependent measurements is open", "Computational vs statistical tradeoffs in compressed sensing (SDP relaxations vs greedy algorithms) are not fully characterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-compressed-sensing-x-sparse-recovery.yaml" }, { "id": "u-conley-index-computable-verification-higher-dim", "title": "Which certified algorithms compute Conley indices (or verified isolating blocks) for empirically extracted Poincaré maps from fluid experiments beyond heuristic cubical complexes — without drowning in computational homology blowups?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Benchmark dynamical systems with ground-truth isolating neighborhoods exported alongside noisy empirical embeddings for algorithm contests", "GPU-accelerated homology engines coupling verified interval arithmetic enclosures from validated ODE integrators with cubical complexes sized for laboratory datasets" ], "suggested_hypotheses": [ "h-morse-homology-x-conley-index-isolated-invariants" ], "file": "unknowns-catalog/mathematics/u-conley-index-computable-verification-higher-dim.yaml" }, { "id": "u-constructive-incompleteness", "title": "What is the constructive content of Godel incompleteness theorems and which unprovable statements have computational meaning?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Proof-theoretic ordinals characterise provability strength", "Computational interpretation of independence results is poorly understood" ], "suggested_hypotheses": [ "Every Pi-0-2 statement independent of PA has a Turing degree that characterises its computational complexity, forming a hierarchy of unprovability" ], "file": "unknowns-catalog/mathematics/u-constructive-incompleteness.yaml" }, { "id": "u-cortical-folding-poisson-flow", "title": "Is the spatial pattern of cortical sulci and gyri governed by a Poisson flow model with a single control parameter, and can this predict inter-individual variability from gene expression data?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The Poisson flow model's prediction for the distribution of sulcal initiation times has not been validated against high-resolution fetal MRI time series.", "Whether the single control parameter of the Poisson flow model can be estimated from gene expression data (from Allen Brain Atlas or similar) without fitting to individual anatomy is unknown.", "The relationship between the Poisson flow model and Turing reaction-diffusion models of cortical folding (e.g., Tallinen et al. 2016) has not been established mathematically." ], "suggested_hypotheses": [ "The Poisson flow control parameter estimated from cortical growth gene expression levels predicts the coefficient of variation of sulcal initiation timing across human subjects with r^2 > 0.5." ], "file": "unknowns-catalog/mathematics/u-cortical-folding-poisson-flow.yaml" }, { "id": "u-deep-learning-approximation-sobolev-optimal", "title": "What is the optimal approximation rate for deep neural networks in Sobolev spaces, and do ReLU networks achieve the minimax optimal rate for estimating functions with different smoothness levels, or do they suffer unavoidable approximation gaps?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Optimal approximation rates for neural networks on low-dimensional manifolds embedded in high-dimensional space are not known.", "Whether practical gradient descent actually finds the approximation-optimal network (vs local minima) is not theoretically resolved.", "The interaction between approximation error, estimation error, and optimization error in real training settings is not understood." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-deep-learning-approximation-sobolev-optimal.yaml" }, { "id": "u-derived-algebraic-geometry", "title": "What are the fundamental obstructions to extending derived algebraic geometry to characteristic p arithmetic geometry?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Perfectoid techniques partially extend characteristic-0 derived geometry", "Prismatic cohomology provides new tools but a fully derived prismatic theory is incomplete" ], "suggested_hypotheses": [ "A derived prismatic site construction provides the correct setting for an arithmetic derived algebraic geometry with functorial six-functor formalism" ], "file": "unknowns-catalog/mathematics/u-derived-algebraic-geometry.yaml" }, { "id": "u-descriptive-set-projective-hierarchy", "title": "What are the full regularity properties (measurability, BP, PSP) of sets in the projective hierarchy?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "L(R) determinacy implies regularity for all projective sets under large cardinal assumptions", "Constructible universe counterexamples exist without large cardinals" ], "suggested_hypotheses": [ "All projective sets have the perfect set property, Lebesgue measurability, and Baire property if and only if Projective Determinacy holds" ], "file": "unknowns-catalog/mathematics/u-descriptive-set-projective-hierarchy.yaml" }, { "id": "u-diffeomorphic-growth-mechanical-constraints", "title": "To what extent are biological shape transformations during development truly diffeomorphic (smooth, invertible), and which developmental processes require topological changes (cell division, death, fusion) that fall outside the diffeomorphism group?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No general framework handling topology changes in computational anatomy.", "The relationship between mechanical constraints (elastic moduli of tissues) and geodesic paths in Diff(M) is not understood.", "Diffeomorphic registration of embryonic vs adult shapes fails when organ topology changes during development." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-diffeomorphic-growth-mechanical-constraints.yaml" }, { "id": "u-ecc-torus-intuition-misconception-rates", "title": "How often does introductory elliptic-curve cryptography instruction that begins with the complex torus picture produce durable misconceptions about security (e.g., confusing periodic complex geometry with hardness of discrete logarithms on 𝔽_q)?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Concept inventories validated against interview protocols with cryptography instructors", "Longitudinal tracking into applied secure-coding courses" ], "suggested_hypotheses": [ "h-sequence-complex-torus-first-ecc-exam-performance" ], "file": "unknowns-catalog/mathematics/u-ecc-torus-intuition-misconception-rates.yaml" }, { "id": "u-erdos-renyi-random-graph-biological", "title": "Do biological networks (gene regulatory, protein-protein interaction, metabolic) show giant component emergence at the same critical connectivity as Erdős-Rényi random graphs, and what does this imply for robustness?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether biological network connectivity loss after systematic gene knockouts follows ER or scale-free percolation has not been tested in a genome-scale experiment", "The critical knockout fraction for giant component loss in real interactomes is not empirically established", "Whether synthetic lethality pairs in yeast correspond to percolation-sensitive network bottlenecks is not quantified" ], "suggested_hypotheses": [ "The critical fraction of gene knockouts needed to destroy the giant component of the yeast protein interaction network is f_c > 0.9 (consistent with scale-free percolation), while targeted deletion of the top 1% hub proteins achieves the same disconnection at f = 0.01 — testable via systematic synthetic lethality datasets" ], "file": "unknowns-catalog/mathematics/u-erdos-renyi-random-graph-biological.yaml" }, { "id": "u-expander-graphs-x-error-correcting-codes", "title": "Do there exist linear-time encodable and decodable error-correcting codes that simultaneously achieve the Gilbert-Varshamov bound and have linear minimum distance, and can quantum expander codes achieve constant rate with linear distance?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The probabilistic existence of good LDPC codes is known but explicit Ramanujan constructions exist only for restricted degree sequences", "Quantum LDPC threshold analysis under circuit-level noise is incomplete; most results assume phenomenological noise models", "The tradeoff between girth, minimum distance, and rate in LDPC codes is only partially characterized algebraically" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-expander-graphs-x-error-correcting-codes.yaml" }, { "id": "u-extreme-value-theory-x-risk-modeling", "title": "Does the multivariate generalization of extreme value theory (spectral measure, max-stable processes) provide a tractable and accurate framework for joint tail risk in high-dimensional financial and climate systems, and what is the minimum data requirement for reliable estimation?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No tractable non-parametric estimator for the spectral measure in dimensions > 10", "Max-stable process fitting in spatial dimensions > 100 is computationally intractable", "No unified theory connecting financial contagion (endogenous tail dependence) and EVT (exogenous rare events)" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-extreme-value-theory-x-risk-modeling.yaml" }, { "id": "u-fem-adaptivity-optimal-mesh-refinement", "title": "What is the optimal adaptive mesh refinement strategy for FEM that achieves the best convergence rate for problems with singularities, and can machine learning automate this?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Optimal convergence theory for AFEM applied to time-dependent Navier-Stokes equations with turbulence is not established.", "Transfer learning of optimal mesh refinement strategies across different PDE types has not been demonstrated.", "Isogeometric AFEM (hp-adaptive NURBS refinement) lacks the complete theoretical convergence proofs available for standard polynomial FEM." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-fem-adaptivity-optimal-mesh-refinement.yaml" }, { "id": "u-fiber-bundle-gauge-field-quantum-gravity", "title": "Can the fiber bundle formulation of gauge theory be extended to describe quantum gravity — where spacetime itself is dynamical — without introducing a fixed background manifold as the base space?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-fiber-bundle-gauge-field-quantum-gravity.yaml" }, { "id": "u-fourier-analysis-non-euclidean-domains", "title": "How should Fourier analysis be generalized to non-Euclidean domains (graphs, manifolds, hyperbolic spaces) for signal processing on complex networks?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No Nyquist-type sampling theorem exists for general graph signals; optimal sampling strategies depend on graph structure in ways not theoretically characterized.", "The appropriate wavelet frames for hyperbolic geometry (relevant for hierarchical networks) have not been fully developed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-fourier-analysis-non-euclidean-domains.yaml" }, { "id": "u-fourier-transform-x-signal-processing", "title": "What are the optimal time-frequency representations for non-stationary signals, and how do Fourier and wavelet transforms generalize to non-Euclidean domains?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No unified theory of optimal time-frequency representation for arbitrary non-stationary processes", "Graph Fourier transform (eigendecomposition of graph Laplacian) lacks the shift-invariance and fast algorithm of classical FFT", "Quantum Fourier transform speedup for classical signal processing problems is not fully characterized" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-fourier-transform-x-signal-processing.yaml" }, { "id": "u-frb-waiting-time-universality", "title": "Do the inter-burst waiting time distributions of repeating fast radio burst sources belong to a specific random matrix theory universality class, and if so, what does the universality class reveal about the physical emission mechanism?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Current FRB repeater catalogs (CHIME/FRB, FAST) have sufficient burst counts for a few sources but typically fewer than 500 bursts, limiting statistical power for RMT universality class discrimination", "The mapping from FRB burst times to RMT eigenvalues is not uniquely defined; different unfolding procedures (local vs. global spectral density normalization) may change the universality class assignment", "Self-organized criticality (SOC) models and RMT models produce overlapping waiting-time statistics at low burst counts, requiring the 3-point or 4-point correlation function to discriminate", "Selection effects (burst detection threshold, telescope cadence) distort the observed waiting-time distribution in ways that may mimic or mask RMT signatures" ], "suggested_hypotheses": [ "FRB 20121102A and 20201124A waiting-time distributions are consistent with the GOE universality class (time-reversal symmetric quantum chaos), implying that magnetar crustal dynamics are in the chaotic rather than integrable regime", "The Weibull shape parameter k < 1 observed in FRB repeater statistics is the finite-N imprint of RMT level repulsion, and will converge to the Wigner surmise P(s) ~ s as burst samples exceed ~1000 per source" ], "file": "unknowns-catalog/mathematics/u-frb-waiting-time-universality.yaml" }, { "id": "u-gnn-expressiveness-beyond-wl", "title": "What architectural modifications allow graph neural networks to exceed the 1-WL expressiveness bound, and at what computational cost relative to the gain in practical task performance?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No systematic benchmark comparing expressiveness improvements to task performance on real graphs", "The gap between theoretical 1-WL equivalence and practical performance is poorly understood", "Subgraph GNNs are more expressive but their combinatorial enumeration cost limits scalability" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-gnn-expressiveness-beyond-wl.yaml" }, { "id": "u-harmonic-analysis-sparse-recovery", "title": "What are the sharp conditions for sparse signal recovery from harmonic measurements with minimal samples?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "RIP conditions guarantee recovery but are NP-hard to verify", "Prony-type methods and super-resolution theory give partial answers" ], "suggested_hypotheses": [ "Super-resolution from n Fourier samples achieves exact recovery of n-sparse signals supported on a grid when source separation exceeds 1/(2n)" ], "file": "unknowns-catalog/mathematics/u-harmonic-analysis-sparse-recovery.yaml" }, { "id": "u-homotopy-type-theory-computational-foundations", "title": "Can homotopy type theory (HoTT) and the univalence axiom serve as a complete and decidable computational foundation for mathematics, and what is the complexity of proof search in intensional dependent type theories?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Computational interpretation of univalence that preserves decidability", "Proof search complexity in dependent type theories", "Consistency strength of HoTT + higher inductive types vs. set theory", "Automated tactics for homotopy-theoretic proofs in proof assistants" ], "suggested_hypotheses": [ "h-univalence-axiom-proof-assistant-verification" ], "file": "unknowns-catalog/mathematics/u-homotopy-type-theory-computational-foundations.yaml" }, { "id": "u-homotopy-type-theory-foundations", "title": "Can homotopy type theory serve as a complete foundation for mathematics replacing ZFC set theory?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "HoTT provides a foundation for homotopy theory but lacks a constructive large cardinal hierarchy", "Univalence axiom has no computational interpretation in all settings" ], "suggested_hypotheses": [ "Cubical type theory with a universe hierarchy equivalent to ZFC with large cardinals provides a complete computable foundation for all current mathematics" ], "file": "unknowns-catalog/mathematics/u-homotopy-type-theory-foundations.yaml" }, { "id": "u-hopf-algebra-qft-nonperturbative-extension", "title": "Can the Connes-Kreimer Hopf algebra structure of perturbative renormalization be extended to nonperturbative quantum field theory, and what algebraic structure governs resurgent trans-series in QFT?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No algebraic framework unifies the perturbative Hopf algebra with resurgent nonperturbative sectors", "The Connes-Kreimer periods (Feynman integrals evaluating to multiple zeta values) are only partially classified", "The relationship between Hopf algebraic renormalization and holography/AdS-CFT is unexplored" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-hopf-algebra-qft-nonperturbative-extension.yaml" }, { "id": "u-infinity-category-limits", "title": "What are the fundamental completeness properties of infinity-categories and when do they have all small limits?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Lurie's Higher Topos Theory establishes many existence results", "Accessibility and presentability conditions are not fully transparent for algebraic applications" ], "suggested_hypotheses": [ "Every locally presentable infinity-category is equivalent to a left exact localisation of a presheaf infinity-topos, providing complete limit-colimit calculus" ], "file": "unknowns-catalog/mathematics/u-infinity-category-limits.yaml" }, { "id": "u-integer-factoring-quantum-classical-boundary", "title": "At what integer size n does Shor's quantum algorithm on a fault-tolerant quantum computer become faster than the number field sieve on the best classical supercomputer, and what circuit depth and physical qubit count is required to break RSA-2048 within one year of quantum computation?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Precise resource estimates for Shor's algorithm depend on magic state distillation overhead which varies across fault-tolerant architectures", "Classical NFS algorithmic improvements (lattice sieving, GPU linear algebra) continue to push classical performance; crossover point is a moving target", "Post-quantum cryptographic migration planning requires the crossover estimate but NIST guidance does not specify a single concrete number" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-integer-factoring-quantum-classical-boundary.yaml" }, { "id": "u-ising-exact-density-states-universality", "title": "Does the exact combinatorial density of states for the critical 1D Ising model generalize to a universal formula for all critical 2D lattice models, providing exact partition functions without Monte Carlo?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "An exact combinatorial density of states formula for the 2D Ising model at T_c has not been derived (Onsager's exact solution gives the free energy, not the density of states).", "Whether the combinatorial structure of Ising density of states has a number-theoretic interpretation (e.g., in terms of modular forms or Rogers-Ramanujan identities) has not been explored.", "Computational complexity of evaluating the exact combinatorial density of states for system sizes relevant to material science simulations (N > 10^6) has not been assessed." ], "suggested_hypotheses": [ "The exact density of states of the 2D Ising model at T_c is expressible as a sum over integer partitions weighted by Catalan numbers, providing a combinatorial derivation of Onsager's formula." ], "file": "unknowns-catalog/mathematics/u-ising-exact-density-states-universality.yaml" }, { "id": "u-island-biogeography-x-percolation", "title": "Does habitat fragmentation follow a true percolation phase transition with universal critical exponents, and if so, what is the biological percolation threshold for landscape connectivity in temperate forest ecosystems?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Empirical z-exponents in the S-A relationship are inconsistent with percolation theory predictions", "Real habitat patches are spatially correlated (not random), invalidating simple percolation models", "No empirical test of percolation-like phase transition in species richness has been conducted at landscape scale" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-island-biogeography-x-percolation.yaml" }, { "id": "u-knot-invariants-rna-tertiary-structure-topology", "title": "Do RNA tertiary structures contain topologically knotted or pseudoknotted configurations that require knot invariants (beyond secondary structure diagrams) to classify, and do these topological constraints shape RNA evolution and function in ways not captured by current structure prediction algorithms?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Systematic topological analysis of all RNA structures in PDB using knot invariant computation (after closing chain termini by standard procedures).", "Computational search for minimal-crossing-number pseudoknots that are biologically functional (frameshifter efficiency vs. pseudoknot topology).", "Experimental test of whether circRNA topology affects translation or protein binding (comparing topological isomers of the same sequence).", "Connection between RNA topological genus (of the surface on which secondary structure graph embeds) and tertiary structural complexity." ], "suggested_hypotheses": [ "Systematic analysis of >5000 RNA 3D structures from the PDB using knotted chain detection algorithms will find ≥10 RNA structures with non-trivial backbone knottedness (trefoil or higher), concentrated in large ribosomal RNAs with buried chain crossings — establishing that RNA knotting is a rare but real phenomenon with functional implications for ribosome assembly kinetics.\n" ], "file": "unknowns-catalog/mathematics/u-knot-invariants-rna-tertiary-structure-topology.yaml" }, { "id": "u-knot-invariants-x-dna-topology", "title": "What is the minimal set of knot-theoretic invariants sufficient to characterize all topological states of chromosomal DNA in vivo, and can topoisomerase reaction mechanisms be inferred from changes in these invariants?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Electron microscopy of DNA knots is limited to short plasmids; chromosome-scale topology is inaccessible to current methods", "HOMFLY polynomial computation is exponentially hard in crossing number; practical for knots up to ~20 crossings only", "In vivo topoisomerase activity is measured biochemically, not topologically; direct measurement of DNA knot type in living cells is not possible" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-knot-invariants-x-dna-topology.yaml" }, { "id": "u-knot-theory-x-quantum-gravity", "title": "Are the quantum knot invariants (Jones polynomial, HOMFLY) complete invariants of 3-manifold topology, and do they encode the geometry of quantum spacetime?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether there exist pairs of non-homeomorphic 3-manifolds with identical WRT invariants at ALL levels r simultaneously has not been determined (completeness problem)", "The categorification of HOMFLY polynomial to HOMFLY-PT homology has not been connected to physical observables in loop quantum gravity", "Whether the semiclassical limit of the Chern-Simons partition function recovers the Einstein-Hilbert action on all 3-manifolds (not just homology spheres) has not been proved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-knot-theory-x-quantum-gravity.yaml" }, { "id": "u-kolmogorov-complexity-computable-approximation", "title": "What is the best computable approximation to Kolmogorov complexity, and how closely can compression algorithms approach the theoretical minimum description length for scientific models?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The ratio K_approx(x)/K(x) for scientific datasets (genomic sequences, climate trajectories) using state-of-the-art compressors is not known, as K(x) is incomputable.", "Whether the normalised compression distance (NCD) between two scientific theories is a reliable proxy for their \"theoretical distance\" in a domain-independent sense has not been validated.", "The relationship between MDL model selection and Bayesian model selection in the non-parametric (neural network) regime is not fully characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-kolmogorov-complexity-computable-approximation.yaml" }, { "id": "u-koopman-dmd-spectrum-convergence-navier-stokes", "title": "Under what Reynolds-number and sampling regimes do DMD/EDMD spectra converge to physically interpretable Koopman-like branches for wall-bounded turbulence without spurious modes dominating?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No community-wide turbulent benchmark with certified ground-truth operator spectra.", "Non-stationarity across long runs breaks stationarity assumptions used in proofs." ], "suggested_hypotheses": [ "h-koopman-linear-dynamics-capture-coherent-structures-limited-window" ], "file": "unknowns-catalog/mathematics/u-koopman-dmd-spectrum-convergence-navier-stokes.yaml" }, { "id": "u-langlands-physics-connection", "title": "What is the precise mathematical connection between the geometric Langlands program and quantum field theory?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Kapustin-Witten established a physics framework via S-duality of 4d gauge theories", "Derived categorical formulation and its relation to QFT is incomplete" ], "suggested_hypotheses": [ "Electric-magnetic duality in 4d N=4 super Yang-Mills is the exact physical counterpart of geometric Langlands duality, and a rigorous proof exists via TQFT factorisation" ], "file": "unknowns-catalog/mathematics/u-langlands-physics-connection.yaml" }, { "id": "u-large-deviations-non-markovian-epidemic", "title": "What are the large-deviation statistics of epidemic final sizes in non-Markovian stochastic processes, and do they predict the probability of anomalously large outbreaks from small seeds?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The rate function for large epidemics in non-Markovian SIR models has only been computed for specific infectious period distributions; a general formula in terms of distribution moments is unknown.", "Whether non-Markovian large deviations predict qualitatively different outbreak risk than Markovian models (e.g., bimodal outbreak size distribution vs. unimodal) has not been established.", "The practical computation of large deviation rate functions from epidemic surveillance data for real diseases has not been demonstrated." ], "suggested_hypotheses": [ "The probability of a pandemic-scale outbreak (>1% of global population) from a single imported case is 10x higher under gamma-distributed vs. exponential infectious periods with identical mean, because the variance contributes to the large-deviation rate function." ], "file": "unknowns-catalog/mathematics/u-large-deviations-non-markovian-epidemic.yaml" }, { "id": "u-lie-groups-x-symmetry-conservation", "title": "What are the conservation laws and symmetry structures of non-equilibrium systems, and how do Lie group methods extend to time-irreversible and dissipative physical systems?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "GENERIC formalism generalizes Noether to dissipative systems but its group-theoretic foundations are not fully developed", "Classification of symmetry-protected topological phases in non-equilibrium (Floquet) systems using Lie group methods is incomplete", "Quantum anomalies (chiral anomaly, conformal anomaly) in condensed matter systems lack a complete Lie group classification" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-lie-groups-x-symmetry-conservation.yaml" }, { "id": "u-lotka-volterra-x-game-theory", "title": "When do multi-species ecological communities admit a Nash equilibrium description, and what evolutionary game dynamics predict community assembly and stability?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Conditions for existence of evolutionary stable strategies (ESS) in games with more than two strategies and continuous trait spaces are not fully characterized", "Relationship between LV community matrix eigenvalues and game-theoretic stability conditions is not established in general", "Empirical tests of replicator dynamics predictions in natural multi-species communities are rare" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-lotka-volterra-x-game-theory.yaml" }, { "id": "u-model-theory-arithmetic", "title": "What model-theoretic properties distinguish the standard model of arithmetic from non-standard models?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Non-standard models satisfy the same first-order theory as the standard model", "Second-order categoricity requires second-order comprehension axioms" ], "suggested_hypotheses": [ "The standard model is the unique model of arithmetic with a definable well-ordering in any extension of ZFC, characterising it up to isomorphism" ], "file": "unknowns-catalog/mathematics/u-model-theory-arithmetic.yaml" }, { "id": "u-morse-theory-x-energy-landscape", "title": "Does the Morse-Witten complex of a protein energy landscape have a computable topological signature that predicts folding cooperativity, and can persistent homology detect all kinetically relevant metastable states from MD trajectories?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Persistent homology of protein energy landscapes has not been validated against experimentally known folding intermediates", "The sampling density required to correctly identify Morse-Witten complex topology in high-dimensional PES is unknown", "Morse theory assumes smooth functions; molecular energy surfaces with cusps (bond breaking) require extensions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-morse-theory-x-energy-landscape.yaml" }, { "id": "u-motivic-cohomology-calculations", "title": "Can motivic cohomology groups be computationally determined for all smooth projective varieties?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Voevodsky's motivic cohomology is defined but hard to compute", "Relationship to algebraic K-theory and étale cohomology is well-developed theoretically" ], "suggested_hypotheses": [ "A spectral sequence relating motivic cohomology to étale and crystalline cohomology allows algorithmic computation for all varieties over finite and number fields" ], "file": "unknowns-catalog/mathematics/u-motivic-cohomology-calculations.yaml" }, { "id": "u-natural-gradient-selection-convergence-rate-fitness-landscape", "title": "What is the quantitative convergence rate advantage of natural (Shahshahani- geometric) selection over Euclidean-gradient selection on realistic fitness landscapes, and does the information-geometric speed limit (Fisher information bound) correctly predict observed rates of adaptation in laboratory evolution experiments?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The Fisher information speed limit for multi-locus adaptation has not been computed for realistic epistatic fitness landscapes (NK model, empirical fitness landscapes from protein engineering).", "No laboratory evolution experiment has been explicitly designed to test whether adaptation rates approach the Fisher information bound.", "The equivalence between natural gradient in ML and natural selection has not been exploited to import convergence rate theorems from ML optimization theory into population genetics.", "The effect of genetic drift (finite population size) on the information- geometric framework has not been systematically analysed — drift perturbs the manifold trajectory." ], "suggested_hypotheses": [ "h-natural-gradient-selection-reaches-fitness-optimum-faster-than-euclidean" ], "file": "unknowns-catalog/mathematics/u-natural-gradient-selection-convergence-rate-fitness-landscape.yaml" }, { "id": "u-neural-network-loss-landscape-global-structure", "title": "What is the global topological and geometric structure of neural network loss landscapes, and does the absence of spurious local minima hold for realistic architectures beyond shallow networks?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No rigorous proof that deep transformers or ResNets have no spurious local minima; theoretical results cover shallow networks only.", "The relationship between implicit SGD regularization (edge of stability, catapult phase) and the geometric structure of flat minima is not understood mathematically.", "Whether winning lottery tickets occupy special geometric positions in loss landscape (e.g., near global minimum manifold) has not been tested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-neural-network-loss-landscape-global-structure.yaml" }, { "id": "u-ntk-finite-width-corrections", "title": "How do finite-width corrections to the Neural Tangent Kernel (NTK) govern feature learning, and what is the precise boundary between the NTK (lazy training) regime and the mean-field (feature learning) regime as a function of network width, learning rate, and initialization scale?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Exact O(1/N) correction to the NTK for multi-layer architectures and non-standard activations", "Theoretical characterization of the NTK-to-μP crossover as a function of depth and width simultaneously", "Whether the NTK regime or feature learning regime better describes practical transformers at scale", "Connection between NTK evolution during training and the empirical neural collapse phenomenon" ], "suggested_hypotheses": [ "h-ntk-deep-learning-kernel-regression" ], "file": "unknowns-catalog/mathematics/u-ntk-finite-width-corrections.yaml" }, { "id": "u-optimal-stopping-biological-decisions", "title": "Do animals implement optimal stopping rules (secretary problem, explore-exploit tradeoff) in foraging and mate choice, and what neural circuit implements the stopping criterion?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether animals implement optimal stopping vs. fixed-threshold vs. aspiration-level rules in sequential mate choice has not been distinguished experimentally", "The neural circuit implementing the stopping criterion in patch foraging has not been identified", "Whether optimal stopping rules scale with cognitive capacity (brain size, information processing speed) across species" ], "suggested_hypotheses": [ "Mate choice in species with variable mate quality follows the 37% rule: animals reject the first 37% of encountered mates as a calibration phase, then accept the first mate exceeding the calibration maximum, detectable by measuring acceptance probability as a function of encounter rank" ], "file": "unknowns-catalog/mathematics/u-optimal-stopping-biological-decisions.yaml" }, { "id": "u-optimal-transport-word-order-universals", "title": "Is optimal transport (Wasserstein distance) minimization the physical principle underlying cross-linguistic word order universals, and can this predict undiscovered universals?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the distribution of word orders across human languages is significantly closer to the Wasserstein-optimal order than to random, for any choice of cognitive cost function, has not been tested systematically.", "The appropriate cost function (working memory distance, dependency length, information density) for the linguistic optimal transport problem has not been identified.", "Whether optimal transport predicts language universals beyond word order (e.g., morpheme order, prosodic structure) is unknown." ], "suggested_hypotheses": [ "The 6 possible basic word orders (SOV, SVO, VSO, VOS, OVS, OVS) are ranked by frequency across languages in exactly the order predicted by Wasserstein distance to the semantic dependency order, with Kendall tau > 0.85." ], "file": "unknowns-catalog/mathematics/u-optimal-transport-word-order-universals.yaml" }, { "id": "u-optimal-transport-x-machine-learning", "title": "Does the Wasserstein metric's geometric sensitivity to support structure make it a better metric for generative model evaluation than Fréchet Inception Distance (FID), and can it be computed scalably for high-dimensional distributions?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No large-scale empirical comparison of Wasserstein vs. FID for detecting specific generative model failure modes", "Sliced Wasserstein approximation quality relative to true W₂ in dimensions > 100 is uncharacterised", "Optimal Sinkhorn regularisation ε as a function of dataset size and dimension has no closed-form rule" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-optimal-transport-x-machine-learning.yaml" }, { "id": "u-origami-fold-design-complexity", "title": "What is the computational complexity of optimal origami crease pattern design for a given 3D target shape, and are there classes of polyhedral targets for which the Demaine-Tachi universality theorem provides computationally efficient fold designs versus NP-hard cases?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The full complexity theory of origami optimization (crease number minimization, paper-usage efficiency) has not been worked out for general polyhedral targets", "Robotic origami fabrication introduces geometric uncertainty not present in mathematical models, limiting the complexity of computable fold designs", "Large-scale origami structures (>10^4 creases) have not been computationally designed and fabricated; practical limits are unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-origami-fold-design-complexity.yaml" }, { "id": "u-origami-math-x-structural-engineering", "title": "Can origami crease pattern combinatorics be inverted — given a target mechanical behavior (stiffness tensor, Poisson's ratio, deployment kinematics), systematically find the crease pattern that achieves it — and is this inverse design problem tractable in general?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No algorithm exists to invert the mechanical property map (crease pattern → stiffness tensor) for general target tensors", "Three-dimensional rigid origami (Miura-ori variants with 3D curvature) has no complete mathematical theory", "Self-folding origami actuated by residual stress fields (4D printing) cannot yet be designed from first principles to achieve target geometries" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-origami-math-x-structural-engineering.yaml" }, { "id": "u-p-vs-np-geometric-barriers", "title": "What geometric barriers prevent current proof techniques from resolving P vs NP?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Relativisation, natural proofs, and algebrisation barriers identified", "No framework captures all known barriers simultaneously" ], "suggested_hypotheses": [ "A fourth barrier related to non-uniform circuit complexity prevents diagonalisation-based approaches from separating P and NP" ], "file": "unknowns-catalog/mathematics/u-p-vs-np-geometric-barriers.yaml" }, { "id": "u-p-vs-np-geometric-complexity", "title": "Can geometric complexity theory (GCT) provide the representation-theoretic obstructions needed to separate the permanent from the determinant and resolve P vs NP?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the required representation-theoretic obstructions exist for the permanent vs determinant separation is open after 25 years of GCT research.", "Natural proof barriers (Razborov-Rudich) apply to many algebraic techniques; it is unclear whether GCT fully avoids these barriers.", "Alternative algebraic geometry approaches (Grochow-Moore) exist but have not produced lower bounds." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-p-vs-np-geometric-complexity.yaml" }, { "id": "u-persistence-homology-x-protein-structure", "title": "Can persistent homology distinguish functional protein conformations from noise, and what topological features predict allosteric communication?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Persistence diagrams have not been validated as predictors of allosteric communication pathways in well-characterized allosteric proteins (hemoglobin, GPCR, kinases)", "The computational complexity of persistent homology (O(n^3) for Vietoris-Rips) prevents systematic TDA of the full AlphaFold2 database without algorithmic improvements", "A principled method for constructing the filtration parameter (distance threshold) for protein contact networks from biophysical first principles has not been established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-persistence-homology-x-protein-structure.yaml" }, { "id": "u-ppi-scale-free-topology-functional-necessity", "title": "Is the scale-free topology of protein-protein interaction networks a functional necessity (required for robustness, evolvability, or regulatory efficiency) or an artifact of network growth mechanisms (preferential attachment generating power laws as a neutral evolutionary consequence)?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Rigorous maximum likelihood tests of power-law vs. log-normal degree distributions in high-quality PPI datasets (AP-MS, proximity ligation)", "Whether hub lethality holds in complementation assays controlling for Y2H interaction detection bias", "Experimental test of scale-free vs. exponential topology in organisms with minimized genomes (Mycoplasma)", "Causal test: does experimental hub deletion cause community fragmentation proportional to betweenness centrality?" ], "suggested_hypotheses": [ "h-hub-lethality-protein-network-drug-targets" ], "file": "unknowns-catalog/mathematics/u-ppi-scale-free-topology-functional-necessity.yaml" }, { "id": "u-pseudo-holomorphic-curve-counts", "title": "What determines the well-definedness of pseudo-holomorphic curve counts in symplectic topology?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Gromov-Witten invariants require virtual perturbation theory to handle multiply-covered curves", "Polyfold and Kuranishi structure approaches compete without full consensus" ], "suggested_hypotheses": [ "A canonical transversality perturbation using abstract simplicial techniques provides well-defined rational curve counts that are independent of all choices" ], "file": "unknowns-catalog/mathematics/u-pseudo-holomorphic-curve-counts.yaml" }, { "id": "u-quantum-group-representation", "title": "What is the complete representation theory of quantum groups at roots of unity and its physical interpretation?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Tilting modules and quantum dimensions partially characterise representations", "Relation to logarithmic conformal field theory is conjectural" ], "suggested_hypotheses": [ "Quantum groups at roots of unity have a semisimplification equivalent to a modular tensor category that classifies all rational 2D CFTs with the corresponding symmetry" ], "file": "unknowns-catalog/mathematics/u-quantum-group-representation.yaml" }, { "id": "u-random-matrix-theory-neural-spectra", "title": "Do the eigenvalue spectra of neural connectivity matrices follow random matrix theory (Marchenko-Pastur) predictions, and do deviations encode learned structure?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Eigenspectrum analysis of biological connectomes at single-synapse resolution has not been performed", "Whether RMT departures in trained networks predict generalization better than other metrics is not established", "The spectral universality class of recurrent neural network dynamics has not been identified" ], "suggested_hypotheses": [ "The fraction of eigenvalues exceeding the Marchenko-Pastur upper edge (bulk) in trained DNNs correlates with test accuracy to within 5% across architectures and datasets, providing a trainability metric without labeled test data" ], "file": "unknowns-catalog/mathematics/u-random-matrix-theory-neural-spectra.yaml" }, { "id": "u-random-matrix-universality", "title": "Why does random matrix universality arise in systems as diverse as nuclear spectra, number theory zeros, and quantum chaos?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Universality classes established empirically across many systems", "The mathematical mechanism linking GOE/GUE statistics to physical chaos is poorly understood" ], "suggested_hypotheses": [ "Quantum ergodicity of eigenstates is the necessary and sufficient condition for RMT level statistics, unifying all known universality instances" ], "file": "unknowns-catalog/mathematics/u-random-matrix-universality.yaml" }, { "id": "u-random-walk-x-brownian-motion", "title": "What is the universality class of the scaling limit for random walks in random environments, and when does the Brownian motion limit break down?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Scaling limit for random walk in 2D random environment is not rigorously established", "Universality class crossover between diffusive and subdiffusive behavior in correlated random walks is not characterized", "Extension of Donsker's theorem to infinite-variance (Levy flight) steps requires stable distribution theory not yet fully applied in physics" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-random-walk-x-brownian-motion.yaml" }, { "id": "u-renyi-entropy-x-multifractal", "title": "What is the multifractal spectrum of turbulent velocity fields at high Reynolds number, and does it have a universal form independent of flow geometry?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The multifractal spectrum f(alpha) of turbulence has not been derived from the Navier-Stokes equations; it is entirely phenomenological", "Whether the multifractal spectrum is universal (independent of Re, geometry, forcing) or weakly Reynolds-number-dependent at finite Re is unresolved", "The connection between Renyi entropy spectrum and anomalous scaling exponents in 2D turbulence (inverse cascade) vs 3D turbulence (direct cascade) has not been established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-renyi-entropy-x-multifractal.yaml" }, { "id": "u-rg-wavelet-beta-function-quantitative-map", "title": "Is there a rigorous correspondence mapping Wilsonian RG beta functions to Mallat multiresolution filters or wavelet shrinkage rules beyond qualitative multiscale narratives?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Peer-reviewed theorems linking threshold policies to irrelevant operator projections on toy lattice models", "Numerical experiments comparing wavelet-filtered block-spin RG to wavelet shrinkage on identical disorder ensembles" ], "suggested_hypotheses": [ "h-wavelet-subband-energy-tracks-rg-relevant-flux" ], "file": "unknowns-catalog/mathematics/u-rg-wavelet-beta-function-quantitative-map.yaml" }, { "id": "u-ricci-price-covariance-analogy-scope", "title": "Is there a rigorous, operational mapping between Ricci-type curvature functionals and Price-equation covariance decompositions outside explicitly constructed information-geometric (Fisher-metric) models?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Published datasets jointly estimating Fisher-information curvature on empirical trait manifolds versus covariance selection components on the same cohort.", "Formal impossibility/possibility results delineating when geometric curvature notions add predictive value beyond linear covariance models." ], "suggested_hypotheses": [ "h-fisher-ricci-price-covariance-analogy-calibration" ], "file": "unknowns-catalog/mathematics/u-ricci-price-covariance-analogy-scope.yaml" }, { "id": "u-riemann-zero-distribution", "title": "What determines the distribution of non-trivial zeros of the Riemann zeta function along the critical line?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Over 10^13 zeros confirmed on the critical line by numerical computation", "Random matrix theory predicts spacing statistics that match, without a proof" ], "suggested_hypotheses": [ "The GUE eigenvalue statistics of zeros reflect an underlying quantum chaotic Hamiltonian whose existence would imply the Riemann Hypothesis" ], "file": "unknowns-catalog/mathematics/u-riemann-zero-distribution.yaml" }, { "id": "u-riemann-zeta-biomedical-discoverability", "title": "Does the Riemann zeta function govern the scaling of biomedical discovery rates with dataset size, and is this a general law for knowledge accumulation in high-dimensional biology?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the Zeta Law of Discoverability holds across multiple biomedical domains (GWAS hits, drug targets, protein structures) or is specific to the domain studied has not been tested.", "The mathematical derivation connecting Riemann zeta function asymptotics to discovery rates in finite-dimensional search spaces has not been provided.", "Whether the s parameter in the zeta law corresponds to a measurable property of the biological system (intrinsic dimensionality, sparsity of effects) is unknown." ], "suggested_hypotheses": [ "The Zeta Law of Discoverability follows from the prime number theorem applied to the prime factorization of biological complexity, with the s parameter equal to the intrinsic dimension of the phenotype space estimated by participation ratio." ], "file": "unknowns-catalog/mathematics/u-riemann-zeta-biomedical-discoverability.yaml" }, { "id": "u-rip-constant-optimal-measurement-matrix-deterministic-construction", "title": "Do deterministic measurement matrices satisfying the Restricted Isometry Property (RIP) with optimal O(k log n/k) measurements exist, and can they be constructed explicitly (not via random matrix arguments), enabling hardware-efficient compressed sensing implementations?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No deterministic construction achieves RIP with δ_k < 1/√2 for m < k² — the coherence barrier appears fundamental but has not been proven to be.", "The existence of \"almost deterministic\" constructions (derandomisation of random constructions) approaching O(k log n) with O(log log n) random bits is unexplored.", "Connections to extremal graph theory (Ramsey numbers, expander graphs) and the RIP condition have not been fully exploited for deterministic constructions.", "Whether the RIP constant δ_{2k} < √2-1 (sufficient for exact ℓ₁ recovery) can be achieved deterministically for any m = o(k²) is unknown." ], "suggested_hypotheses": [ "h-compressed-sensing-mri-10x-scan-time-reduction-clinical-safety" ], "file": "unknowns-catalog/mathematics/u-rip-constant-optimal-measurement-matrix-deterministic-construction.yaml" }, { "id": "u-sindy-noise-and-collinearity-under-limited-sensing", "title": "How do finite-difference derivative noise and collinearity across library columns degrade sparse PDE-structure recovery when only a sparse sensor budget is available?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Limited standardized benchmarks reporting recovery probability versus sensor count under realistic noise floors.", "Sparse integration between optimal experimental design and symbolic regression hyperparameter selection.", "Under-documented false-discovery rates when libraries are slightly misspecified." ], "suggested_hypotheses": [ "h-sparse-sensor-placement-improves-pde-structure-recovery" ], "file": "unknowns-catalog/mathematics/u-sindy-noise-and-collinearity-under-limited-sensing.yaml" }, { "id": "u-sir-percolation-temporal-network-threshold", "title": "What is the exact epidemic threshold for SIR dynamics on temporal contact networks, and how does temporal burstiness shift the threshold relative to static-network percolation predictions?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No analytic expression for R₀ on temporal networks with arbitrary inter-contact time distributions.", "The effect of simultaneous temporal burstiness and heterogeneous degree is not captured by existing approximations.", "Empirical validation of temporal-network epidemic thresholds using real contact data (e.g., SocioPatterns) is limited to specific settings." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-sir-percolation-temporal-network-threshold.yaml" }, { "id": "u-social-network-centrality-x-eigenvector", "title": "For temporal social networks (with time-varying edges), do eigenvector-based centrality measures generalize in a mathematically consistent way that preserves the Perron-Frobenius guarantees of static network centrality, and which temporal centrality measure best predicts real-world influence propagation?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No axiomatic characterization of temporal centrality analogous to Bonacich's axioms for static centrality", "Comparison of temporal centrality measures on real-world spreading benchmarks (SIR simulation on empirical contact networks) has not been done systematically", "Computational complexity of temporal eigenvector centrality scales poorly with temporal resolution; no approximate algorithm exists with provable approximation guarantees" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-social-network-centrality-x-eigenvector.yaml" }, { "id": "u-spectral-geometry-phylogenetic-trees", "title": "Do heat kernels on phylogenetic trees encode the same spectral geometry as Riemannian manifolds, and does this provide a unified framework for comparing evolutionary divergence and spatial distance?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the phylogenetic tree heat kernel asymptotics converge to Riemannian manifold heat kernel asymptotics in a biologically interpretable limit has not been established.", "The biological interpretation of spectral invariants (eigenvalue spectrum) of phylogenetic tree Laplacians beyond tree topology has not been developed.", "Whether heat kernel distance on phylogenetic trees outperforms Robinson-Foulds or Kendall-Colijn distance for comparing evolutionary models has not been tested." ], "suggested_hypotheses": [ "The leading spectral invariant of the phylogenetic tree heat kernel (analogous to the integrated Gaussian curvature for manifolds) is proportional to the mean evolutionary rate averaged over the tree, providing a geometric formula for molecular clock estimation." ], "file": "unknowns-catalog/mathematics/u-spectral-geometry-phylogenetic-trees.yaml" }, { "id": "u-statistical-mechanics-income-wealth", "title": "Can a rigorous statistical mechanics derivation from firm birth-death dynamics explain the empirical Pareto tail of household wealth distributions without free parameters?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Whether the Pareto exponent alpha is uniquely determined by the mean firm growth rate and death rate (no free parameters), or requires additional moment constraints, has not been established.", "The analogy between the Boltzmann distribution and the wealth distribution breaks down above a critical wealth scale; where this scale is and why it exists is unknown.", "Whether the maximum entropy derivation correctly predicts the cross-country variation in Pareto exponents (US alpha ~ 1.5 vs. Nordic alpha ~ 2.0) without country-specific parameters is unknown." ], "suggested_hypotheses": [ "The Pareto exponent of household wealth equals 1/(1-f_e), where f_e is the fraction of economic activity in firms with superlinear returns to scale, providing a parameter-free prediction testable across economies." ], "file": "unknowns-catalog/mathematics/u-statistical-mechanics-income-wealth.yaml" }, { "id": "u-subriemannian-geodesic-abnormal-optimality", "title": "Under what geometric conditions are abnormal geodesics in sub-Riemannian geometry locally length-minimizing, and does the existence of abnormal minimizers prevent smooth parameterization of the sub-Riemannian geodesic flow — with direct implications for optimal robot motion planning?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Characterization of SR structures admitting abnormal minimizers", "Smooth parameterization conditions for SR geodesic flows", "Algorithmic detection of abnormal minimizers in control systems", "Extension of Agrachev-Sarychev theory to infinite-dimensional control systems" ], "suggested_hypotheses": [ "h-lie-bracket-depth-complexity-robot-planning" ], "file": "unknowns-catalog/mathematics/u-subriemannian-geodesic-abnormal-optimality.yaml" }, { "id": "u-symplectic-capacities", "title": "Are Ekeland-Hofer and Gromov-Witten symplectic capacities equal for all convex bodies?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Equality conjectured by Viterbo and proved in special cases", "General proof or counterexample would require new geometric measure theory" ], "suggested_hypotheses": [ "Symplectic capacities of convex bodies are all equal and determined by the length of the shortest Reeb orbit on the boundary" ], "file": "unknowns-catalog/mathematics/u-symplectic-capacities.yaml" }, { "id": "u-symplectic-quantization-semiclassical", "title": "What is the precise relationship between the symplectic geometry of a classical phase space and the spectral properties of its quantisation, beyond the leading-order WKB approximation?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The relationship between Floer homology of the symplectic manifold and the quantum spectrum has not been fully established beyond special cases.", "Whether all symplectic topological invariants (e.g. symplectic capacities) have quantum spectral counterparts is unknown.", "The convergence properties of the formal Kontsevich star-product in physically relevant examples are not resolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-symplectic-quantization-semiclassical.yaml" }, { "id": "u-tda-x-shape-recognition", "title": "Can persistent homology provide a computationally tractable and statistically powerful shape fingerprint for 3D molecular structures that outperforms graph-based molecular descriptors for drug-target binding affinity prediction, and what is the optimal filtration for biochemical data?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No systematic comparison of filtration choices (with atom-type weighting vs. distance-only) for protein-ligand binding prediction", "Persistence diagram vectorization methods (persistence landscape, silhouette, image) have not been compared on a large diverse drug dataset", "Computational scaling of persistent homology for proteins > 1000 atoms is cubic; no linear-time approximation preserves stability theorem guarantees" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-tda-x-shape-recognition.yaml" }, { "id": "u-thermodynamics-convex-geometry-non-equilibrium", "title": "Does the Legendre-transform / convex-duality structure of equilibrium thermodynamics generalise to non-equilibrium steady states — and can contact geometry or information geometry provide the correct mathematical framework for non-equilibrium potentials?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No consensus on the correct mathematical framework for non-equilibrium potentials in NESS systems with broken detailed balance.", "Contact geometry and information geometry proposals have not been experimentally tested against active matter or driven chemical systems.", "The relationship between the Jarzynski equality / Crooks fluctuation theorem and a generalised Legendre structure for NESS is not fully worked out." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-thermodynamics-convex-geometry-non-equilibrium.yaml" }, { "id": "u-topological-data-analysis-phase-transitions", "title": "Can persistent homology (TDA) detect phase transitions in statistical mechanics systems earlier and more reliably than order parameter divergence methods?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No large-scale comparison of TDA vs. order parameter methods for phase transition detection in >10 distinct systems", "Computational scaling of TDA makes application to high-d systems (>100 spin) infeasible without approximations", "Which Betti numbers (H0, H1, H2) are most informative for different universality classes is not known" ], "suggested_hypotheses": [ "The Betti number B1 (loops) of the configuration space persistence diagram diverges at second-order phase transitions with the same critical exponent as susceptibility, providing a topological definition of the critical point independent of order parameter choice" ], "file": "unknowns-catalog/mathematics/u-topological-data-analysis-phase-transitions.yaml" }, { "id": "u-topological-data-analysis-x-cancer-genomics", "title": "Can persistent homology features of single-cell genomic data reliably identify cancer stem cell populations and predict tumor evolutionary trajectories, outperforming dimensionality reduction methods (UMAP, t-SNE) in robustness and interpretability?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Persistent homology computation scales as O(n^3) in number of cells; practical for bulk data but slow for >10,000 single cells", "Biological interpretation of topological features (what does a 1-cycle mean biologically?) requires domain expertise not present in TDA papers", "No prospective clinical study has tested whether TDA-based cancer subtyping predicts treatment response better than standard molecular subtypes" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-topological-data-analysis-x-cancer-genomics.yaml" }, { "id": "u-tropical-geometry-combinatorics", "title": "What is the precise relationship between tropical geometry and the combinatorics of polytopes and matroids?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Tropical hyperplane arrangements correspond to subdivisions of polytopes", "Matroid theory connection to tropical geometry remains partially developed" ], "suggested_hypotheses": [ "Every matroid has a canonical tropical linear space whose f-vector encodes all Whitney numbers and settles the conjecture of Dowling and Wilson" ], "file": "unknowns-catalog/mathematics/u-tropical-geometry-combinatorics.yaml" }, { "id": "u-tropical-geometry-x-neural-networks", "title": "Can the tropical geometry of a trained neural network predict its generalisation error — specifically, does lower tropical hypersurface complexity (fewer linear regions) correlate with better generalisation in the overparameterised regime?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No empirical study has measured tropical hypersurface complexity of trained vs. random ReLU networks", "The relationship between tropical complexity and implicit regularisation of SGD is theoretical", "Tropical geometry assumes exact arithmetic; floating-point errors and batch normalisation break the exact tropical structure" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-tropical-geometry-x-neural-networks.yaml" }, { "id": "u-tsp-approximation-barrier-metric", "title": "Is the Christofides 3/2 approximation ratio for metric TSP optimal, or does a polynomial-time algorithm exist with a better worst-case guarantee — and what is the true approximation hardness threshold for metric TSP?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The Held-Karp LP integrality gap has been open since 1970 — a major gap between the best known LP lower bound and the best achieved approximation ratio.", "Inapproximability results for metric TSP are weak compared to other NP-hard approximation problems where tight PCP-based bounds are known.", "The gap between the Karlin-Klein-Gharan algorithm (3/2 - ε, ε very small) and the conjectured optimal 4/3 approximation remains entirely open." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-tsp-approximation-barrier-metric.yaml" }, { "id": "u-turbulence-mathematical-formulation", "title": "Can turbulence in three-dimensional fluids be described by a complete mathematical theory?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Existence and smoothness of Navier-Stokes solutions is a Millennium Prize problem", "Statistical theories (Kolmogorov) work in practice but lack rigorous foundation" ], "suggested_hypotheses": [ "Navier-Stokes solutions remain globally smooth in 3D but with energy cascade statistics that are non-perturbatively controlled by a UV fixed point of the renormalisation group" ], "file": "unknowns-catalog/mathematics/u-turbulence-mathematical-formulation.yaml" }, { "id": "u-voting-theory-x-social-choice", "title": "Does the topological proof of Arrow's theorem (Baryshnikov 1993) generalize to continuous social choice functions on infinite voter populations, and does it predict specific voting paradox geometries that identify which real-world preference distributions are closest to Arrow impossibility?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Baryshnikov's theorem has not been extended to infinite voter populations in measure-theoretic probability spaces", "Topological social choice for multi-dimensional policy spaces (beyond 1D left-right spectrum) is not developed", "No empirical study has measured the geometric distance of real preference survey data to Condorcet cycles" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics/u-voting-theory-x-social-choice.yaml" }, { "id": "u-wasserstein-cell-fate-noise-geodesic-uniqueness", "title": "Are cell differentiation trajectories in Wasserstein space geodesically unique, and does transcriptional noise determine whether a progenitor has a definite fate or a mixed lineage distribution?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "The curvature of W₂ restricted to the manifold of single-cell gene expression distributions has not been computed for any real developmental dataset; it is unknown whether geodesic non-uniqueness corresponds to observed fate bifurcations.", "Whether transcriptional noise is the stochastic mechanism selecting between multiple W₂ geodesics (fate branches) vs. noise being irrelevant to fate and only affecting timing has not been determined.", "The optimal entropy regularization ε in Sinkhorn OT for single-cell data has no principled derivation from biological noise levels." ], "suggested_hypotheses": [ "Regions of high curvature in the W₂ geometry of developmental gene expression correspond exactly to observed fate decision points; curvature can be measured from static snapshots and predicts which progenitors are multipotent." ], "file": "unknowns-catalog/mathematics/u-wasserstein-cell-fate-noise-geodesic-uniqueness.yaml" }, { "id": "u-wavelet-optimal-basis-nonstationary-signal-adaptation", "title": "What is the optimal adaptive wavelet basis for non-stationary signals with time-varying spectral content, and can a data-driven basis selection algorithm achieve provably minimax-optimal compression and denoising simultaneously?", "status": "open", "domain": "mathematics", "systematic_gaps": [ "No wavelet-packet or learnable basis algorithm achieves provably minimax-optimal denoising over piecewise-Sobolev function classes simultaneously with adaptive basis selection; the gap between the best known theoretical guarantee and empirical performance of adaptive methods is large.", "The information-theoretic lower bound on the best achievable compression ratio for non-stationary signals with known spectral variability has not been derived; it is unknown how much adaptivity can improve over fixed Daubechies bases.", "Neural wavelet transforms (Wavelets learned end-to-end) show improved empirical performance but their generalization guarantees and relationship to classical minimax theory are not established." ], "suggested_hypotheses": [ "A locally stationary wavelet (LSW) basis selected by a Bayesian nonparametric spectral estimator achieves within a log(N) factor of the oracle minimax risk for piecewise-Sobolev signals, matching the information-theoretic lower bound and outperforming fixed Daubechies bases by a polynomial factor for non-stationary signals." ], "file": "unknowns-catalog/mathematics/u-wavelet-optimal-basis-nonstationary-signal-adaptation.yaml" }, { "id": "u-zipf-law-mechanism-adaptive-vs-null", "title": "Is Zipf's law (f_r ∝ r^{-1}) in natural language a consequence of adaptive communication efficiency (entropy maximisation under speaker-listener effort trade-off) or an inevitable consequence of any random partitioning process (the Miller monkey-typing null model)?\n", "status": "open", "domain": "mathematics", "systematic_gaps": [ "Miller (1957) monkey model has been analytically confirmed to produce approximate power laws, but the exponent depends on alphabet size and stop probability — no rigorous proof that α = 1 emerges without tuning", "Ferrer i Cancho & Solé (2003) phase transition result requires mutual information maximisation which has not been empirically validated in language acquisition or language change", "Sign languages and gestural communication systems have not been systematically tested for Zipf's law to control for acoustic/articulatory constraints of spoken language", "Comparison between languages with very different morphological structure (isolating Chinese vs. polysynthetic Inuktitut) at morpheme level has not been done controlling for segmentation method" ], "suggested_hypotheses": [ "h-zipf-critical-point-communication-efficiency" ], "file": "unknowns-catalog/mathematics/u-zipf-law-mechanism-adaptive-vs-null.yaml" }, { "id": "u-leslie-matrix-density-dependence-extension", "title": "Whether the Perron-Frobenius guarantee of a stable age distribution extends to density-dependent Leslie matrices (where vital rates depend on population size), and what replaces the dominant eigenvalue as the growth rate predictor in nonlinear structured population models\n", "status": "open", "domain": "mathematics-ecology", "systematic_gaps": [ "The classical Leslie matrix is linear; Perron-Frobenius guarantees a stable age distribution only for constant (density-independent) vital rates. Real populations have density-dependent vital rates.", "Nonlinear structured population models (IPMs — integral projection models) have a more complex asymptotic behaviour; the analogue of the Perron root is a nonlinear eigenvalue problem without a closed-form solution.", "Transient dynamics (before the stable age distribution is reached) can dominate observed population trajectories over ecologically relevant timescales; sensitivity analysis of transient amplification is less developed.", "Stochastic Leslie matrices (vital rates vary randomly in time) have a stochastic growth rate (log λ_s = lim (1/t) log |L(t)...L(1)w|) that depends on the full distribution of matrix entries, not just their means." ], "suggested_hypotheses": [ "h-elasticity-analysis-conservation-prioritisation" ], "file": "unknowns-catalog/mathematics-ecology/u-leslie-matrix-density-dependence-extension.yaml" }, { "id": "u-marginal-value-theorem-bandit-bridge", "title": "Can field foraging data be fit by index policies equivalent to Gittins or UCB rules under realistic patch renewal noise, and where do animals systematically deviate?", "status": "open", "domain": "mathematics-ecology", "systematic_gaps": [ "Sparse datasets with simultaneous travel times and capture series suitable for index inference.", "Risk-sensitive foragers may violate mean-rate shadow prices assumed in basic MVT." ], "suggested_hypotheses": [ "h-charnov-marginal-value-maps-to-index-policy-budgeting" ], "file": "unknowns-catalog/mathematics-ecology/u-marginal-value-theorem-bandit-bridge.yaml" }, { "id": "u-almgren-regularity-singular-set-sharp-dimension", "title": "Is Almgren's regularity theorem — that the singular set of an area-minimising current in ℝⁿ has Hausdorff dimension ≤ n-2 (and ≤ n-8 for hypersurfaces) — sharp, and what is the correct singular set dimension for physically relevant minimal surfaces in curved Riemannian manifolds?", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "The optimal singular set dimension for area-minimising currents in negatively curved manifolds (e.g. hyperbolic space, anti-de Sitter) has not been established; the flat-space bound may not be sharp.", "The relationship between Almgren's abstract singular set and the physically observable features of apparent horizons in numerical relativity has not been systematically studied; rare horizon topology changes may correspond to the exceptional cases in GMT.", "A computer-verified proof of Almgren's big regularity theorem does not exist; the 1700-page manuscript has been formally verified only in parts and contains gaps acknowledged in the mathematical community." ], "suggested_hypotheses": [ "In Riemannian manifolds with sectional curvature K < -1, the sharp singular set dimension for area-minimising hypersurfaces is n-7 rather than n-8 (one dimension lower than in flat space), due to curvature-induced stability improvement of the Simons cone analog." ], "file": "unknowns-catalog/mathematics-physics/u-almgren-regularity-singular-set-sharp-dimension.yaml" }, { "id": "u-catastrophe-normal-form-completeness", "title": "Are Thom's seven elementary catastrophes truly complete for codimension ≤4, and do higher-codimension catastrophes appear in real physical or biological systems?", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "Catastrophe theory applies to gradient systems (V = -dF/dx); non-gradient systems (limit cycles, strange attractors) require bifurcation theory, not catastrophe theory — the boundaries are not always clearly distinguished.", "Codimension >4 catastrophes (ADE series beyond D4) have not been systematically searched for in physical or biological experimental data.", "The connection between catastrophe-theoretic phase diagrams and modern renormalization group fixed-point classification has not been made fully rigorous." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics-physics/u-catastrophe-normal-form-completeness.yaml" }, { "id": "u-chaos-quantum-correspondence-lyapunov-exponents", "title": "How does classical chaos emerge from quantum mechanics in the semiclassical limit — and is there a quantum analog of the classical Lyapunov exponent that characterizes information scrambling in many-body quantum systems?\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "The semiclassical derivation of λ_L from classical Lyapunov exponents for generic quantum systems (not just special integrable or SYK-like models) is incomplete.", "Experimental measurement of OTOCs in cold atom, trapped ion, or superconducting qubit simulators has achieved only short-time OTOC growth, not the exponential regime predicted by the MSS bound.", "The relationship between quantum Lyapunov exponents (OTOC growth rates) and thermalization timescales in many-body systems has not been established generally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics-physics/u-chaos-quantum-correspondence-lyapunov-exponents.yaml" }, { "id": "u-ergodic-failure-quantum-thermalization", "title": "Under what conditions do quantum many-body systems fail to thermalise (violate ergodicity) and what is the complete classification of ergodic vs. non-ergodic phases?", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "The MBL phase transition point in 2D systems is unsettled", "Whether MBL is stable at thermodynamic limit (N → ∞) is unresolved", "Quantum many-body scars represent a new class not captured by ETH/MBL dichotomy" ], "suggested_hypotheses": [ "KAM theorem for quantum systems: near-integrable Hamiltonians retain approximate conservation laws that slow thermalisation on accessible timescales, mimicking MBL\n" ], "file": "unknowns-catalog/mathematics-physics/u-ergodic-failure-quantum-thermalization.yaml" }, { "id": "u-goldstone-boson-higher-dimensional-systems", "title": "Whether the full spectrum of pseudo-Goldstone bosons in realistic symmetry-breaking scenarios (explicit breaking, finite volume, non-equilibrium) can be systematically classified beyond the idealised Goldstone theorem, and what their masses imply for phase transitions in novel materials\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "The Goldstone theorem applies to global continuous symmetries broken spontaneously in infinite-volume equilibrium systems; finite-volume corrections and explicit symmetry-breaking terms (pseudo-Goldstone masses) lack a systematic treatment for generic group structures.", "Counting Goldstone bosons in systems with non-relativistic dispersion (type-I vs type-II Goldstone bosons; Nielsen-Chadha theorem) is incomplete for multi-component order parameters.", "Topological obstructions to Goldstone mode condensation in 2D (Mermin-Wagner) interact with spin-orbit coupling and disorder in ways not fully described by current theory." ], "suggested_hypotheses": [ "h-symmetry-breaking-universal-phase-transition-classifier" ], "file": "unknowns-catalog/mathematics-physics/u-goldstone-boson-higher-dimensional-systems.yaml" }, { "id": "u-integrability-breaking-perturbations-soliton-stability-realistic-systems", "title": "How do integrability-breaking perturbations (higher-order dispersion, dissipation, noise, higher-dimensional geometry) degrade soliton stability and modify spreading speed in realistic physical systems — and is there a general perturbation theory for nearly-integrable systems that predicts the soliton lifetime and effective dynamics?\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "Quantitative experimental measurement of soliton lifetime vs. perturbation strength in optical fibers (beyond Gordon-Haus jitter, including Raman).", "General perturbation theory for soliton stability in 2+1D (KP equation, 2D NLS) — instability mechanisms and radiation patterns.", "Stochastic ISPT for noise-driven soliton dynamics — connection to Karhunen- Loève expansion of noise and optimal noise-tolerant soliton design.", "Connection between classical soliton stability and quantum many-body thermalization near integrable points (ETH vs. KAM theorem analog)." ], "suggested_hypotheses": [ "Raman-induced soliton self-frequency shift in optical fibers will cause solitons to accelerate logarithmically in time (frequency red-shift → faster group velocity in anomalous dispersion regime), and this acceleration rate will be exactly predicted by ISPT to within 5% over propagation distances up to 1000 km — validating perturbative soliton theory for realistic communication-grade fiber parameters.\n" ], "file": "unknowns-catalog/mathematics-physics/u-integrability-breaking-perturbations-soliton-stability-realistic-systems.yaml" }, { "id": "u-measure-theoretic-foundations-quantum-probability", "title": "Does quantum probability admit a rigorous measure-theoretic foundation that accounts for contextuality and non-commutativity — and if so, what is the correct σ-algebra over which quantum events are defined?\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "The operational basis for quantum probability axioms remains disputed — frequency, propensity, and Bayesian interpretations each imply different extensions to relativistic quantum field theory and quantum gravity.", "Quantum measure theory (Sorkin) has not been fully developed for continuous state spaces or interacting quantum field theories.", "The relationship between Gleason's theorem and non-commutative integration theory (Segal, Dixmier) is not fully clarified for infinite-dimensional systems." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics-physics/u-measure-theoretic-foundations-quantum-probability.yaml" }, { "id": "u-nonperturbative-rg-completeness", "title": "Is the exact (Wilsonian) renormalization group complete — does it capture all universality classes and phase transitions including those with no perturbative expansion?", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "No proof that the Wetterich equation's truncation hierarchy converges to the exact result for strongly coupled 3D CFTs.", "The asymptotic safety scenario for quantum gravity depends on the existence of a non-perturbative UV fixed point not confirmed by other methods.", "Classification of universality classes in 2+1 dimensional quantum phase transitions is incomplete." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics-physics/u-nonperturbative-rg-completeness.yaml" }, { "id": "u-percolation-phase-transition-interdependent-networks-cascading-failures", "title": "In interdependent networks (e.g. power grid ↔ internet), where failure of nodes in one network triggers failures in the other, the percolation transition becomes first-order (abrupt) — what determines the critical coupling strength between network layers below which the transition reverts to second-order, and can this threshold be engineered to prevent catastrophic infrastructure cascades?\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "q* has been computed for ER-ER and SF-SF interdependent pairs but not for real infrastructure network topologies (power grid + telecom + water).", "Cascading failure models do not account for temporal dynamics (recovery, load redistribution timescales) — the static percolation model is a worst case that may overestimate cascade risk.", "Optimal design of interdependency links (assortative vs. disassortative coupling between network layers) to maximise q* has not been solved.", "Empirical validation against historical cascade events (2003 Italy, 2006 European blackout, 2021 Texas winter storm) has not been done with the quantitative percolation framework." ], "suggested_hypotheses": [ "h-targeted-hub-vaccination-achieves-herd-immunity-fewer-doses-scale-free" ], "file": "unknowns-catalog/mathematics-physics/u-percolation-phase-transition-interdependent-networks-cascading-failures.yaml" }, { "id": "u-symplectic-quantization-gap", "title": "What is the precise mathematical relationship between symplectic geometry and quantum mechanics beyond deformation quantization, and when does geometric quantization fail to produce physically correct Hilbert spaces?\n", "status": "open", "domain": "mathematics-physics", "systematic_gaps": [ "No general theorem determining when geometric quantization yields a physically correct irreducible representation.", "Relationship between metaplectic correction and physical spin remains not fully understood.", "Quantization of non-linear symplectic reductions (reduced phase spaces of gauge theories) leads to inequivalent quantum theories." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mathematics-physics/u-symplectic-quantization-gap.yaml" }, { "id": "u-auction-market-design-kidney-exchange", "title": "What market design mechanisms optimally match kidney donors and recipients to maximize lives saved while respecting equity and compatibility constraints?", "status": "partial", "domain": "mechanism-design", "systematic_gaps": [ "Long-horizon (multi-year) kidney exchange matching has not been fully solved even computationally for realistic market sizes (>500 pairs per region).", "Incentive compatibility for hospitals (not hiding easy pairs to avoid cross-hospital exchanges) requires information revelation mechanisms not currently deployed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mechanism-design/u-auction-market-design-kidney-exchange.yaml" }, { "id": "u-combinatorial-auction-computational-complexity", "title": "Can combinatorial auction design (spectrum, landing slots, kidney exchange chains) achieve near-optimal allocations in polynomial time using approximation algorithms or machine learning, and what are the theoretical limits of strategyproof combinatorial mechanisms?", "status": "open", "domain": "mechanism-design", "systematic_gaps": [ "No polynomial-time strategyproof mechanism achieves a constant-factor approximation to optimal welfare in general combinatorial auctions — the computational-incentive compatibility frontier has not been fully characterized, and whether such a mechanism exists is an open complexity theory question.", "Kidney exchange chains of length >4 are NP-hard to optimize; current US kidney exchange pools use IP solvers that find optimal solutions for the current pool size (~5000 pairs) but will fail as pools scale by 10x — no approximation algorithm with known strategyproofness properties exists for long kidney chains.", "The sample complexity of learning an approximately optimal auction from bidder behavior data (without knowing the true value distribution) has not been established for combinatorial settings; existing results for single-item auctions do not generalize to multi-item settings with correlations." ], "suggested_hypotheses": [ "Deep neural network auction mechanisms (Dutting et al. \"RochetNet\" architecture) trained on the empirical distribution of FCC spectrum bidder preferences achieve within 5% of VCG optimal revenue while satisfying approximate strategyproofness (ex-post Nash equilibrium) with probability >0.95 over the training distribution." ], "file": "unknowns-catalog/mechanism-design/u-combinatorial-auction-computational-complexity.yaml" }, { "id": "u-mechanism-design-ai-alignment", "title": "Can mechanism design theory (revelation principle, VCG, incentive compatibility) provide rigorous frameworks for aligning AI agent behavior with human values in multi-agent and single-agent settings?", "status": "open", "domain": "mechanism-design", "systematic_gaps": [ "Mechanism design assumes fixed rational agents with stable preferences; AI agents change during training and have no fixed \"true type\" to reveal.", "VCG and related mechanisms require exact value elicitation; approximate incentive compatibility in AI training settings is not well understood.", "Multi-agent AI systems (multi-agent reinforcement learning) are game-theoretic environments where mechanism design directly applies, but the connection to alignment is underexplored." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mechanism-design/u-mechanism-design-ai-alignment.yaml" }, { "id": "u-mechanism-design-collusion-resistance", "title": "What auction mechanisms are simultaneously incentive-compatible, collusion-resistant, and computationally tractable for multi-item combinatorial settings?", "status": "open", "domain": "mechanism-design", "systematic_gaps": [ "No polynomial-time mechanism achieves both incentive compatibility and collusion resistance for general combinatorial valuations.", "The minimum revenue loss from relaxing collusion resistance to approximately core-selecting has not been bounded analytically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/mechanism-design/u-mechanism-design-collusion-resistance.yaml" }, { "id": "u-truthful-elicitation-mechanism-duality", "title": "How large are truthfulness gains from VCG-style payments in real preference elicitation when participants have cognitive costs and incomplete understanding?", "status": "open", "domain": "mechanism-design", "systematic_gaps": [ "Limited field A/B tests comparing Vickrey payments to cheap-talk elicitation at scale.", "Budget balance and fairness constraints often prevent literal VCG deployment." ], "suggested_hypotheses": [ "h-vickrey-clarke-groves-payments-improve-lab-truthful-reporting" ], "file": "unknowns-catalog/mechanism-design/u-truthful-elicitation-mechanism-duality.yaml" }, { "id": "u-bayesian-imaging-inverse-problem-posterior-calibration", "title": "When do posterior uncertainty maps in inverse imaging remain calibrated under forward-model mismatch and sparse sensing?", "status": "open", "domain": "medical-imaging", "systematic_gaps": [ "Public datasets with known ground-truth latent fields for calibration stress tests are limited.", "Coverage metrics are inconsistently reported across reconstruction methods and modalities.", "Clinical utility studies rarely compare calibrated uncertainty against deterministic confidence surrogates." ], "suggested_hypotheses": [], "file": "unknowns-catalog/medical-imaging/u-bayesian-imaging-inverse-problem-posterior-calibration.yaml" }, { "id": "u-ddpm-mri-prior-mismatch-artifact-risk", "title": "When do diffusion-model priors introduce clinically harmful artifacts in accelerated MRI reconstruction?", "status": "open", "domain": "medical-imaging", "systematic_gaps": [ "No consensus artifact taxonomy for diffusion-prior MRI reconstructions.", "Limited subgroup analysis for rare lesions and low-SNR acquisitions.", "Reader studies are inconsistent across institutions and protocols." ], "suggested_hypotheses": [ "h-ddpm-priors-reduce-mri-reconstruction-error-at-fixed-dose" ], "file": "unknowns-catalog/medical-imaging/u-ddpm-mri-prior-mismatch-artifact-risk.yaml" }, { "id": "u-eit-fisher-information-electrode-geometry-optimality", "title": "Which electrode geometries and drive protocols maximize clinically relevant Fisher information in EIT under realistic contact uncertainty?", "status": "open", "domain": "medical-imaging", "systematic_gaps": [ "Public datasets with controlled electrode-contact perturbations for design validation are scarce.", "Optimization studies often ignore workflow constraints from wearable and bedside EIT hardware.", "Lesion-level detectability objectives are inconsistently linked to information-theoretic criteria." ], "suggested_hypotheses": [], "file": "unknowns-catalog/medical-imaging/u-eit-fisher-information-electrode-geometry-optimality.yaml" }, { "id": "u-persistent-homology-parameter-stability-noisy-microscopy", "title": "Which filtration and embedding choices make persistent-homology QC metrics stable across optics drift, staining variability, and finite sampling in fluorescence microscopy stacks?", "status": "open", "domain": "medical-imaging", "systematic_gaps": [ "Few prospective studies tie persistence QC alarms to clinically meaningful segmentation failure modes.", "Under-documented sensitivity of barcodes to autofocus drift and PSF miscalibration.", "Limited benchmarks reporting inter-site reproducibility for topology-derived QC thresholds." ], "suggested_hypotheses": [ "h-multiscale-filtration-persistence-improves-microscopy-segmentation-qc" ], "file": "unknowns-catalog/medical-imaging/u-persistent-homology-parameter-stability-noisy-microscopy.yaml" }, { "id": "u-alzheimer-causal-biomarkers", "title": "Which amyloid and tau species are causal versus correlational in Alzheimer's disease progression?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Anti-amyloid trials have had mixed results", "Temporal ordering of amyloid, tau, and neurodegeneration biomarkers remains debated" ], "suggested_hypotheses": [ "Soluble amyloid oligomers rather than plaques drive synaptic dysfunction, explaining why plaque clearance does not consistently improve cognition" ], "file": "unknowns-catalog/medicine/u-alzheimer-causal-biomarkers.yaml" }, { "id": "u-ancestry-shift-sensitivity-of-elastic-net-prs", "title": "What ancestry shift levels destabilize `b-elastic-net-regularization-x-polygenic-risk-model-stability` calibration in prospective cohorts?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Prospective transfer audits are underreported compared with retrospective validation.", "Thresholding decisions are seldom co-optimized with subgroup calibration goals." ], "suggested_hypotheses": [ "h-elastic-net-prs-retraining-with-ancestry-balancing-reduces-calibration-drift" ], "file": "unknowns-catalog/medicine/u-ancestry-shift-sensitivity-of-elastic-net-prs.yaml" }, { "id": "u-anesthesia-consciousness", "title": "By what mechanism do general anaesthetics suppress consciousness and could this inform theories of consciousness?", "status": "open", "domain": "medicine", "systematic_gaps": [ "GABA-A potentiation and NMDA inhibition are primary targets", "Why different drugs at different doses produce the same endpoint of unconsciousness is unclear" ], "suggested_hypotheses": [ "General anaesthetics suppress consciousness by disrupting thalamocortical feedback necessary for global workspace ignition, not by directly silencing cortex" ], "file": "unknowns-catalog/medicine/u-anesthesia-consciousness.yaml" }, { "id": "u-antibiotic-resistance-rate", "title": "What determines the rate at which antibiotic resistance evolves in clinical settings?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Horizontal gene transfer and selection pressure are key factors", "Quantitative prediction of resistance emergence timeline is lacking" ], "suggested_hypotheses": [ "Phage predation pressure co-determines resistance evolution rate, and phage therapy can slow resistance emergence by imposing evolutionary trade-offs" ], "file": "unknowns-catalog/medicine/u-antibiotic-resistance-rate.yaml" }, { "id": "u-assimilation-window-stability-for-patient-specific-glucose-dynamics", "title": "What failure boundaries determine when `b-variational-data-assimilation-x-personalized-glucose-forecasting` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-variational-assimilation-derived-glucose-predictions-outperform-sliding-window-baselines" ], "file": "unknowns-catalog/medicine/u-assimilation-window-stability-for-patient-specific-glucose-dynamics.yaml" }, { "id": "u-autoimmune-trigger-identification", "title": "What environmental triggers initiate autoimmune disease in genetically susceptible individuals?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Molecular mimicry between pathogen peptides and self-antigens identified in some conditions", "Timing and dose-response of trigger exposure poorly characterised" ], "suggested_hypotheses": [ "Gut epithelial barrier breach during specific bacterial dysbiosis states is the necessary co-trigger for autoimmune onset in genetically susceptible hosts" ], "file": "unknowns-catalog/medicine/u-autoimmune-trigger-identification.yaml" }, { "id": "u-blood-brain-barrier-regulation", "title": "What molecular signals dynamically regulate blood-brain barrier permeability in health and disease?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Tight junction proteins and efflux transporters characterised", "Dynamic regulation by neural activity and inflammation poorly understood" ], "suggested_hypotheses": [ "Astrocyte end-feet signalling through aquaporin-4 dynamically regulates paracellular permeability in response to neuronal activity" ], "file": "unknowns-catalog/medicine/u-blood-brain-barrier-regulation.yaml" }, { "id": "u-cancer-immunoediting", "title": "How does tumour immunoediting shape the neoantigen landscape and what drives immune escape?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Loss of HLA alleles and neoantigen downregulation documented", "Kinetics of immunoediting during early oncogenesis poorly characterised" ], "suggested_hypotheses": [ "Early clonal neoantigens are preferentially lost through immunoediting, and the degree of neoantigen loss predicts checkpoint blockade response" ], "file": "unknowns-catalog/medicine/u-cancer-immunoediting.yaml" }, { "id": "u-cancer-stem-cell-hierarchy", "title": "Is cancer stem cell hierarchy fixed or plastic and what determines transition between states?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Lineage tracing shows clonal evolution in some cancers", "Non-hierarchical stochastic models also fit data in some cancers" ], "suggested_hypotheses": [ "Microenvironmental signalling gradients maintain cancer stem cell hierarchy in vivo, and this hierarchy is plastic and reversed by EMT induction" ], "file": "unknowns-catalog/medicine/u-cancer-stem-cell-hierarchy.yaml" }, { "id": "u-cardiac-regeneration-barriers", "title": "Why do adult mammalian cardiomyocytes fail to regenerate after myocardial infarction?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Neonatal hearts can regenerate but adults cannot", "Transition from regenerative to non-regenerative phenotype occurs around postnatal day 7 in rodents" ], "suggested_hypotheses": [ "Oxidative metabolism transition at postnatal day 7 induces cardiomyocyte binucleation and cell cycle arrest, and reverting to glycolytic metabolism restores proliferative capacity" ], "file": "unknowns-catalog/medicine/u-cardiac-regeneration-barriers.yaml" }, { "id": "u-chronic-pain-sensitization", "title": "What drives the transition from acute to chronic pain via central sensitization?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Spinal dorsal horn long-term potentiation is a candidate mechanism", "Genetic and psychological risk factors for chronification poorly integrated" ], "suggested_hypotheses": [ "Microglial-mediated synaptic stripping in the spinal dorsal horn establishes a self-sustaining central sensitization state independent of peripheral input" ], "file": "unknowns-catalog/medicine/u-chronic-pain-sensitization.yaml" }, { "id": "u-control-barrier-formal-safety-under-sensor-lag", "title": "How robust are CBF safety guarantees under realistic CGM lag and meal-estimation errors?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Limited in vivo evaluation of CBF feasibility under delayed glucose sensing.", "No widely accepted benchmark with meal-announcement and sensor-noise stress tests." ], "suggested_hypotheses": [ "h-cbf-enforced-insulin-constraints-prevent-severe-lows" ], "file": "unknowns-catalog/medicine/u-control-barrier-formal-safety-under-sensor-lag.yaml" }, { "id": "u-dmri-tortuosity-effective-medium-identifiability", "title": "Which tissue or phantom tortuosity parameters are identifiable from diffusion MRI once acquisition noise, compartment exchange, orientation dispersion, and model degeneracy are included?\n", "status": "open", "domain": "medicine", "systematic_gaps": [ "Phantom datasets with independently measured pore geometry and tortuosity.", "Identifiability maps for competing diffusion models under shared acquisition constraints." ], "suggested_hypotheses": [ "h-multi-shell-dmri-estimates-track-phantom-tortuosity" ], "file": "unknowns-catalog/medicine/u-dmri-tortuosity-effective-medium-identifiability.yaml" }, { "id": "u-domain-shift-calibration-for-resnet-retinal-screening", "title": "How much domain shift can `b-residual-learning-x-automated-retinal-screening-robustness` tolerate before calibration becomes unsafe?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Prospective monitoring protocols for calibration drift are not standardized.", "Cross-device validation often underrepresents low-resource screening environments." ], "suggested_hypotheses": [ "h-self-supervised-residual-pretraining-reduces-retinal-screening-false-negatives" ], "file": "unknowns-catalog/medicine/u-domain-shift-calibration-for-resnet-retinal-screening.yaml" }, { "id": "u-dose-spacing-fisher-information-design-trial-calibration", "title": "For realistic nonlinear dose-response models, when does Fisher-information-optimal dose spacing materially improve parameter precision over clinically conventional dose grids under safety and recruitment constraints?\n", "status": "open", "domain": "medicine", "systematic_gaps": [ "Transparent simulation library comparing dose grids across plausible pharmacodynamic curves.", "Sensitivity analysis for model misspecification and adverse-event constraints." ], "suggested_hypotheses": [ "h-fisher-optimal-dose-grid-reduces-parameter-variance-simulation" ], "file": "unknowns-catalog/medicine/u-dose-spacing-fisher-information-design-trial-calibration.yaml" }, { "id": "u-eikonal-anisotropy-identifiability-in-cardiac-activation-inverse-problems", "title": "What validation boundary conditions determine when `b-eikonal-wavefronts-x-cardiac-activation-mapping` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-eikonal-regularized-inversion-improves-cardiac-activation-map-fidelity" ], "file": "unknowns-catalog/medicine/u-eikonal-anisotropy-identifiability-in-cardiac-activation-inverse-problems.yaml" }, { "id": "u-ensemble-kalman-icu-parameter-identifiability", "title": "Which ICU physiological parameters remain unidentifiable under practical EnKF observation schedules?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Few open datasets report identifiability diagnostics together with EnKF performance.", "Localization and inflation heuristics vary widely across published ICU EnKF studies." ], "suggested_hypotheses": [ "h-localized-enkf-reduces-icu-forecast-error" ], "file": "unknowns-catalog/medicine/u-ensemble-kalman-icu-parameter-identifiability.yaml" }, { "id": "u-first-passage-warning-times-clinical-deterioration-model-shift", "title": "Do first-passage formulations maintain calibrated warning lead-times under clinical covariate shift?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-first-passage-hitting-time-models-extend-clinical-warning-lead-time" ], "file": "unknowns-catalog/medicine/u-first-passage-warning-times-clinical-deterioration-model-shift.yaml" }, { "id": "u-flim-t2star-multiexp-phantom-transfer", "title": "Can harmonized multi-exponential fitting pipelines calibrated on fluorescence lifetime imaging phantoms reduce bias when reused on MRI T2* relaxometry phantom datasets at comparable SNR?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Phantom studies with matched compartment counts and SNR ladders bridging TCSP FLIM and GRE T2* acquisitions", "Open datasets pairing voxel-wise posterior widths across modalities for identical gel compositions" ], "suggested_hypotheses": [ "h-shared-biexponential-fitting-bias-function-across-modalities-same-snr" ], "file": "unknowns-catalog/medicine/u-flim-t2star-multiexp-phantom-transfer.yaml" }, { "id": "u-ftle-derived-thrombosis-risk-threshold-transferability", "title": "Are FTLE-derived thrombosis risk thresholds transferable across imaging modalities and patient anatomies?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No multi-center harmonization study for FTLE threshold calibration.", "Insufficient uncertainty quantification for velocity-field reconstruction errors feeding FTLE estimates." ], "suggested_hypotheses": [ "h-ftle-ridge-persistence-predicts-left-atrial-appendage-stasis" ], "file": "unknowns-catalog/medicine/u-ftle-derived-thrombosis-risk-threshold-transferability.yaml" }, { "id": "u-hearing-regeneration-mammals", "title": "Why do mammals fail to regenerate cochlear hair cells after noise or drug-induced loss?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Birds and fish regenerate hair cells via supporting cell transdifferentiation", "Wnt and Notch pathway manipulation partially restores hair cell number in mice" ], "suggested_hypotheses": [ "Epigenetic silencing of pro-regenerative Atoh1 target genes in adult mammalian supporting cells prevents transdifferentiation and is reversible by HDAC inhibition" ], "file": "unknowns-catalog/medicine/u-hearing-regeneration-mammals.yaml" }, { "id": "u-hopf-normal-form-cardiac-alternans-mapping", "title": "To what extent do codimension-one bifurcation normal forms (Hopf, period-doubling) quantitatively predict measured alternans onset and spatial patterns in human ventricular preparations when channelopathies and fibrosis are included?\n", "status": "open", "domain": "medicine", "systematic_gaps": [ "Population studies linking fitted ion-channel models to empirically tracked bifurcation parameters across drug interventions", "Standardized reporting of alternans magnitude versus pacing cycle length with paired nonlinear-model continuation outputs" ], "suggested_hypotheses": [ "h-bifurcation-continuation-predicts-alternans-onset-optical-mapping" ], "file": "unknowns-catalog/medicine/u-hopf-normal-form-cardiac-alternans-mapping.yaml" }, { "id": "u-immune-aging-rejuvenation", "title": "What drives age-related immune decline (immunosenescence) and can it be pharmacologically reversed?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Thymic involution and naive T cell pool contraction are key features", "Transcriptional vs epigenetic basis of T cell exhaustion poorly separated" ], "suggested_hypotheses": [ "Thymic regeneration through IL-7 and FGF7 signalling combined with senescent cell clearance restores naive T cell output and reverses functional immunosenescence" ], "file": "unknowns-catalog/medicine/u-immune-aging-rejuvenation.yaml" }, { "id": "u-immunotherapy-nonresponders", "title": "Why do most solid tumour patients not respond to PD-1/PD-L1 checkpoint blockade?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Tumour mutational burden and PD-L1 expression are insufficient predictors", "Microbiome, tumour microenvironment, and systemic immunity all contribute" ], "suggested_hypotheses": [ "Dysfunction of CD8+ T cell precursor exhaustion state rather than terminal exhaustion determines whether checkpoint blockade restores anti-tumour immunity" ], "file": "unknowns-catalog/medicine/u-immunotherapy-nonresponders.yaml" }, { "id": "u-language-biomarker-clinical-validity", "title": "Which NLP-derived speech and language biomarkers have sufficient sensitivity, specificity, and longitudinal stability to meet regulatory standards for clinical use in Alzheimer's and psychiatric diagnosis?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Most NLP biomarker studies use cross-sectional designs; longitudinal validation with clinical endpoints is rare", "No NLP biomarker has received FDA or EMA regulatory approval for clinical use", "Performance in diverse languages, dialects, and education levels is understudied — most datasets are English-speaking WEIRD populations", "Signal vs confound: voice quality, accent, recording conditions, and topic may drive apparent group differences", "Regulatory pathway for a digital speech biomarker (device software function vs clinical decision support) is unclear" ], "suggested_hypotheses": [ "Semantic coherence decline (sentence-to-sentence cosine similarity slope over 2 years) predicts conversion from MCI to Alzheimer's dementia with AUC > 0.80, non-inferior to amyloid PET in the same cohort", "A combined NLP panel (lexical richness, semantic coherence, speech rate, pause frequency) outperforms any single biomarker and matches clinical interview sensitivity for major depressive episode classification" ], "file": "unknowns-catalog/medicine/u-language-biomarker-clinical-validity.yaml" }, { "id": "u-long-covid-mechanism", "title": "What are the pathological mechanisms driving long COVID symptoms persisting beyond 12 weeks?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Viral persistence, autoimmunity, and microbiome disruption are candidate mechanisms", "No single mechanism has been confirmed in all patients" ], "suggested_hypotheses": [ "Persistent SARS-CoV-2 RNA in gut reservoir drives systemic inflammation and explains the heterogeneous multi-system symptoms of long COVID" ], "file": "unknowns-catalog/medicine/u-long-covid-mechanism.yaml" }, { "id": "u-lyapunov-guided-antibiotic-cycling-resistance-ecology", "title": "Can Lyapunov-guided antibiotic cycling remain effective under ecological feedback and heterogeneous patient compliance?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-lyapunov-constrained-antibiotic-cycling-reduces-resistance-and-relapse" ], "file": "unknowns-catalog/medicine/u-lyapunov-guided-antibiotic-cycling-resistance-ecology.yaml" }, { "id": "u-lymphatic-system-brain", "title": "How does the glymphatic-lymphatic system clear metabolic waste from the brain and what impairs this in aging?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Sleep-dependent AQP4-mediated CSF-ISF exchange characterised", "Whether glymphatic impairment causes or follows Alzheimer's pathology unclear" ], "suggested_hypotheses": [ "AQP4 depolarisation from reactive astrogliosis impairs glymphatic clearance and accelerates amyloid accumulation in a self-sustaining feedback loop" ], "file": "unknowns-catalog/medicine/u-lymphatic-system-brain.yaml" }, { "id": "u-measurement-drift-effects-on-lasso-biomarker-sparsity", "title": "How robust is `b-lasso-sparsity-x-biomarker-panel-design` when assay drift perturbs low-abundance markers?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Longitudinal assay-drift datasets with paired outcomes are scarce.", "Panel-retraining cadence is rarely optimized jointly with clinical workflow constraints." ], "suggested_hypotheses": [ "h-stability-selected-lasso-panels-outperform-fixed-biomarkers-under-assay-noise" ], "file": "unknowns-catalog/medicine/u-measurement-drift-effects-on-lasso-biomarker-sparsity.yaml" }, { "id": "u-microbiome-mental-health", "title": "Does gut microbiome composition causally influence mental health outcomes via the gut-brain axis?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Germ-free animal studies show gut microbiome affects anxiety-like behaviour", "Human causal evidence limited by confounding" ], "suggested_hypotheses": [ "Specific short-chain fatty acid producers modulate tryptophan availability to the brain and causally influence depression susceptibility" ], "file": "unknowns-catalog/medicine/u-microbiome-mental-health.yaml" }, { "id": "u-morphogenetic-field-bioelectric-code", "title": "What is the complete bioelectric code — the mapping from tissue resting membrane potential patterns to anatomical outcomes — in planaria and vertebrate appendage regeneration, and can this code be read and rewritten pharmacologically to regenerate complex structures such as limbs in non-regenerative species?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No comprehensive atlas of Vmem patterns across planarian body regions correlated with downstream gene expression exists", "Mechanistic link from Vmem pattern to downstream transcription factor gradients is molecularly incomplete", "Pharmacological tools for precise spatial Vmem manipulation in 3D tissues are not yet available" ], "suggested_hypotheses": [], "file": "unknowns-catalog/medicine/u-morphogenetic-field-bioelectric-code.yaml" }, { "id": "u-mrna-vaccine-durability", "title": "What limits the durability of immunity from mRNA vaccines and can formulation changes extend it?", "status": "open", "domain": "medicine", "systematic_gaps": [ "mRNA vaccine immunity wanes faster than live-attenuated vaccines", "Germinal centre dynamics and long-lived plasma cell generation differ between platforms" ], "suggested_hypotheses": [ "Lipid nanoparticle clearance kinetics determine antigen exposure duration and are the primary determinant of germinal centre quality and memory B cell output" ], "file": "unknowns-catalog/medicine/u-mrna-vaccine-durability.yaml" }, { "id": "u-negative-control-selection-bias-pharmacovigilance-target-trials", "title": "Which negative-control libraries best calibrate confounding bias in target-trial-style pharmacovigilance studies?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-negative-control-calibrated-estimators-reduce-pharmacovigilance-signal-bias" ], "file": "unknowns-catalog/medicine/u-negative-control-selection-bias-pharmacovigilance-target-trials.yaml" }, { "id": "u-neuroinflammation-psychiatric", "title": "What is the causal role of neuroinflammation in treatment-resistant psychiatric disorders?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Elevated inflammatory markers correlate with treatment resistance", "Whether inflammation causes or results from psychiatric symptoms is unresolved" ], "suggested_hypotheses": [ "Microglia-mediated synaptic pruning in the prefrontal cortex is a causal mechanism in treatment-resistant depression that is reversible by anti-inflammatory intervention" ], "file": "unknowns-catalog/medicine/u-neuroinflammation-psychiatric.yaml" }, { "id": "u-observation-operator-misspecification-in-ensemble-smoother-oncology-models", "title": "What validation boundary conditions determine when `b-ensemble-smoother-x-precision-oncology-state-estimation` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-ensemble-smoothers-improve-precision-oncology-trajectory-calibration" ], "file": "unknowns-catalog/medicine/u-observation-operator-misspecification-in-ensemble-smoother-oncology-models.yaml" }, { "id": "u-organ-clock-synchrony", "title": "How do peripheral circadian clocks in organs synchronise with the central SCN clock and what disrupts this?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Feeding time entrains peripheral clocks independently of light cues", "Molecular mechanism of peripheral desynchrony in shift workers unclear" ], "suggested_hypotheses": [ "Liver clock desynchrony from feeding-fasting cycles in shift workers is the primary driver of metabolic syndrome risk independent of sleep disruption" ], "file": "unknowns-catalog/medicine/u-organ-clock-synchrony.yaml" }, { "id": "u-organ-fibrosis-reversibility", "title": "Under what conditions is established organ fibrosis reversible rather than permanent?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Liver fibrosis can regress after HCV cure", "Myofibroblast fate and matrix cross-linking extent determine reversibility" ], "suggested_hypotheses": [ "Myofibroblast reversion to quiescent stellate cells occurs when TGF-β signalling is withdrawn before irreversible collagen cross-linking, defining a treatment window" ], "file": "unknowns-catalog/medicine/u-organ-fibrosis-reversibility.yaml" }, { "id": "u-pain-sex-differences", "title": "What biological mechanisms underlie sex differences in pain sensitivity and chronic pain prevalence?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Microglia play a sexually dimorphic role in pain signalling in rodents", "Hormonal versus genetic contributions to human sex differences are poorly separated" ], "suggested_hypotheses": [ "T cell-dependent microglial activation in the spinal cord drives chronic pain in males while females use a T cell-independent CGRP-mediated pathway" ], "file": "unknowns-catalog/medicine/u-pain-sex-differences.yaml" }, { "id": "u-pancreatic-beta-cell-exhaustion", "title": "What drives beta cell exhaustion in type 2 diabetes and can exhausted cells be functionally rescued?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Glucotoxicity and lipotoxicity impair insulin secretion", "Whether beta cell mass loss or functional exhaustion dominates is unresolved" ], "suggested_hypotheses": [ "Endoplasmic reticulum stress from unfolded proinsulin is the primary driver of beta cell dysfunction and is reversible by GLP-1 receptor agonism" ], "file": "unknowns-catalog/medicine/u-pancreatic-beta-cell-exhaustion.yaml" }, { "id": "u-patient-specific-front-speed-estimation-in-wound-healing-kpp-models", "title": "What failure boundaries determine when `b-fisher-kpp-fronts-x-wound-healing-closure-forecasting` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-fisher-kpp-front-models-improve-wound-closure-time-forecasting" ], "file": "unknowns-catalog/medicine/u-patient-specific-front-speed-estimation-in-wound-healing-kpp-models.yaml" }, { "id": "u-placebo-neural-basis", "title": "What are the neural mechanisms mediating placebo analgesia and can they be therapeutically enhanced?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Endogenous opioid activation is one mechanism", "Non-opioid placebo pathways and their magnitude are poorly characterised" ], "suggested_hypotheses": [ "Expectation-driven descending inhibitory control through the periaqueductal gray mediates the majority of placebo analgesia independent of opioid tone" ], "file": "unknowns-catalog/medicine/u-placebo-neural-basis.yaml" }, { "id": "u-prion-spread-pathway", "title": "By what cellular and intercellular mechanisms do prion proteins spread between neurons?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Exosome-mediated transfer and trans-synaptic spread are candidate pathways", "In vivo kinetics of prion propagation poorly quantified" ], "suggested_hypotheses": [ "Tunnelling nanotube-mediated transfer of misfolded PrP between neurons is the dominant spread pathway and explains anatomical progression patterns" ], "file": "unknowns-catalog/medicine/u-prion-spread-pathway.yaml" }, { "id": "u-prior-sensitivity-of-laplace-based-interim-decision-rules", "title": "What failure boundaries determine when `b-laplace-approximation-x-clinical-trial-adaptive-enrichment` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-laplace-approximated-interim-rules-improve-enrichment-decision-efficiency" ], "file": "unknowns-catalog/medicine/u-prior-sensitivity-of-laplace-based-interim-decision-rules.yaml" }, { "id": "u-renewal-kernel-selection-readmission-burst-identifiability", "title": "Which renewal/self-excitation kernels are identifiable enough for reliable readmission burst forecasting across hospitals?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Few shared benchmark datasets expose failure modes needed for cross-domain falsification.", "Limited reporting standards quantify uncertainty calibration under distribution shift." ], "suggested_hypotheses": [ "h-self-exciting-renewal-models-improve-readmission-burst-forecasting" ], "file": "unknowns-catalog/medicine/u-renewal-kernel-selection-readmission-burst-identifiability.yaml" }, { "id": "u-sepsis-heterogeneity", "title": "What molecular subtypes of sepsis determine differential responses to standard-of-care treatment?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Two genomic endotypes (SRS1/SRS2) identified from ICU transcriptomics", "Causal pathway from subtype to outcome unresolved" ], "suggested_hypotheses": [ "SRS1 immunosuppressed endotype requires immune reconstitution rather than anti-inflammatory therapy to improve mortality" ], "file": "unknowns-catalog/medicine/u-sepsis-heterogeneity.yaml" }, { "id": "u-spinal-cord-complete-repair", "title": "Is complete motor function recovery after complete spinal cord injury achievable and what barriers remain?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Epidural stimulation restores stepping in incomplete injuries", "Axonal bridging across complete lesions has not been achieved in clinical settings" ], "suggested_hypotheses": [ "Combinatorial treatment with axon guidance molecules, neural stem cell bridges, and activity-dependent stimulation achieves functional reconnection across complete lesions in primates" ], "file": "unknowns-catalog/medicine/u-spinal-cord-complete-repair.yaml" }, { "id": "u-stain-variation-failure-modes-for-unet-histopathology-segmentation", "title": "What stain and scanner shifts break `b-unet-segmentation-x-histopathology-quantification-workflows` in multi-site deployment?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Multi-site pathology benchmarks with harmonized labels remain limited.", "Failure-case taxonomy is often qualitative and not tied to diagnostic risk." ], "suggested_hypotheses": [ "h-stain-normalized-unet-training-improves-cross-site-pathology-consistency" ], "file": "unknowns-catalog/medicine/u-stain-variation-failure-modes-for-unet-histopathology-segmentation.yaml" }, { "id": "u-state-representation-gaps-for-hjb-guided-adaptive-radiotherapy", "title": "What validation boundary conditions determine when `b-hamilton-jacobi-bellman-x-adaptive-radiotherapy` remains decision-useful?", "status": "open", "domain": "medicine", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-hjb-derived-adaptive-fractionation-improves-tumor-control-toxicity-tradeoff" ], "file": "unknowns-catalog/medicine/u-state-representation-gaps-for-hjb-guided-adaptive-radiotherapy.yaml" }, { "id": "u-stem-cell-niche-regulation", "title": "What signals maintain adult stem cell quiescence and what triggers activation for tissue repair?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Wnt, Notch and mTOR pathways regulate stem cell state", "Cell-extrinsic metabolic signals from the niche are poorly characterised" ], "suggested_hypotheses": [ "Lactate secreted by niche stromal cells is a primary metabolic signal that maintains HSC quiescence via epigenetic regulation" ], "file": "unknowns-catalog/medicine/u-stem-cell-niche-regulation.yaml" }, { "id": "u-tbi-repair-limits", "title": "What limits neurological recovery after severe traumatic brain injury and what interventions cross this limit?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Axonal regeneration in the CNS is suppressed by myelin-associated inhibitors", "Secondary injury cascades in the weeks following TBI worsen outcomes" ], "suggested_hypotheses": [ "Scar-forming reactive astrocytes create a physical and molecular barrier that limits axonal regeneration, and matrix metalloproteinase-mediated scar remodelling restores connectivity" ], "file": "unknowns-catalog/medicine/u-tbi-repair-limits.yaml" }, { "id": "u-telomere-aging-causality", "title": "Does telomere shortening causally drive aging or is it a biomarker of other aging processes?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Mendelian randomisation studies show mixed results", "Telomerase activation in model organisms extends healthspan but not consistently lifespan" ], "suggested_hypotheses": [ "Telomere shortening in replicative tissues causally limits healthspan via senescence induction, but is not the primary driver of post-mitotic tissue aging" ], "file": "unknowns-catalog/medicine/u-telomere-aging-causality.yaml" }, { "id": "u-topological-biomarker-robustness-across-wearables", "title": "Are topology-based arrhythmia biomarkers robust across consumer and clinical wearable devices?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Insufficient cross-device benchmark datasets with synchronized ground truth.", "No agreed preprocessing standard for topological rhythm features." ], "suggested_hypotheses": [ "h-persistent-h1-rise-precedes-afib-onset" ], "file": "unknowns-catalog/medicine/u-topological-biomarker-robustness-across-wearables.yaml" }, { "id": "u-transformer-ehr-long-horizon-attribution-validity", "title": "Are long-horizon attention attributions in EHR transformers clinically valid across institutions?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Limited prospective evaluation of attribution-guided clinical review workflows.", "Sparse cross-site studies with harmonized coding and timestamp conventions.", "Weak agreement standards for clinician-grounded explanation quality." ], "suggested_hypotheses": [ "h-transformer-temporal-attention-improves-ehr-risk-stratification" ], "file": "unknowns-catalog/medicine/u-transformer-ehr-long-horizon-attribution-validity.yaml" }, { "id": "u-tumor-evolution-topology-branching", "title": "Does the topology (Betti numbers β₀, β₁) of tumor copy-number variation space predict clinical outcomes — specifically, does β₁ > 0 (presence of evolutionary loops, indicating homologous recombination or convergent evolution) correlate with worse prognosis and resistance to targeted therapy?\n", "status": "open", "domain": "medicine", "systematic_gaps": [ "No clinical study has correlated Betti numbers of tumor CNV topology with patient outcomes (survival, time to relapse, drug resistance)", "Standard phylogenetic tree reconstruction discards topological information about non-tree evolutionary events; no benchmark comparing TDA and tree methods for predicting clonal dynamics exists", "Computational tools for persistent homology of single-cell CNV data are not integrated into clinical bioinformatics pipelines (GATK, Seurat, etc.)" ], "suggested_hypotheses": [ "Breast cancer tumors with β₁ > 0 in their single-cell CNV persistent homology have significantly worse 5-year progression-free survival than β₁ = 0 tumors at matched stage and grade, because evolutionary loops indicate convergent selection for fit genotypes with multiple independent paths to resistance" ], "file": "unknowns-catalog/medicine/u-tumor-evolution-topology-branching.yaml" }, { "id": "u-type2-diabetes-reversal", "title": "What is the mechanism of type 2 diabetes remission following bariatric surgery or very low calorie diets?", "status": "open", "domain": "medicine", "systematic_gaps": [ "Rapid glucose normalisation precedes weight loss, suggesting gut hormone effects", "Relative contribution of gut hormones, caloric restriction, and gut microbiome is disputed" ], "suggested_hypotheses": [ "Portal fatty acid signalling disruption after bariatric surgery is the primary mechanism of rapid beta cell function recovery independent of weight loss" ], "file": "unknowns-catalog/medicine/u-type2-diabetes-reversal.yaml" }, { "id": "u-vaccine-adjuvant-mechanism", "title": "How do vaccine adjuvants enhance adaptive immune responses at the cellular and molecular level?", "status": "open", "domain": "medicine", "systematic_gaps": [ "TLR agonist adjuvants activate innate immunity to provide danger signals", "Downstream mechanisms linking adjuvant to germinal centre quality are unclear" ], "suggested_hypotheses": [ "Adjuvant-induced type I interferon production by dendritic cells is the primary signal enhancing germinal centre reactions and long-lived plasma cell output" ], "file": "unknowns-catalog/medicine/u-vaccine-adjuvant-mechanism.yaml" }, { "id": "u-fano-metamaterial-dark-mode-q-engineering", "title": "For coupled radiative–subradiant metamolecule designs, which systematic design rules raise loaded Q while keeping mode overlap robust to fabrication disorder — beyond post-hoc Fano fitting of transmission spectra?\n", "status": "open", "domain": "metamaterials", "systematic_gaps": [ "Limited statistical studies correlating corner-rounding variance to Fano parameter drift across wafers.", "Multiphysics loss (thermal, nonlinear) during high-Q operation rarely co-optimized with linear Fano models." ], "suggested_hypotheses": [ "h-fano-q-factor-tracks-radiative-darkness-order-parameter" ], "file": "unknowns-catalog/metamaterials/u-fano-metamaterial-dark-mode-q-engineering.yaml" }, { "id": "u-atmospheric-blocking-climate-change-frequency", "title": "Will climate change increase or decrease the frequency and persistence of atmospheric blocking events in the Northern Hemisphere, and what is the dominant physical mechanism driving any change?\n", "status": "open", "domain": "meteorology", "systematic_gaps": [ "CMIP6 models disagree on sign of future blocking frequency change", "Observational trend in blocking frequency is statistically ambiguous in ERA5", "Charney-DeVore model is barotropic; baroclinic effects on blocking are not included" ], "suggested_hypotheses": [], "file": "unknowns-catalog/meteorology/u-atmospheric-blocking-climate-change-frequency.yaml" }, { "id": "u-atmospheric-predictability-limit-extended", "title": "Is the 10-14 day weather predictability limit fundamental (set by the Lyapunov exponent of atmospheric dynamics) or a technological barrier that could be extended with better initial conditions and models?", "status": "open", "domain": "meteorology", "systematic_gaps": [ "The Lyapunov exponent of the full atmospheric attractor has not been directly measured from global reanalysis data", "The relative contributions of initial condition uncertainty vs. model error to forecast degradation are not separated", "Subseasonal predictability sources (MJO, stratospheric sudden warmings) are not fully incorporated into operational models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/meteorology/u-atmospheric-predictability-limit-extended.yaml" }, { "id": "u-biofilm-viscoelasticity-dispersal-trigger", "title": "What mechanical or chemical signal triggers the switch from biofilm viscoelastic solid (attached persistence) to fluid (active dispersal), and can the yield stress and viscoelastic transition of EPS networks be manipulated pharmacologically to prevent biofilm formation on medical devices?", "status": "open", "domain": "microbiology", "systematic_gaps": [ "Bulk rheology of intact biofilms is technically limited to surface-accessible geometries; measuring subsurface mechanical properties requires AFM or MRI", "The molecular mechanism linking c-di-GMP signalling to EPS polymer network crosslink density is not fully resolved", "Anti-biofilm mechanical strategies (ultrasound, flow pulsation) are empirically tested but not designed from viscoelastic yield-stress first principles" ], "suggested_hypotheses": [], "file": "unknowns-catalog/microbiology/u-biofilm-viscoelasticity-dispersal-trigger.yaml" }, { "id": "u-microbial-mineral-weathering-rate-in-situ", "title": "What fraction of in situ mineral weathering rates in soils and sediments is directly attributable to microbial activity versus abiotic dissolution, and how does this partition vary with mineralogy and redox conditions?\n", "status": "open", "domain": "microbiology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/microbiology/u-microbial-mineral-weathering-rate-in-situ.yaml" }, { "id": "u-parameter-regimes-where-lotka-volterra-surrogates-fail-for-phage-bacteria-chemostats", "title": "What validation boundary conditions determine when `b-lotka-volterra-competition-x-phage-bacteria-chemostat-control` remains decision-useful?", "status": "open", "domain": "microbiology", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-lotka-volterra-informed-feedback-control-delays-phage-resistance-dominance" ], "file": "unknowns-catalog/microbiology/u-parameter-regimes-where-lotka-volterra-surrogates-fail-for-phage-bacteria-chemostats.yaml" }, { "id": "u-persister-cell-switching-rates-clinical", "title": "What are the switching rates alpha and beta for persister formation in clinically relevant bacterial species (S. aureus, E. coli, P. aeruginosa) under different antibiotic and stress conditions, and can these rates predict treatment failure in recurrent infections?\n", "status": "open", "domain": "microbiology", "systematic_gaps": [ "Switching rates in clinical isolates during actual infection have not been measured", "Effect of host immune pressure on persister switching rates is unknown", "No clinical trial has tested Markov-model-optimised dosing intervals" ], "suggested_hypotheses": [], "file": "unknowns-catalog/microbiology/u-persister-cell-switching-rates-clinical.yaml" }, { "id": "u-sindy-library-selection-bias-in-host-pathogen-inference", "title": "How sensitive is `b-sindy-sparse-discovery-x-host-pathogen-dynamics` to candidate library misspecification in realistic host-pathogen datasets?", "status": "open", "domain": "microbiology", "systematic_gaps": [ "No common benchmark quantifies biological plausibility versus predictive fit for discovered models.", "Library design heuristics are rarely stress-tested under measurement noise and sparse sampling." ], "suggested_hypotheses": [ "h-sindy-guided-control-policies-delay-phage-resistance-takeover" ], "file": "unknowns-catalog/microbiology/u-sindy-library-selection-bias-in-host-pathogen-inference.yaml" }, { "id": "u-droplet-microfluidics-cell-viability-encapsulation-efficiency", "title": "What are the physical and biochemical mechanisms of cell viability loss during droplet microfluidics encapsulation ΓÇö and can encapsulation efficiency and viability be simultaneously optimized for rare cell types (circulating tumor cells, primary neurons) where cell loss is critical?\n", "status": "open", "domain": "microfluidics", "systematic_gaps": [ "The relationship between nozzle geometry, flow velocity, and cell membrane stress (Maxwell stress, viscous stress) has not been quantitatively mapped for diverse cell types.", "Sub-Poisson loading approaches achieving >80% single-cell droplets (reducing the Poisson waste) have not been validated for fragile cell types at high throughput.", "Recovery of rare cells from mixed populations requires combining microfluidics with upstream enrichment; the integrated system performance for CTC capture from whole blood has not met clinical sensitivity requirements." ], "suggested_hypotheses": [], "file": "unknowns-catalog/microfluidics/u-droplet-microfluidics-cell-viability-encapsulation-efficiency.yaml" }, { "id": "u-attention-head-interpretability-in-protein-language-models", "title": "Which attention patterns in `b-transformer-attention-x-protein-language-model-fitness-prediction` are mechanistically meaningful versus spurious?", "status": "open", "domain": "molecular-biology", "systematic_gaps": [ "Ground-truth mechanistic benchmarks for attention explanations are sparse.", "Interpretability claims are rarely tied to downstream design decisions." ], "suggested_hypotheses": [ "h-attention-regularized-protein-language-models-improve-fitness-ranking" ], "file": "unknowns-catalog/molecular-biology/u-attention-head-interpretability-in-protein-language-models.yaml" }, { "id": "u-riboswitch-cotranscriptional-folding-kinetics", "title": "How does cotranscriptional folding kinetics determine riboswitch switching accuracy in vivo, and can the switching threshold be quantitatively predicted from measured aptamer K_d and RNA polymerase elongation rate?\n", "status": "open", "domain": "molecular-biology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/molecular-biology/u-riboswitch-cotranscriptional-folding-kinetics.yaml" }, { "id": "u-when-does-alternating-projection-outperform-em-in-cryoem-orientation-inference", "title": "What validation boundary conditions determine when `b-phase-retrieval-x-cryoem-orientation-inference` remains decision-useful?", "status": "open", "domain": "molecular-biology", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-alternating-projection-warm-starts-reduce-cryoem-orientation-assignment-errors" ], "file": "unknowns-catalog/molecular-biology/u-when-does-alternating-projection-outperform-em-in-cryoem-orientation-inference.yaml" }, { "id": "u-mycelial-network-optimization-principle", "title": "Does mycelial network topology represent a Pareto-optimal trade-off between transport cost minimization and fault tolerance, and what developmental rule (local or global) generates this near-optimal topology without centralized coordination?", "status": "open", "domain": "mycology", "systematic_gaps": [ "Time-lapse imaging of mycelial growth at sufficient resolution to infer local growth rules spans days; automating growth rule extraction from videos is not standardized", "The signalling mechanisms for long-range coordination during network remodeling are molecularly uncharacterized in most species", "Comparative topology studies across ecologically distinct fungal guilds using standardized graph metrics have not been published" ], "suggested_hypotheses": [], "file": "unknowns-catalog/mycology/u-mycelial-network-optimization-principle.yaml" }, { "id": "u-gcn-transmission-edge-direction-identifiability", "title": "Can graph-convolution models reliably recover directionality in pathogen transmission networks under sparse observations?", "status": "open", "domain": "network-science", "systematic_gaps": [ "Direction-sensitive benchmarks are scarce for realistic outbreak surveillance settings.", "Few methods quantify uncertainty in inferred edge direction.", "Comparisons to phylogenetic baselines are often incomplete." ], "suggested_hypotheses": [ "h-graph-convolution-with-mobility-priors-improves-outbreak-link-recovery" ], "file": "unknowns-catalog/network-science/u-gcn-transmission-edge-direction-identifiability.yaml" }, { "id": "u-hyperbolic-embeddings-hierarchy-identifiability", "title": "When can we reliably infer that empirical graph data require hyperbolic rather than Euclidean embedding from finite noisy samples?", "status": "open", "domain": "network-science", "systematic_gaps": [ "Few statistical tests distinguish hyperbolic fit from mixture Euclidean models on real networks.", "Training dynamics can collapse curvature unless regularized, confounding interpretation." ], "suggested_hypotheses": [ "h-real-hierarchies-embed-better-in-hyperbolic-space" ], "file": "unknowns-catalog/network-science/u-hyperbolic-embeddings-hierarchy-identifiability.yaml" }, { "id": "u-interdependent-network-restoration-dynamics", "title": "How do repair and restoration processes (human responders, automated rerouting) modify the cascade failure threshold in interdependent infrastructure networks?", "status": "open", "domain": "network-science", "systematic_gaps": [ "Empirical data on restoration dynamics (time-to-repair distributions, crew dispatch logistics) is not integrated into percolation models of infrastructure.", "Whether real infrastructure failures show first-order (discontinuous) or second-order (continuous) cascade dynamics is not empirically established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/network-science/u-interdependent-network-restoration-dynamics.yaml" }, { "id": "u-structural-holes-dynamics-network-evolution-brokerage-persistence", "title": "How stable are structural holes and brokerage positions over time in real social and organizational networks ΓÇö do brokers maintain their advantage as networks evolve, or do structural holes close as bridged groups discover each other through the broker?\n", "status": "open", "domain": "network-science", "systematic_gaps": [ "Longitudinal network data with sufficient temporal resolution to measure structural hole dynamics (weekly or monthly snapshots) with individual identifiers is rare; most studies use cross-sectional data.", "The causal direction between brokerage and performance (does brokerage cause performance, or do high performers accumulate brokerage positions?) has not been established with quasi-experimental evidence.", "The effect of digital communication platforms on structural hole dynamics (do platforms that surface mutual contacts reduce structural holes?) has not been studied longitudinally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/network-science/u-structural-holes-dynamics-network-evolution-brokerage-persistence.yaml" }, { "id": "u-state-dependent-phase-response-model-drift-in-adaptive-dbs", "title": "What failure boundaries determine when `b-phase-response-curves-x-adaptive-deep-brain-stimulation-timing` remains decision-useful?", "status": "open", "domain": "neurology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-phase-response-adaptive-dbs-reduces-off-target-neural-entrainment" ], "file": "unknowns-catalog/neurology/u-state-dependent-phase-response-model-drift-in-adaptive-dbs.yaml" }, { "id": "u-neuroprosthetic-decoder-long-term-stability-mechanisms", "title": "What are the relative contributions of electrode impedance increase, neuronal loss from glial encapsulation, neural plasticity, and decoder parameter drift to the long-term performance degradation of intracortical neuroprosthetic decoders, and which failure mechanism should adaptive algorithms prioritise?\n", "status": "open", "domain": "neuroprosthetics", "systematic_gaps": [ "Longitudinal multi-measure datasets (impedance + unit count + decoder accuracy + histology at explant) in human BCI participants have not been analysed with causal mediation models to attribute performance degradation to specific mechanisms.", "Closed-loop adaptive decoders that simultaneously track electrode impedance drift and neural tuning drift have not been implemented; current methods address only tuning drift.", "The effect of cortical stimulation (for sensory feedback) on the longevity of recording electrodes in the same array has not been systematically characterised." ], "suggested_hypotheses": [ "In BrainGate2 participants with >2 years of implant, impedance-mediated SNR reduction explains >50% of variance in decoder performance degradation, whereas neural plasticity (tuning change) explains <20% — implying that materials improvements in electrode coatings would have greater clinical impact than improved adaptive decoding algorithms.\n" ], "file": "unknowns-catalog/neuroprosthetics/u-neuroprosthetic-decoder-long-term-stability-mechanisms.yaml" }, { "id": "u-adult-human-hippocampal-neurogenesis-existence-rate-controversy", "title": "Does adult human hippocampal neurogenesis persist at a functionally significant rate (>100 neurons/day) in healthy adults over 30, and what methodological factors explain the discrepancy between Spalding et al. (2013) radiocarbon dating (~700/day) and Sorrells et al. (2018) immunohistochemistry (near zero in adults)?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Standardized post-mortem tissue banking protocol (< 6h PMI, standardized fixation duration and temperature) for neurogenesis marker preservation.", "Single-nucleus RNA sequencing of human dentate gyrus (snRNA-seq) for unbiased detection of immature neuron transcriptional signatures.", "Validation of ¹⁴C birth-dating against direct immunohistochemistry in non-human primates (where both can be measured simultaneously).", "DCX antibody cross-validation across labs using the same positive control tissue." ], "suggested_hypotheses": [ "Single-nucleus RNA sequencing of fresh (PMI < 4h) human dentate gyrus tissue from donors aged 20-70 will detect a small but consistent population of cells (<0.1% of granule layer cells) expressing immature neuron markers (DCX, PSA-NCAM, PROX1 low) that is absent in fixed autopsy tissue — demonstrating that AHN exists at low rates in adults but is below the detection threshold of standard immunohistochemistry on fixed tissue.\n" ], "file": "unknowns-catalog/neuroscience/u-adult-human-hippocampal-neurogenesis-existence-rate-controversy.yaml" }, { "id": "u-attention-neural-mechanisms", "title": "What are the neural circuit mechanisms by which top-down attention selects and enhances sensory signals, and does attention act by gain, timing, or noise reduction?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The relative contributions of gain, noise reduction, and temporal synchronisation to attention effects have not been dissociated in a single experimental paradigm.", "The attentional locus of selection (early sensory vs later decision stages) is disputed for different attentional types (spatial, feature, object).", "Neuromodulatory basis of attention (acetylcholine, norepinephrine) has been established pharmacologically but circuit-level mechanisms are not known." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-attention-neural-mechanisms.yaml" }, { "id": "u-axon-soliton-collision-dynamics", "title": "Do action potentials at axon branch points interact according to soliton collision rules, and can soliton perturbation theory predict conduction failure thresholds?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No systematic test of soliton collision rules at axon branch points in vitro", "Perturbation theory predictions not compared to Hodgkin-Huxley simulation outcomes", "Channelopathy effects on conduction velocity not framed in soliton amplitude language" ], "suggested_hypotheses": [ "h-axon-soliton-collision-dynamics" ], "file": "unknowns-catalog/neuroscience/u-axon-soliton-collision-dynamics.yaml" }, { "id": "u-bayesian-brain-prior-encoding", "title": "How are Bayesian priors physically encoded in neural circuits, and how do they change with learning?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The neural circuits encoding specific perceptual priors (e.g. slow motion prior in MT, cardinal orientation prior in V1) have not been identified at the synaptic level.", "Whether prior strength changes with development (critical periods) and adult learning follows Bayesian update rules is not tested quantitatively.", "The prior distributions over high-level semantic categories (objects, faces, social intentions) are not characterised in computational or neural terms." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-bayesian-brain-prior-encoding.yaml" }, { "id": "u-biological-backpropagation-mechanism", "title": "How does the brain implement something functionally equivalent to backpropagation for credit assignment across multi-layer circuits without a global error signal?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No in-vivo measurement of whether synaptic weight updates in cortex match backpropagation predictions versus feedback alignment versus random targets.", "The weight transport problem: no biophysical mechanism for neurons to use transposed feedback weights has been identified.", "Whether predictive coding circuits in cortex implement exact or approximate gradient computation has not been tested with electrophysiology." ], "suggested_hypotheses": [ "h-predictive-coding-implements-backprop" ], "file": "unknowns-catalog/neuroscience/u-biological-backpropagation-mechanism.yaml" }, { "id": "u-brain-criticality-universality-class", "title": "What is the universality class of the critical point at which the brain operates — mean-field branching process, directed percolation, or another universality class — and does this class vary across brain regions, species, or cognitive states?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Single-unit recording at cellular resolution across a macroscopic cortical area", "Finite-size scaling analysis of avalanche distributions in vivo", "Comparison of 2D vs 3D cortical network critical exponents", "Role of long-range cortico-cortical connections in modifying universality class" ], "suggested_hypotheses": [ "h-criticality-maximizes-neural-dynamic-range" ], "file": "unknowns-catalog/neuroscience/u-brain-criticality-universality-class.yaml" }, { "id": "u-brain-organoid-validity", "title": "How well do cerebral organoids model human brain development and disease, and what are the limits of their validity as research models?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The correspondence between organoid transcriptome and fetal brain transcriptome at equivalent developmental stages has been quantified but its functional implications are unclear.", "Disease-relevant organoid phenotypes are often subtle and not reproducible across labs using different protocols.", "The ethical status of organoids exhibiting neural activity patterns similar to preterm infants has not been resolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-brain-organoid-validity.yaml" }, { "id": "u-cerebellar-prediction-coding", "title": "Does the cerebellum implement a forward model for predicting sensory consequences of motor commands, and can this explain cerebellar involvement in non-motor functions?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The non-motor forward models hypothesized for language and working memory have not been identified at the circuit level", "Whether cerebellar timing predictions use the same mossy fiber/parallel fiber/climbing fiber machinery as motor learning is not established", "DREADD or optogenetic silencing of specific cerebellar lobules during cognitive tasks has not been performed in humans" ], "suggested_hypotheses": [ "Cerebellar lobule VI-VII BOLD activation during language tasks encodes prediction error (mismatch between predicted and actual word meaning), not motor preparation, measurable as a surprise response to semantic violations with distinct timing from language cortex" ], "file": "unknowns-catalog/neuroscience/u-cerebellar-prediction-coding.yaml" }, { "id": "u-cerebellum-cognitive-function", "title": "What cognitive functions does the cerebellum perform beyond motor coordination, and what is its computational principle?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The cognitive functions attributed to the cerebellum are based primarily on connectivity and lesion studies; the causal role is not established.", "Cerebellar predictions of non-motor events have not been directly measured; the forward model is inferred from motor behaviour.", "The role of the cerebellum in autism spectrum condition (cerebellar abnormalities are common) is not mechanistically understood." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-cerebellum-cognitive-function.yaml" }, { "id": "u-circadian-desynchrony-disease-mechanisms", "title": "What are the causal mechanisms linking chronic circadian desynchrony (shift work, social jet lag) to metabolic syndrome, cancer, and neurodegeneration?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Most human studies are observational; the effect of controlled experimental circadian misalignment on molecular clock parameters in accessible tissues (blood, biopsy) is incompletely characterized.", "The timescale of irreversible damage from chronic desynchrony versus fully reversible phase-shift has not been established in animal models.", "Pharmacological chronotherapy (timing drug delivery to circadian phase) lacks standardized patient-specific phase estimation methods." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-circadian-desynchrony-disease-mechanisms.yaml" }, { "id": "u-connectome-neurodegeneration-spread-rate", "title": "What determines the rate and trajectory of trans-synaptic pathological protein spread through the connectome in Alzheimer's and Parkinson's disease?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Network diffusion models predict spatial pattern of tau spread but not individual rate variation", "In vivo validation of trans-synaptic spread requires longitudinal PET with sub-year intervals unavailable in existing cohorts", "Whether spread rate is set by connectome topology, local neuronal activity, or pathology-specific properties is unknown", "No mechanistic model integrates axonal transport kinetics with graph-theoretic propagation" ], "suggested_hypotheses": [ "Spread rate is proportional to hub node activity level — high-activity default-mode hubs secrete more amyloid and spread tau faster via the activity-dependent release mechanism", "Spectral gap of the structural connectome predicts individual differences in disease progression speed" ], "file": "unknowns-catalog/neuroscience/u-connectome-neurodegeneration-spread-rate.yaml" }, { "id": "u-connectome-spectral-laplacian", "title": "What is the mechanistic link between individual differences in connectome Laplacian eigenspectrum and variability in cognitive performance, and how does the spectral gap change with learning?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No large-scale study has directly correlated Laplacian spectral gap λ₂ with cognitive battery scores while controlling for cortical thickness and white-matter microstructure.", "The test-retest reliability of connectome Laplacian eigenvalues from tractography is not established, limiting their use as biomarkers.", "Longitudinal studies tracking Laplacian eigenspectrum changes with learning, aging, or disease (multiple sclerosis, TBI) are absent." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-connectome-spectral-laplacian.yaml" }, { "id": "u-consciousness-binding-problem", "title": "How does the brain bind spatially and temporally distributed neural signals into a unified conscious percept — is the binding mechanism synchrony, convergence zones, or a global workspace?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No causal test distinguishes synchrony from convergence-zone from global workspace binding in the same paradigm", "The temporal resolution of binding (how fast features are integrated) is not quantitatively explained by any theory", "Whether binding is a global broadcast or local circuit phenomenon is unresolved for multisensory integration" ], "suggested_hypotheses": [ "Gamma synchrony is necessary but not sufficient for feature binding: binding requires both gamma coherence AND long-range beta (15-30 Hz) phase coupling between feature areas and prefrontal cortex, measurable via granger causality in MEG" ], "file": "unknowns-catalog/neuroscience/u-consciousness-binding-problem.yaml" }, { "id": "u-consciousness-information-integration-scale", "title": "At what spatial and temporal scale does information integration relevant to consciousness occur in the brain, and how does this scale relate to clinical consciousness loss?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No systematic study of how Phi (or proxies) varies with measurement window duration and spatial scale in conscious vs. unconscious subjects has been published.", "Whether the clinically validated consciousness proxy PCI (perturbational complexity index) converges to a Phi approximation in any limit has not been shown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-consciousness-information-integration-scale.yaml" }, { "id": "u-default-mode-network-function", "title": "What is the functional role of the default mode network, and why is it suppressed during externally directed tasks?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The causal role of DMN activity versus associated activity cannot be established by fMRI correlations alone.", "DMN disruption in Alzheimer's, depression, and schizophrenia is documented but whether it is a cause or consequence is not known.", "The relationship between DMN activity and conscious experience has not been formalised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-default-mode-network-function.yaml" }, { "id": "u-dopamine-prediction-error-temporal-credit", "title": "Does dopaminergic prediction error signaling implement temporal-difference learning exactly, and how does it solve the temporal credit assignment problem for rewards separated by minutes?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Neural mechanism for temporal credit assignment over minutes-long delays unidentified", "Whether dopamine encodes variance (risk) in addition to mean value is contested", "How dopamine neurons learn to produce correct prediction errors (meta-learning problem) is unknown" ], "suggested_hypotheses": [ "Hippocampal time cells (neurons encoding elapsed time) provide temporal context signals to dopamine neurons via VTA afferents, implementing an effective eligibility trace with timescale set by hippocampal theta oscillation frequency" ], "file": "unknowns-catalog/neuroscience/u-dopamine-prediction-error-temporal-credit.yaml" }, { "id": "u-eeg-source-localization-skull-conductivity", "title": "How much does inter-individual variability in skull electrical conductivity degrade EEG source localization accuracy, and can in vivo conductivity imaging sufficiently correct for this?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-eeg-source-localization-skull-conductivity.yaml" }, { "id": "u-efficient-coding-bottleneck-tradeoff-measurability", "title": "When can information-bottleneck curves fitted from artificial neural networks be compared fairly to empirical sufficiency–complexity tradeoffs measured from biological sensory circuits?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Sparse datasets jointly reporting calibrated stimulus ensembles, neural variability, and ML model predictions with identical task labels.", "Limited uncertainty quantification on mutual-information estimates used for comparisons.", "Under-studied effects of temporal dynamics versus static coding analyses." ], "suggested_hypotheses": [ "h-information-bottleneck-alignment-improves-neural-encoding-metrics" ], "file": "unknowns-catalog/neuroscience/u-efficient-coding-bottleneck-tradeoff-measurability.yaml" }, { "id": "u-efficient-coding-metabolic-optimality", "title": "Does the visual cortex actually operate at or near its Shannon channel capacity for natural images, and what is the quantitative metabolic efficiency (bits transmitted per ATP molecule) of early visual processing?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No in vivo measurement of bits/ATP for a complete retinogeniculate pathway under natural stimulation.", "The efficient coding optimum depends on the natural image ensemble; what counts as \"natural\" for a given animal's ecological niche is poorly defined.", "Correlated noise in neural populations reduces channel capacity; the extent of noise correlations in vivo under natural stimulation is debated.", "Whether efficient coding is a developmental optimisation (learned) or evolutionary (innate) has not been resolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-efficient-coding-metabolic-optimality.yaml" }, { "id": "u-ei-balance-diversity-robustness", "title": "How does the diversity of inhibitory interneuron subtypes contribute to cortical circuit stability, and does neural heterogeneity follow the same diversity-stability relationship as ecological communities?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No systematic measurement of random matrix eigenspectrum for biological cortical connectivity matrices including interneuron subtypes.", "The functional consequences of selectively eliminating one interneuron subtype (beyond PV and SST) on overall circuit stability have not been measured.", "Whether interneuron diversity in primates provides greater stability benefits than in rodents (consistent with circuit complexity scaling) has not been tested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-ei-balance-diversity-robustness.yaml" }, { "id": "u-emotion-discrete-vs-constructed", "title": "Are emotions discrete natural kinds with distinct neural signatures, or are they constructed from more basic affective and cognitive building blocks?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Meta-analyses of neuroimaging studies show no consistent emotion-specific patterns; regions claimed as emotion-specific activate across multiple functions.", "Universal facial expression claims fail cross-cultural replication in some studies, supporting constructivist accounts.", "A unified computational model of emotion that predicts both neural and behavioural data has not been developed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-emotion-discrete-vs-constructed.yaml" }, { "id": "u-engram-molecular-basis", "title": "What are the molecular and synaptic mechanisms that store specific memories in engram cells, and how are they maintained over decades?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The problem of molecular maintenance (proteins turn over in weeks; memories last decades) has no agreed solution; candidates include RNA-binding proteins and PKMzeta.", "Engram cell reactivation is sufficient to drive memory recall in mice, but the neural code translating engram activity into specific memory content is not known.", "Whether engrams are localised to single cells or distributed across neural ensembles is not resolved for complex (semantic, episodic) memories." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-engram-molecular-basis.yaml" }, { "id": "u-fmri-connectivity-graphical-model-validity", "title": "Do partial correlation graphical models estimated from resting-state fMRI BOLD signals accurately reflect direct synaptic connectivity, and what sources of confounding (hemodynamic variability, motion artifacts, physiological noise) most severely compromise the validity of functional connectivity estimates?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Ground truth for human functional connectivity validation requires non-existent complete human connectome at the cellular level", "Regional hemodynamic response function variability is poorly characterized in aged, diseased, and pharmacologically-treated brains", "The statistical power to detect individual edges in functional connectivity graphs from typical fMRI datasets (~10 min) is low for small effect sizes" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-fmri-connectivity-graphical-model-validity.yaml" }, { "id": "u-glial-cell-computation", "title": "Do astrocytes perform genuine computational operations on neural signals through tripartite synapses, or is gliotransmission a modulatory background process?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Whether astrocyte calcium events carry information (encode stimulus features) or merely reflect activity levels", "The computational capacity of tripartite synapse networks has not been formally estimated", "Whether blocking gliotransmission impairs specific computations (pattern separation, coincidence detection) vs. global excitability" ], "suggested_hypotheses": [ "Astrocyte D-serine release implements a second-order temporal correlation detector: synaptic inputs within 500 ms from different synapses are potentiated only if the astrocyte calcium threshold is reached, implementing coincidence detection unavailable to the neuron alone" ], "file": "unknowns-catalog/neuroscience/u-glial-cell-computation.yaml" }, { "id": "u-glymphatic-flow-impairment-alzheimers", "title": "Does glymphatic system impairment causally drive amyloid-β and tau accumulation in Alzheimer's disease, and what interventions can restore glymphatic clearance in aging brains?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Direct measurement of glymphatic flow rates in living human brains has not been achieved with sufficient spatial and temporal resolution to distinguish early AD from healthy aging.", "Whether AQP4 polarization loss in human AD brains precedes or follows amyloid plaque formation is unknown.", "No interventional study has enhanced glymphatic clearance in humans and measured downstream effects on amyloid/tau burden and cognitive function." ], "suggested_hypotheses": [ "Glymphatic dysfunction (measured by CSF tracer MRI) precedes amyloid PET positivity in APOE4 carriers by 5-10 years, establishing glymphatic impairment as an upstream event in the AD cascade." ], "file": "unknowns-catalog/neuroscience/u-glymphatic-flow-impairment-alzheimers.yaml" }, { "id": "u-grid-cell-cognitive-map-geometry", "title": "Do grid cells provide a universal metric coordinate system for abstract cognitive spaces beyond spatial navigation, and what determines the hexagonal grid scale?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Mechanism generating hexagonal grids (attractor network vs oscillatory interference vs Turing instability) not distinguished experimentally", "Whether non-spatial grid-like firing in fMRI reflects genuine hexagonal coding or confounded BOLD responses", "The computationally optimal grid scale ratio (sqrt(2)? golden ratio?) has not been derived from information theory" ], "suggested_hypotheses": [ "The hexagonal grid scale follows the sqrt(2) progression because this minimizes the average positional uncertainty across multiple grid modules for fixed total neuron count — derivable from Shannon information maximization" ], "file": "unknowns-catalog/neuroscience/u-grid-cell-cognitive-map-geometry.yaml" }, { "id": "u-grid-cell-fourier-basis-navigation", "title": "Does the multi-scale grid cell system implement an optimal Fourier basis for encoding spatial position with minimum neurons, and what is the theoretical lower bound on the number of grid modules needed for unique position encoding across an environment without ambiguity?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The number of grid modules in humans is estimated from fMRI but individual module resolution is insufficient for toroidal manifold analysis", "The scale ratio geometric series hypothesis has been tested in rodents but not rigorously across environmental sizes and shapes", "Phase continuity of the toroidal manifold across grid modules has not been measured during active navigation in large environments" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-grid-cell-fourier-basis-navigation.yaml" }, { "id": "u-hair-cell-bundle-x-hopf-bifurcation", "title": "How does the inner ear maintain tuning of individual hair cells at the Hopf bifurcation across the full auditory frequency range (20 Hz to 20 kHz), and what active feedback mechanisms set the bifurcation parameter?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Molecular identity of the adaptation motor maintaining the Hopf bifurcation point is debated (myosin vs Ca2+-gating)", "Quantitative measurement of the bifurcation parameter in vivo is limited by accessibility of the mammalian cochlea", "Interaction between the traveling wave and individual hair cell Hopf oscillators is not fully modeled" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-hair-cell-bundle-x-hopf-bifurcation.yaml" }, { "id": "u-hawkes-branching-ratio-seizure-cascade-threshold", "title": "Is there a reproducible Hawkes branching-ratio threshold for impending seizure clusters?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No consensus calibration protocol across EEG hardware and sampling rates.", "Limited prospective evidence linking estimated eta to actionable intervention windows." ], "suggested_hypotheses": [ "h-hawkes-branching-threshold-predicts-seizure-clusters" ], "file": "unknowns-catalog/neuroscience/u-hawkes-branching-ratio-seizure-cascade-threshold.yaml" }, { "id": "u-hippocampal-replay-sequence-selection-criteria", "title": "By what mechanism does the hippocampus select which waking experience sequences are replayed during sharp-wave ripples, and what determines whether replay is forward or reverse?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-hippocampal-replay-sequence-selection-criteria.yaml" }, { "id": "u-hodgkin-huxley-channel-heterogeneity-neuron-diversity", "title": "How do differences in ion channel composition and density across neuron types produce the diverse firing patterns observed experimentally, and can a unified conductance-based framework predict firing phenotype from transcriptomic channel expression data?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "mRNA-to-conductance calibration curves are available only for a handful of channel types", "Axonal vs. somatic channel distributions are not captured by bulk or single-cell RNA-seq", "The space of channel combinations producing a given firing phenotype is degenerate (many solutions)" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-hodgkin-huxley-channel-heterogeneity-neuron-diversity.yaml" }, { "id": "u-holographic-memory-neural-phase-encoding-test", "title": "Can the holographic memory model make quantitatively distinct predictions from localist or sparse coding memory models that are testable with current neural recording technology?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-holographic-memory-neural-phase-encoding-test.yaml" }, { "id": "u-hopfield-capacity-cortical-memory", "title": "Does the human cortex implement associative memory consistent with Hopfield-network capacity limits, and what neural architecture enables storage approaching the modern Hopfield exponential bound?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No direct measurement of hippocampal or cortical associative memory capacity using naturalistic stimuli with known number of stored patterns.", "The synaptic learning rule that maximizes memory capacity subject to biological constraints (sparse connectivity, Dale's law) is not fully characterized.", "Whether the transformer-attention / modern Hopfield equivalence implies that cortical circuits implement attention-like operations is speculative." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-hopfield-capacity-cortical-memory.yaml" }, { "id": "u-identifiability-of-hysteresis-biomarkers-in-neurofatigue-monitoring", "title": "What failure boundaries determine when `b-hysteresis-loop-area-x-neural-fatigue-recovery-dynamics` remains decision-useful?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-hysteresis-loop-biomarkers-predict-neurofatigue-recovery-lag" ], "file": "unknowns-catalog/neuroscience/u-identifiability-of-hysteresis-biomarkers-in-neurofatigue-monitoring.yaml" }, { "id": "u-insect-navigation-path-integration", "title": "How does the insect central complex ring attractor circuit implement the nonlinear noise correction that prevents path integration error from accumulating faster than the √L random-walk prediction?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The relationship between the width of the heading bump in the Drosophila CX and the effective heading uncertainty (in degrees) has not been calibrated using simultaneous electrophysiology and behavioral tracking.", "Whether E-PG neurons in the fly CX implement a form of lateral inhibition that sharpens the bump under high-noise conditions is untested.", "Path integration error accumulation has not been measured in mutant flies with altered CX circuit properties (e.g., reduced E-PG → P-EN connectivity)." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-insect-navigation-path-integration.yaml" }, { "id": "u-interoception-consciousness-link", "title": "How does interoceptive signalling from body organs contribute to emotional experience and conscious self-awareness?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The predictive coding account of interoception makes quantitative predictions but lacks experimental designs that could falsify it.", "Individual differences in interoceptive accuracy correlate with emotional and psychiatric outcomes, but causality has not been established.", "How interoceptive signals are integrated with exteroceptive perception to generate a unified sense of self is not modelled computationally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-interoception-consciousness-link.yaml" }, { "id": "u-intrinsic-motivation-information-maximization", "title": "Does the brain implement empowerment maximization (maximising mutual information between actions and future states) as the computational substrate for intrinsic motivation, and can this be detected as a distinctive neural signature that predicts autonomy need satisfaction independent of reward?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No neural decoding of empowerment as distinct from expected reward in human or animal studies", "Active inference model predictions for autonomy need satisfaction not tested against SDT predictions in matched paradigms", "Information-theoretic crowding-out predictions not tested with neural measures alongside behavioral measures" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-intrinsic-motivation-information-maximization.yaml" }, { "id": "u-ion-channel-barrier-heights-from-multiscale-md-posteriors", "title": "Can atomistic molecular dynamics posteriors on ion-channel voltage-sensor conformations be compressed into effective two-state barrier heights whose voltage dependence matches patch-clamp τ(V) curves within experimental uncertainty?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Integrated pipelines publishing joint likelihoods spanning MD order parameters and macroscopic clamp datasets for identical constructs", "Uncertainty quantification propagating force-field errors into predicted barrier ΔG‡(V)" ], "suggested_hypotheses": [ "h-markov-gating-graph-consistency-with-kramers-scaling-under-voltage-clamp-protocols" ], "file": "unknowns-catalog/neuroscience/u-ion-channel-barrier-heights-from-multiscale-md-posteriors.yaml" }, { "id": "u-kramers-drift-diffusion-barrier-mapping-neural-decisions", "title": "Can Kramers-style barrier and noise parameters provide useful priors or diagnostics for drift-diffusion decision models without overextending the chemical-kinetics analogy?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Benchmarks comparing standard drift-diffusion fits against Kramers-informed priors.", "Tests on reaction-time tails, not only mean reaction time and accuracy." ], "suggested_hypotheses": [ "h-reaction-time-tail-scales-with-effective-barrier-height" ], "file": "unknowns-catalog/neuroscience/u-kramers-drift-diffusion-barrier-mapping-neural-decisions.yaml" }, { "id": "u-landauer-limit-neuronal-computation", "title": "How close does neuronal computation operate to the Landauer thermodynamic limit, and does evolutionary pressure drive neural circuits toward thermodynamic efficiency?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No systematic comparison of energy-per-bit for C. elegans vs mammalian neurons in vitro", "No framework to compute mutual information per spike across species under different metabolic constraints", "Landauer limit never directly referenced in neural efficiency literature" ], "suggested_hypotheses": [ "h-landauer-limit-neuronal-computation" ], "file": "unknowns-catalog/neuroscience/u-landauer-limit-neuronal-computation.yaml" }, { "id": "u-lstm-gating-biological-analogue", "title": "Does the prefrontal cortex implement a biological analogue of LSTM gating where neuromodulatory signals (dopamine, acetylcholine) set an effective temperature controlling the persistence versus updating of working memory representations?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No direct test of neuromodulatory signals as effective temperature in PFC attractor models", "No measurement of forget-gate analogues in neural recording data during working memory tasks", "Statistical mechanics phase diagram for PFC working memory remains uncharacterised" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-lstm-gating-biological-analogue.yaml" }, { "id": "u-meg-inverse-source-localization", "title": "What regularization method for MEG inverse source localization best recovers distributed vs focal neural activity simultaneously, and can deep learning architectures trained on realistic head models outperform classical minimum-norm and beamformer approaches for clinical seizure localization?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Ground truth for MEG source localization requires concurrent intracranial EEG or intraoperative recordings, which are available only for epilepsy patients", "Most MEG inverse methods assume stationary sources; non-stationary sources (moving or frequency-modulated) violate the linear model", "Deep learning MEG solvers have been trained on synthetic data with limited generalization testing to diverse pathological source patterns" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-meg-inverse-source-localization.yaml" }, { "id": "u-meg-inverse-source-nonunique-regularization-bounds", "title": "What quantitative bounds link SQUID array layout, sensor noise, and regularization choice to worst-case localization error for distributed cortical sources in realistic head models?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Few public phantoms combine known ground-truth current patterns with whole-head SQUID noise covariances.", "Model mismatch between BEM/FEM conductivity maps and tissue anisotropy is rarely upper-bounded in inversions." ], "suggested_hypotheses": [ "h-squid-array-regularization-improves-meg-source-localization" ], "file": "unknowns-catalog/neuroscience/u-meg-inverse-source-nonunique-regularization-bounds.yaml" }, { "id": "u-mirror-neuron-function", "title": "Do mirror neurons in humans implement action understanding through motor simulation, or is their activation an epiphenomenon of learned sensorimotor associations?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Single-unit recording of human mirror neurons is not feasible outside of presurgical epilepsy monitoring, giving limited data", "No causal test (TMS disruption) of mirror neuron area specifically impairs action understanding without motor disruption confound", "Whether mirror neurons generalize to abstract actions (understanding a concept vs. a physical gesture) is unknown" ], "suggested_hypotheses": [ "Mirror neuron area (IFG/premotor) TMS disruption specifically impairs judgments of goal-directed action similarity but not perceptual similarity, demonstrating causal role in action understanding with a double dissociation" ], "file": "unknowns-catalog/neuroscience/u-mirror-neuron-function.yaml" }, { "id": "u-motor-cortex-population-dynamics-motor-programs", "title": "Are the rotational dynamics in motor cortex (Churchland 2012) a universal feature of all voluntary movements, and does the low-dimensional neural manifold represent an abstract motor program or a specific muscle activation pattern — and how does the manifold change during motor learning?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Rotational dynamics have been demonstrated in reaching but not systematically characterised in locomotion, grasping, or speech articulation.", "The causal necessity of rotational dynamics for movement execution has not been established (optogenetic or microstimulation perturbation of the rotation).", "The manifold geometry changes during motor learning have not been measured with simultaneous recordings across all motor learning stages." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-motor-cortex-population-dynamics-motor-programs.yaml" }, { "id": "u-myelination-conduction-velocity-optimality", "title": "Is the observed g-ratio (myelin thickness / axon diameter ≈ 0.6) of mammalian myelinated axons truly optimal for maximising conduction velocity per unit axon volume, and does the cable-equation prediction match measured g-ratios across species and fibre types?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No comprehensive dataset of g-ratios across species paired with conduction velocity measurements and cable-equation predictions.", "The contribution of periaxonal space resistance and paranodal seals to effective myelin capacitance has not been incorporated in most optimality analyses.", "The evolutionary cost function (energy per bit of information transmitted) has not been rigorously defined and tested against real axon data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-myelination-conduction-velocity-optimality.yaml" }, { "id": "u-neural-binding-mechanism-synchrony", "title": "Is gamma-band synchrony a causal mechanism for neural binding or an epiphenomenon of shared input, and what alternative mechanisms could solve the binding problem?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No causal test has simultaneously induced gamma synchrony and measured perceptual binding in a controlled paradigm", "The read-out problem (how downstream neurons detect synchrony) lacks a clear mechanistic answer", "Binding-by-synchrony is hard to distinguish from binding-by-rate-coding in most experimental paradigms" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-binding-mechanism-synchrony.yaml" }, { "id": "u-neural-criticality-consciousness-substrate", "title": "Is neural criticality (operation near a second-order phase transition) a necessary condition for conscious information integration, or merely an optimisation of computational performance?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No experiment has causally manipulated criticality and measured consciousness directly", "Whether local or global criticality is relevant to consciousness is unresolved", "The relationship between IIT's Φ and critical exponents has not been derived" ], "suggested_hypotheses": [ "Conscious access in bistable perception is gated by near-critical neural amplification; subcritical bias eliminates perception even with identical sensory input" ], "file": "unknowns-catalog/neuroscience/u-neural-criticality-consciousness-substrate.yaml" }, { "id": "u-neural-criticality-tipping-shared-mathematics", "title": "Do neural systems and climate systems share the same universality class of bifurcation, making early-warning indicator methods developed in one field directly transferable to the other with quantitatively predictable performance?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No cross-domain validation study has applied neural criticality EWI methods to climate time series or vice versa under controlled conditions", "The universality class of neural criticality (mean-field DP vs. conserved DP vs. subcritical Hopf) remains contested, preventing definitive mathematical mapping to climate fold bifurcation", "Multivariate EWI methods from neuroscience have not been applied to climate model output or paleoclimate proxy records" ], "suggested_hypotheses": [ "Multivariate EWI methods from neural criticality analysis (principal eigenvector of correlation matrix) applied to CMIP6 model output near simulated AMOC tipping will improve detection lead time by >20% vs. univariate AR1" ], "file": "unknowns-catalog/neuroscience/u-neural-criticality-tipping-shared-mathematics.yaml" }, { "id": "u-neural-decay-poisson-deviation-shared-overdispersion-tests", "title": "Which residual diagnostics best separate true Poisson counting from detector dead-time, nonstationary rate drift, and bursty history dependence across radioactive-decay and neural spike-train datasets?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Shared synthetic corpus spanning dead-time, refractory, bursting, and rate-modulated processes.", "Calibration of time-rescaling and Fano-factor tests under finite observation windows." ], "suggested_hypotheses": [ "h-time-rescaled-residuals-separate-poisson-from-bursty-counting-systems" ], "file": "unknowns-catalog/neuroscience/u-neural-decay-poisson-deviation-shared-overdispersion-tests.yaml" }, { "id": "u-neural-field-theory-empirical-connectome-validation", "title": "Do the eigenmodes of the empirical human connectome structural Laplacian quantitatively predict the spatial and temporal structure of resting-state fMRI networks and EEG frequency bands across individuals?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Individual-level prediction of fMRI networks from diffusion tractography connectomes has not been validated against held-out functional data in large cohorts (n > 1000).", "The number of connectome eigenmodes needed to explain behavioral variability in cognitive tasks is unknown.", "Nonlinear extensions of neural field theory (Hopf bifurcations, amplitude equations) have not been systematically compared to the linear eigenmode model on empirical data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-field-theory-empirical-connectome-validation.yaml" }, { "id": "u-neural-manifold-dimensionality-behavior", "title": "What determines the intrinsic dimensionality of neural population activity manifolds, and does manifold geometry encode behaviorally meaningful variables beyond firing rates?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The relationship between synaptic weight matrix spectral properties and the resulting manifold geometry has not been derived analytically for biologically realistic connectivity.", "Methods for comparing manifold geometry across sessions, animals, and brain areas (e.g., Procrustes alignment, geodesic distances) lack validated statistical frameworks.", "Whether manifold dimensionality increases during learning (more variables encoded) or decreases (compression into a lower-dimensional solution) is debated with contradictory empirical results across task types." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-manifold-dimensionality-behavior.yaml" }, { "id": "u-neural-manifold-topology-cognitive-states", "title": "What is the topology of neural population activity manifolds during higher cognitive tasks (decision-making, working memory, abstract reasoning)?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Systematic persistent homology analysis of prefrontal, parietal, and temporal cortex activity during cognitive tasks is lacking in both rodent and primate models.", "Whether the Betti numbers of neural manifolds scale with cognitive complexity (task difficulty, memory load) has not been tested.", "The topological changes in neural manifolds during learning (formation of new memories, acquisition of new skills) have not been characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-manifold-topology-cognitive-states.yaml" }, { "id": "u-neural-optimal-control-noise-model", "title": "What is the correct noise model for biological motor control — signal-dependent (multiplicative) noise as in Todorov's OFC model, or state-dependent noise from neural population variability — and does the choice change predictions for motor rehabilitation and brain-computer interface design?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Simultaneous multi-electrode recordings at motor cortex, spinal cord, and EMG during precisely quantified motor tasks are available in primates but rarely in humans", "OFC model variants have been tested against movement kinematics but rarely against the full joint angle covariance structure (UCM vs. OFC predictions)", "Bayesian comparison of noise models (signal-dependent vs. Poisson vs. low-rank network) using model evidence has not been done on existing datasets" ], "suggested_hypotheses": [ "h-cerebellum-kalman-prediction-error" ], "file": "unknowns-catalog/neuroscience/u-neural-optimal-control-noise-model.yaml" }, { "id": "u-neural-plasticity-x-hebbian-learning", "title": "Does spike-timing dependent plasticity (STDP) implement exact gradient descent on a well-defined loss function in recurrent neural circuits, and can this be exploited to train spiking neural networks on cognitive tasks without explicit backpropagation?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No proof that three-factor STDP rules implement BPTT in arbitrary recurrent networks", "The biological substrate encoding the reward eligibility trace (time window for dopamine to act) is not identified", "STDP-trained spiking networks have not matched backpropagation-trained networks on complex cognitive benchmarks" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-plasticity-x-hebbian-learning.yaml" }, { "id": "u-neural-spike-coding-x-information-compression", "title": "How does the brain maintain efficient coding of natural scenes across adaptation, attention, and changes in stimulus statistics, and what plasticity rules implement online information maximization?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Information-theoretic measurement of neural coding efficiency requires knowledge of the complete stimulus distribution, which is unknown for complex natural stimuli", "Role of spike timing (temporal codes) vs rate coding in information transmission is debated", "Energy cost of neural computation is not integrated into efficient coding models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neural-spike-coding-x-information-compression.yaml" }, { "id": "u-neuroinflammation-depression-causality", "title": "Does neuroinflammation causally drive major depressive disorder, and can anti-inflammatory treatments reliably treat depression in inflammation-high patients?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Reverse causation (depression causing inflammation through behaviour, stress, obesity) cannot be ruled out in observational studies.", "Anti-inflammatory trials show benefit only in inflammation-high subgroups; biomarker stratification is not standardised.", "The neural circuit mechanisms by which peripheral inflammation alters mood are only partially characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neuroinflammation-depression-causality.yaml" }, { "id": "u-neuronal-avalanche-soc-universality-class", "title": "What is the correct universality class of cortical neuronal avalanches, and does the brain operate at a true critical point or in a near-critical driven regime with sub-sampling artefacts masking the true exponents?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "True critical exponents have not been measured with sufficient neuron counts to avoid sub-sampling bias", "The universality class of cortical networks (directed percolation vs. conserved DP) is unresolved", "Brain-state dependence of sigma has been measured in anesthesia but not across natural behavioral states in primates" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neuronal-avalanche-soc-universality-class.yaml" }, { "id": "u-neuronal-avalanches-branching-process", "title": "Is cortical criticality (branching parameter σ=1) a robustly maintained operating point or an epiphenomenon of anesthesia and slice preparation artifacts, and what homeostatic mechanism sets σ?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "High-density Neuropixels recordings in awake behaving animals show avalanche statistics that deviate from power-law predictions in at least some behavioral states.", "The branching parameter σ is sensitive to bin-width choice and electrode selection, and no consensus protocol exists for robust estimation.", "No causal manipulation of σ (e.g., pharmacologically setting σ to 0.9, 1.0, 1.1) while measuring functional performance has been performed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neuronal-avalanches-branching-process.yaml" }, { "id": "u-neuroplasticity-adult-limits", "title": "What are the molecular and circuit mechanisms that limit neuroplasticity in the adult brain, and how can they be safely reopened?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The molecular triggers for critical period closure vary across brain regions and have not been unified in a single mechanistic model.", "Reopening plasticity in adult animals can improve function in some paradigms but cause regression in others; net effects are unpredictable.", "Human critical period timing for different functions (language, face processing, social cognition) is not precisely mapped." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neuroplasticity-adult-limits.yaml" }, { "id": "u-neurovascular-coupling-x-fluid-dynamics", "title": "What determines the spatial spread of the hemodynamic response in fMRI, and how does vessel architecture limit the resolution of neurovascular coupling?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The spatial extent of conducted vasodilation (arteriolar upstream propagation) as a function of neural activation size and duration has not been measured in vivo with sufficient resolution", "Computational fluid dynamics models of realistic cortical vascular networks have not been validated against two-photon microscopy velocity measurements in awake animals", "Whether the r^4 nonlinearity of Hagen-Poiseuille creates a threshold effect in BOLD sensitivity (below which vessels cannot be detected) has not been quantified" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-neurovascular-coupling-x-fluid-dynamics.yaml" }, { "id": "u-optogenetics-x-control-theory", "title": "What is the fundamental bandwidth limit of closed-loop optogenetic control imposed by channelrhodopsin kinetics, and can model predictive control overcome this limit for oscillatory neural dynamics?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Closed-loop optogenetic bandwidth has not been characterised as a function of opsin kinetics across available channelrhodopsins", "MPC has not been applied to closed-loop optogenetics with fast opsins (ChRmine, CoChR)", "The minimum light dose required for closed-loop gamma oscillation control has not been established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-optogenetics-x-control-theory.yaml" }, { "id": "u-pain-gate-control-molecular-basis", "title": "What is the molecular identity of the 'gate' in Melzack-Wall gate control theory, and does it correspond to a specific interneuron type in the dorsal horn?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Full connectivity of the gate circuit at single-cell resolution has not been mapped", "Whether TENS and SCS activate the same gate interneurons as natural A-beta input is unknown", "How psychological factors (attention, expectation) modulate the gate at the molecular level" ], "suggested_hypotheses": [ "Bhlhb5+ inhibitory interneurons form a bistable switch (gate) whose state is set by the ratio of A-beta to C-fiber input, with a sharp threshold at A-beta:C-fiber = 3:1 input ratio, measurable by electrophysiology in dorsal horn slices" ], "file": "unknowns-catalog/neuroscience/u-pain-gate-control-molecular-basis.yaml" }, { "id": "u-persistent-homology-neural-manifold-geometry-vs-topology-decoupling", "title": "Can persistent homology reliably distinguish the topology of neural population manifolds from their geometry — specifically, can it detect a change in manifold topology (e.g. torus → sphere during learning) independently of changes in manifold curvature, dimensionality, or firing field shape?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The null distribution for persistent homology applied to neural data with realistic noise and non-uniform sampling has not been systematically computed, making statistical significance testing unreliable.", "Methods to correct for non-uniform manifold sampling (variable firing rates, place field overlap) in the topological filtration have not been developed.", "The relationship between persistent homology and diffusion maps / UMAP dimensionality reduction (commonly used in neuroscience) has not been formally characterised — can UMAP topological distortions create false β₁?", "Changes in manifold topology during learning (structural plasticity changing connectivity) vs. remapping (same manifold, different coordinate assignment) have not been distinguished using TDA." ], "suggested_hypotheses": [ "h-hippocampal-place-cell-population-topology-reflects-navigated-space-topology" ], "file": "unknowns-catalog/neuroscience/u-persistent-homology-neural-manifold-geometry-vs-topology-decoupling.yaml" }, { "id": "u-phi-measurement-neural-correlates", "title": "Can integrated information (Phi) be practically measured in neural systems, and do its values correlate with empirical markers of conscious level?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No scalable Phi approximation has been validated against all empirical consciousness markers in a preregistered study.", "The cerebellar challenge to IIT (large cerebellum, abundant neurons, but lesions don't abolish consciousness) remains unresolved.", "Whether Phi measures consciousness or merely functional complexity (which correlates with consciousness as a confound) is methodologically unresolved." ], "suggested_hypotheses": [ "h-integrated-information-entropy-equivalence" ], "file": "unknowns-catalog/neuroscience/u-phi-measurement-neural-correlates.yaml" }, { "id": "u-predictive-coding-laminar-circuit-mechanism", "title": "What specific cortical circuit elements implement prediction error computation in layers 2/3 and prediction propagation in layer 6, and do these circuits show the differential response properties predicted by the free energy principle?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No laminar-specific recording study has demonstrated the predicted anti-correlation between superficial-layer prediction-error responses and deep-layer prediction signals.", "The identity of the neural substrate for precision-weighting (the gain-control signal) is not established; VIP interneurons are a candidate but not confirmed.", "Whether the mismatch negativity (MMN) in EEG/MEG reflects superficial-layer prediction-error neurons or a more distributed response has not been resolved with laminar recordings." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-predictive-coding-laminar-circuit-mechanism.yaml" }, { "id": "u-predictive-coding-neural-implementation-evidence", "title": "What is the direct experimental evidence that cortical circuits implement hierarchical predictive coding, specifically: do superficial-layer pyramidal cells carry prediction errors (bottom-up) and deep-layer pyramidal cells carry predictions (top-down), and can single-cell recordings during violations of sensory predictions validate these layer-specific functional assignments?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Layer-resolved Neuropixels recordings during mismatch negativity paradigm (oddball sequence violations) have not been analysed with sufficient anatomical precision to confirm L2/3 prediction error vs. L5 prediction signal assignment.", "Causal optogenetic experiments silencing layer-specific cell types during prediction learning (conditioning) and prediction violation (extinction) have not been done in the same preparation.", "Whether predictive coding extends to motor cortex (in the active inference sense — motor cortex sends proprioceptive predictions, not commands) has not been directly tested with movement-selective layer-specific recordings." ], "suggested_hypotheses": [ "Layer 2/3 pyramidal cells in primary visual cortex show significantly higher firing rates for stimulus omissions (pure prediction errors) than for expected stimuli, while layer 5/6 cells show the reverse pattern in the same recording sessions; this layer specificity is abolished by NMDA receptor blockade (ketamine) consistent with prediction integration requiring NMDA-mediated apical dendritic computation.\n" ], "file": "unknowns-catalog/neuroscience/u-predictive-coding-neural-implementation-evidence.yaml" }, { "id": "u-prefrontal-working-memory-mechanism", "title": "Is prefrontal cortex working memory maintained by persistent firing (attractor dynamics) or by activity-silent synaptic weight changes — and are these mechanisms complementary or mutually exclusive?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No experiment distinguishes STP-based from firing-based working memory in the same trial", "Whether the two mechanisms store different content (identity vs. location) or are redundant is unknown", "The capacity limits of STP-based working memory have not been derived theoretically" ], "suggested_hypotheses": [ "Working memory items held for <2 s are stored in STP with no sustained firing; items held >2 s require attractor recruitment, predicting a bimodal distribution of delay-period firing rates in PFC with a gap at 2 s delay duration" ], "file": "unknowns-catalog/neuroscience/u-prefrontal-working-memory-mechanism.yaml" }, { "id": "u-prion-like-spread-neurodegeneration-circuit-specificity", "title": "What determines the circuit-specific vulnerability and spreading pattern of prion-like protein aggregates in neurodegeneration — connectivity, local protein expression, or regional metabolic activity?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No study has simultaneously mapped connectome, SNCA/MAPT expression, metabolic activity, and Lewy body burden in the same brains at cellular resolution.", "The route of cell-to-cell alpha-synuclein transfer (exosome, tunneling nanotube, lysosomal exocytosis) has not been uniquely determined in vivo.", "Whether impeding axonal transport (e.g., by disrupting dynein) slows or accelerates Braak-staging progression has not been tested in a primate model." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-prion-like-spread-neurodegeneration-circuit-specificity.yaml" }, { "id": "u-ptlds-neuroinflammation-self-sustaining", "title": "Is PTLDS cognitive impairment caused by a self-sustaining reactive astrogliosis and microglial activation loop that persists after Borrelia clearance, and if so, would anti-neuroinflammatory therapy be more effective than repeat antibiotics?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No longitudinal CSF biomarker study (CXCL13, IL-6, GFAP, neurofilament light chain) has been conducted in PTLDS patients to determine whether neuroinflammatory markers persist after documented antibiotic clearance", "No microglial activation PET imaging (TSPO ligands) has been performed in PTLDS patients to assess in vivo neuroinflammation burden", "No animal model study has directly tested whether anti-IL-6 or anti-TNF-α therapy improves cognitive outcomes after Borrelia clearance", "No clinical trial of any anti-neuroinflammatory agent (tocilizumab, adalimumab, low-dose naltrexone) has been conducted in PTLDS patients", "The boundary between Borrelia-driven neuroinflammation and post-infectious self-sustaining neuroinflammation has not been established (i.e., at what time point after antibiotic treatment does inflammation become self-sustaining?)" ], "suggested_hypotheses": [ "h-ptlds-neuroinflammation-il6-blockade" ], "file": "unknowns-catalog/neuroscience/u-ptlds-neuroinflammation-self-sustaining.yaml" }, { "id": "u-reconsolidation-synaptic-locus-ampa-receptor", "title": "At which specific synapses does AMPA receptor endocytosis occur during memory labilisation after retrieval, and is reconsolidation synapse-specific or distributed across the encoding ensemble?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "AMPAR surface expression during reconsolidation has not been measured with synapse-specific resolution in vivo.", "Whether the reconsolidation labilisation window correlates with AMPAR endocytosis kinetics has not been directly tested.", "The degree to which reconsolidation affects only the retrieved engram vs. overlapping memories is not characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-reconsolidation-synaptic-locus-ampa-receptor.yaml" }, { "id": "u-retinal-wave-spatial-statistics-map-precision", "title": "What determines the spatial statistics (correlation length, wave-initiation density) of retinal waves, and is there an information-theoretic optimum that matches the precision of mature retinotopic maps?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The spatial autocorrelation function of Stage II retinal waves has not been measured with sufficient temporal resolution to compute mutual information between wave pattern and retinal position.", "The relationship between wave correlation length and final retinotopic map precision across manipulated animals (ACh dose, temperature) has not been quantified.", "The information-theoretic efficiency of wave-based topographic coding has not been calculated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-retinal-wave-spatial-statistics-map-precision.yaml" }, { "id": "u-rl-novelty-bonus-information-gain-mapping", "title": "Which experimentally measurable neural quantities align with count-based novelty bonuses versus Bayesian information-gain objectives across tasks — without confounding reward prediction error and uncertainty reduction?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Longitudinal recordings during controlled novelty schedules with matched behavioral assays across species where dopamine imaging is feasible.", "Human/non-human datasets comparing intrinsic-motivation model fits when reward schedules switch abruptly." ], "suggested_hypotheses": [ "h-count-novelty-scales-bayesian-information-gain-proxy" ], "file": "unknowns-catalog/neuroscience/u-rl-novelty-bonus-information-gain-mapping.yaml" }, { "id": "u-signal-sparsity-neural-coding", "title": "Are neural population codes sparse in some transform basis (Fourier, wavelet, learned dictionary), and does sparsity optimize energy consumption vs. information capacity?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The basis in which neural population codes are sparse is not known for most brain regions beyond primary sensory cortex.", "The energy-accuracy tradeoff of sparse vs. dense coding has not been measured directly in behaving animals with metabolic imaging." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-signal-sparsity-neural-coding.yaml" }, { "id": "u-sleep-memory-consolidation-mechanism", "title": "Does sleep memory consolidation occur through hippocampal-cortical replay during sharp-wave ripples, and is this a necessary condition or a correlate of consolidation?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Causal necessity of SWR replay for human declarative memory consolidation not established", "Direction of information flow (hippocampus→cortex vs cortex→hippocampus) during replay is contested", "Mechanism by which replay changes synaptic weights (LTP? homeostatic scaling?) is not known" ], "suggested_hypotheses": [ "Targeted suppression of sharp-wave ripples specifically during the first 90 minutes of NREM sleep following learning will impair next-day declarative memory by >30%, while suppression during REM will not — tested in humans with real-time SWR detection EEG" ], "file": "unknowns-catalog/neuroscience/u-sleep-memory-consolidation-mechanism.yaml" }, { "id": "u-sleep-replay-causal-role-memory-specificity", "title": "Does hippocampal sharp-wave ripple replay during sleep causally strengthen specific memory traces, and can targeted memory reactivation selectively enhance or suppress individual memories?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No causal test of whether replay sequence content (not just SPW-R occurrence rate) determines memory specificity — requires closed-loop detection and disruption of content-specific replay events.", "The mechanistic link between hippocampal SPW-Rs and neocortical sleep spindles (the proposed transfer mechanism) has not been causally demonstrated in humans.", "Whether glymphatic clearance during sleep is functionally independent of or causally linked to memory replay processes is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-sleep-replay-causal-role-memory-specificity.yaml" }, { "id": "u-snare-complex-partial-zippering-spontaneous-release-rate", "title": "What fraction of synaptic vesicles undergo partial SNARE complex zippering (the \"primed\" state) at rest, and how does the thermodynamic energy landscape of SNARE zippering determine the spontaneous miniature release rate (mEPSP frequency)?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The number and energetics of intermediate states in SNARE complex zippering have been characterised by single-molecule force spectroscopy (optical tweezers) in vitro but the in-vivo energy landscape at a real synapse is inaccessible.", "Whether spontaneous and evoked release draw from the same vesicle pool (unified model) or distinct pools (parallel model) has been contested with conflicting experimental evidence; the stochastic thermodynamics model to discriminate them has not been rigorously derived.", "The calcium-independent spontaneous release mechanism — whether it involves rare thermal fluctuations over the fusion barrier or mechanically-triggered release by membrane curvature fluctuations — has not been established." ], "suggested_hypotheses": [ "Spontaneous mEPSP frequency is quantitatively predicted by the Boltzmann probability of thermal fluctuations over the SNARE fusion barrier ΔG_barrier, such that log(rate) = -ΔG_barrier/k_BT + const, with ΔG_barrier measurable from single-molecule tweezer experiments." ], "file": "unknowns-catalog/neuroscience/u-snare-complex-partial-zippering-spontaneous-release-rate.yaml" }, { "id": "u-snare-force-threshold-in-vivo", "title": "What is the minimum SNARE zippering force required to trigger synaptic vesicle fusion in intact synaptic terminals, and how does this threshold vary across synapse types?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-snare-force-threshold-in-vivo.yaml" }, { "id": "u-softmax-attention-cortical-normalization-mapping", "title": "Which quantitative experiments separate softmax-like normalization from cortical divisive normalization in behaving animals when stimuli mirror transformer benchmark suites?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Few datasets jointly recording population calcium imaging during controlled pseudo-natural datasets analogous to token contexts", "Attention temperatures lack direct biophysical correlates across cortical layers" ], "suggested_hypotheses": [ "h-softmax-attention-x-cortical-divisive-normalization" ], "file": "unknowns-catalog/neuroscience/u-softmax-attention-cortical-normalization-mapping.yaml" }, { "id": "u-sparse-coding-x-neural-basis", "title": "Does sparse coding in visual cortex V1 use biologically plausible ISTA dynamics (lateral inhibition networks) as the inference algorithm, and does this predict the specific timing and magnitude of surround suppression observed in primate V1 electrophysiology?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "ISTA predicts specific temporal dynamics of lateral inhibition that have not been quantitatively compared to V1 spike trains during natural scene viewing", "The overcomplete ratio (number of V1 neurons per pixel) in primate V1 is not precisely known; estimates range from 5× to 50×", "Sparse coding cannot explain color, temporal, and binocular disparity tuning jointly without ad hoc dictionary constraints" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-sparse-coding-x-neural-basis.yaml" }, { "id": "u-spinal-gate-control-interneuron-identity", "title": "What is the molecular identity of the gate control interneuron in the spinal dorsal horn, and which genetically defined interneuron subtypes implement A-beta-mediated inhibition of nociceptive transmission?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Optogenetic silencing of candidate interneuron subtypes during mechanical allodynia has not been systematically performed", "Quantitative circuit model of gate control with identified cell types has not been validated", "Central sensitisation changes in gate circuit interneurons are poorly characterised at molecular level" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-spinal-gate-control-interneuron-identity.yaml" }, { "id": "u-stdp-natural-stimuli-in-vivo-plasticity-rules", "title": "What are the actual synaptic plasticity rules operating in vivo during natural stimulus-driven activity, and do STDP windows measured with artificial spike-pair protocols in vitro accurately predict plasticity under natural firing patterns with realistic spike train statistics?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Chronic in vivo recording during natural stimulation with simultaneous optogenetic monitoring of synaptic weight changes.", "BCM sliding threshold measurement in vivo — direct measurement of theta_M dynamics during sensory experience.", "Dendritic STDP rules (compartment-specific plasticity) in intact neurons in vivo.", "Neuromodulator-dependent gating of STDP in identified cortical circuits." ], "suggested_hypotheses": [ "STDP rules measured with artificial paired-pulse protocols in vitro will fail to predict the sign of plasticity (LTP vs. LTD) in >30% of cases when tested with in vivo natural firing patterns, because triplet/quadruplet interactions and neuromodulatory state substantially reshape the effective learning rule beyond what pair-STDP captures.\n" ], "file": "unknowns-catalog/neuroscience/u-stdp-natural-stimuli-in-vivo-plasticity-rules.yaml" }, { "id": "u-stdp-synaptic-weight-saturation", "title": "How do biological neural networks prevent runaway potentiation under STDP, and what mechanisms enforce weight normalization to maintain stable learned representations?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "In vivo weight distributions during learning have not been measured at single-synapse resolution in behaving animals", "The relative contribution of homeostatic versus Hebbian plasticity to weight stabilization is unknown", "Whether multiplicative or additive STDP better describes biological data is contested" ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-stdp-synaptic-weight-saturation.yaml" }, { "id": "u-stochastic-resonance-neural-coding-optimality", "title": "Is the spontaneous firing rate of primary sensory neurons (hair cells, mechanoreceptors) optimally tuned to maximize stochastic resonance detection of their characteristic stimulus frequencies?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No systematic test of SR optimality across sensory modalities (auditory, tactile, vestibular)", "Spontaneous rates and signal thresholds not jointly measured in the same neuron preparations", "Evolutionary conservation of SR tuning not assessed across species" ], "suggested_hypotheses": [ "h-stochastic-resonance-neural-coding-optimality" ], "file": "unknowns-catalog/neuroscience/u-stochastic-resonance-neural-coding-optimality.yaml" }, { "id": "u-synapse-heterogeneity-function", "title": "What is the functional significance of the enormous molecular heterogeneity of synapses, and does synapse-type diversity encode information?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "High-throughput synaptic proteomics can measure molecular composition but cannot map this to physiological strength in living tissue.", "The information storage capacity of synapse heterogeneity versus synaptic strength alone has not been estimated from experimental data.", "Whether synapse molecular heterogeneity is actively regulated (a code) or a consequence of stochastic protein assembly is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-synapse-heterogeneity-function.yaml" }, { "id": "u-td-learning-dopamine-biological-implementation", "title": "How does the brain implement the temporal difference prediction error at the circuit level — specifically, how do dopamine neurons compute V(s_{t+1}) − V(s_t) given that they receive no direct projection from a single brain region encoding V(s)?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The circuit projection that carries V(s_{t+1}) to VTA dopamine neurons has not been identified; all afferents to VTA (striatum, prefrontal cortex, brainstem) carry value-related signals but none has been shown to specifically encode the temporal credit assignment signal needed for TD computation.", "The time window over which DA neurons integrate value predictions to compute δ — the \"eligibility trace\" of TD learning — has not been measured at single-neuron resolution; τ is estimated at 1-3 seconds from behavioral data but not validated electrophysiologically.", "Distributional coding of the return distribution across DA neuron subtypes has been replicated in mice (Tsutsui-Kimura et al. 2020) but the synaptic mechanism distinguishing optimistic from pessimistic DA neurons (different inputs? different D1/D2 receptor ratios in target MSNs?) is unknown." ], "suggested_hypotheses": [ "VTA dopamine neurons compute the TD prediction error via a disinhibition circuit — tonically active GABAergic interneurons in the striatum (ChAT interneurons) carry a running V(s) signal that suppresses DA firing; reward-triggered suppression of this inhibition causes the δ > 0 burst, implementing δ = r + γV(s') - V(s) via circuit-level arithmetic.\n" ], "file": "unknowns-catalog/neuroscience/u-td-learning-dopamine-biological-implementation.yaml" }, { "id": "u-tda-brain-disease-biomarkers", "title": "Can topological data analysis of brain connectivity or EEG/fMRI time series provide disease-specific biomarkers distinguishing psychiatric conditions?", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "No large-scale (N > 500) preregistered study of TDA brain biomarkers for any psychiatric condition has been published.", "The choice of filtration (correlation threshold, distance metric) substantially affects TDA results but has not been standardized across studies." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-tda-brain-disease-biomarkers.yaml" }, { "id": "u-vmpfc-reference-dependent-coding-mechanism", "title": "What is the computational mechanism by which vmPFC encodes reference-dependent subjective value, how does the reference point update during multi-item choice, and does this mechanism explain the neural basis of the framing effect and loss aversion?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "Pre-registered experiment distinguishing divisive vs. range normalization in vmPFC using designed stimulus sets", "Neural correlate of the loss aversion coefficient λ and its modulation by pharmacological intervention", "How the reference point is set before choice (expectation formation) vs. updated during choice (on-line integration)", "Whether vmPFC reference-dependent coding differs between gains domain and losses domain at the single-neuron level" ], "suggested_hypotheses": [ "h-beta-delta-neuroeconomics-dual-system" ], "file": "unknowns-catalog/neuroscience/u-vmpfc-reference-dependent-coding-mechanism.yaml" }, { "id": "u-weber-fechner-stevens-unifying-neural-mechanism", "title": "Is there a single neural mechanism that unifies Weber's law, Fechner's logarithmic compression, and Stevens' power law — or do different sensory systems use fundamentally different computational strategies to achieve similar psychophysical scaling?\n", "status": "open", "domain": "neuroscience", "systematic_gaps": [ "The psychophysical law (log vs. power) has not been definitively resolved because both can fit most experimental data within measurement noise.", "The neural correlate of the Stevens power law exponent (why n = 0.33 for brightness but n = 3.5 for electric shock) has not been identified in single-unit recordings.", "The contribution of central (cortical) vs. peripheral (receptor) mechanisms to final perceptual magnitude estimates has not been disentangled for most modalities." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience/u-weber-fechner-stevens-unifying-neural-mechanism.yaml" }, { "id": "u-computational-psychiatry-treatment-response-prediction", "title": "Can computational phenotypes (learning rates, prior precision parameters) derived from brief computerised behavioural tasks predict individual antidepressant or antipsychotic treatment response before drug administration, enabling precision psychiatry prescribing?\n", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "No RCT using computational phenotype to guide antidepressant selection has been completed.", "Test-retest reliability of learning rate parameters across weeks/months (the relevant clinical timescale) is not established.", "The neurobiological mechanism linking α⁺ to synaptic plasticity (AMPA, NMDA, BDNF signalling) has not been causally demonstrated in humans." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience-engineering/u-computational-psychiatry-treatment-response-prediction.yaml" }, { "id": "u-forward-model-cerebellum-learning-rule", "title": "What learning rule does the cerebellum use to update its forward model predictions, and can the supervised climbing fiber error signal account for the full range of motor adaptation timescales from milliseconds to months?\n", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "The exact teaching signal for fast (sub-100ms) motor adaptation is unknown.", "Whether cerebellar forward models update via Hebbian, error-based, or predictive coding rules is debated.", "The transition from internal model learning to use by the motor cortex is not understood at the circuit level." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience-engineering/u-forward-model-cerebellum-learning-rule.yaml" }, { "id": "u-kalman-filter-neural-implementation-limits", "title": "Under what conditions do cortical circuits implement variance-weighted prediction–correction equivalent to a Kalman gain, and when do they require nonlinear filtering?", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "Joint estimation of forward-model drift and sensory reliability is rarely done with identifiability checks.", "Nonlinear dynamics in spiking networks may mimic Kalman-like updates only in local regimes." ], "suggested_hypotheses": [ "h-sensory-cortex-implements-approximate-kalman-updates" ], "file": "unknowns-catalog/neuroscience-engineering/u-kalman-filter-neural-implementation-limits.yaml" }, { "id": "u-lif-parameter-identifiability-noisy-synapses", "title": "Under correlated synaptic input and active dendrites, when do membrane τ estimates from somatic recordings remain identifiable with simple RC reductions?", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "Joint electrophysiology datasets fitting multicompartment models versus RC fits under identical stimulation ensembles", "Quantitative guardrails exporting τ priors from silicon neurons back to biological neuron modeling workflows" ], "suggested_hypotheses": [ "h-leaky-if-neuron-x-rc-membrane-circuit" ], "file": "unknowns-catalog/neuroscience-engineering/u-lif-parameter-identifiability-noisy-synapses.yaml" }, { "id": "u-neural-spike-coding-rate-vs-temporal", "title": "Whether the brain primarily uses rate coding, temporal coding, or a multiplexed combination for information representation, and what the relative information capacity of each scheme is in identified neural circuits\n", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "Rate coding (Barlow 1961) and temporal coding (Hopfield 1995) make different experimental predictions but both are consistent with most single-unit recording data due to insufficient recording precision.", "The \"precision\" of spike timing relevant for information transmission differs across brain regions; 1 ms precision in cerebellar circuits may be irrelevant in prefrontal cortex operating at theta (4–8 Hz) rhythms.", "Information-theoretic analyses of neural data (direct method, model-based) give different estimates of coding capacity depending on methodological choices; consensus values are lacking.", "Neuromorphic hardware implements mainly rate coding (spikes per time window); temporal coding requires sub-millisecond timestamp precision that is hardware-costly and may not be necessary." ], "suggested_hypotheses": [ "h-neuromorphic-chips-edge-ai-energy-advantage" ], "file": "unknowns-catalog/neuroscience-engineering/u-neural-spike-coding-rate-vs-temporal.yaml" }, { "id": "u-neuromuscular-control-redundancy-resolution", "title": "How does the central nervous system resolve the redundancy problem in muscle coordination — the fact that any joint torque can be produced by infinitely many combinations of muscle activation levels — and does the nervous system optimise a single cost function or use task-dependent switching?\n", "status": "open", "domain": "neuroscience-engineering", "systematic_gaps": [ "No ground truth measurement of all muscle forces simultaneously during natural movement exists (ultrasound and EMG give indirect estimates only).", "The cost function the nervous system actually optimises during muscle coordination has not been uniquely identified across a range of tasks.", "The neural circuits implementing redundancy resolution (cerebellar internal model, corticospinal tract, spinal interneurons) are not identified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience-engineering/u-neuromuscular-control-redundancy-resolution.yaml" }, { "id": "u-microglia-synapse-pruning-alzheimers-pathological-threshold", "title": "What determines the threshold between physiological microglial synapse pruning (circuit refinement) and pathological pruning (synaptic loss in Alzheimer's disease) ΓÇö and can this threshold be pharmacologically modulated to preserve synapses while maintaining immune surveillance?\n", "status": "open", "domain": "neuroscience-glia", "systematic_gaps": [ "The concentration threshold of soluble A╬▓ oligomers required to trigger C1q deposition at synapses has not been determined in vivo.", "Whether microglial synapse pruning in AD brain preferentially removes specific synapse types (excitatory vs. inhibitory, dendritic spine vs. shaft) is not characterized at scale.", "The long-term consequences of C1q inhibition (preventing developmental pruning in adult CNS repair contexts) are not characterized in non-human primates." ], "suggested_hypotheses": [], "file": "unknowns-catalog/neuroscience-glia/u-microglia-synapse-pruning-alzheimers-pathological-threshold.yaml" }, { "id": "u-nuclear-waste-transmutation-accelerator-driven-systems", "title": "Can accelerator-driven subcritical systems (ADS) economically transmute long-lived actinides (┬▓Γü┤Γü░Pu, Am, Cm) and reduce nuclear waste hazard timescale from 240,000 to ~300 years ΓÇö what are the engineering barriers to demonstrating a prototype ADS that operates reliably at MW-scale?\n", "status": "open", "domain": "nuclear-engineering", "systematic_gaps": [ "Reliable high-intensity proton linac operation (>99.5% availability) has not been demonstrated at the MW-scale power levels needed for ADS.", "Lead-bismuth eutectic target corrosion of stainless steel at high irradiation and temperature has not been tested at representative flux levels for extended periods (>5 years).", "Full fuel cycle integration (ADS + actinide reprocessing + fuel fabrication) has not been demonstrated at any scale beyond laboratory experiments." ], "suggested_hypotheses": [], "file": "unknowns-catalog/nuclear-engineering/u-nuclear-waste-transmutation-accelerator-driven-systems.yaml" }, { "id": "u-stellar-nucleosynthesis-r-process-site", "title": "What astrophysical site or sites dominate r-process nucleosynthesis — neutron star mergers (kilonovae), collapsars, or rare core-collapse supernovae — and can the relative contributions be disentangled by matching observed [Eu/Fe] abundance trends in metal-poor stars with delay-time distributions and galactic chemical evolution models?", "status": "open", "domain": "nuclear-physics", "systematic_gaps": [ "Nuclear masses and beta-decay rates of very neutron-rich isotopes on the r-process path are unmeasured; FRIB data is beginning to fill this gap", "r-process yield predictions are highly sensitive to the neutron star merger rate and delay-time distribution, both observationally uncertain", "Collapsars as r-process sites require magnetorotational jet models that are computationally expensive and numerically uncertain" ], "suggested_hypotheses": [], "file": "unknowns-catalog/nuclear-physics/u-stellar-nucleosynthesis-r-process-site.yaml" }, { "id": "u-a-stability-region-operator-splitting-reaction-diffusion", "title": "What timestep and splitting policies best preserve both stability and mechanistic fidelity in stiff reaction-diffusion models?", "status": "open", "domain": "numerical-analysis", "systematic_gaps": [ "Cross-solver benchmarks reporting both stability failures and mechanistic bias are sparse.", "Operator-splitting error interactions with adaptive timestepping are undercharacterized.", "Reproducible diagnostics for spectrum-aware timestep selection are not standard in domain toolchains." ], "suggested_hypotheses": [], "file": "unknowns-catalog/numerical-analysis/u-a-stability-region-operator-splitting-reaction-diffusion.yaml" }, { "id": "u-internal-tide-mixing-efficiency-spatial", "title": "What fraction of internal tide energy is locally dissipated near generation sites versus radiated to the open ocean, and how does this spatial distribution control abyssal stratification?", "status": "open", "domain": "oceanography", "systematic_gaps": [ "Direct turbulence measurements near internal tide generation sites are sparse; most estimates rely on parameterizations", "The fate of low-mode internal tides between generation and far-field dissipation sites is unmapped", "Climate models use spatially uniform tidal mixing parameterizations inconsistent with observed heterogeneity" ], "suggested_hypotheses": [], "file": "unknowns-catalog/oceanography/u-internal-tide-mixing-efficiency-spatial.yaml" }, { "id": "u-neural-spectral-ocean-forecast-stability-horizon", "title": "What stability horizon can neural spectral ocean surrogates maintain for submesoscale forecasts?", "status": "open", "domain": "oceanography", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-neural-spectral-ocean-model-improves-submesoscale-forecast-skill" ], "file": "unknowns-catalog/oceanography/u-neural-spectral-ocean-forecast-stability-horizon.yaml" }, { "id": "u-ocean-acidification-carbonate-threshold", "title": "What are the critical carbonate chemistry thresholds (aragonite saturation state Ω_arag, pH, CO3^2- concentration) below which calcification failure occurs in reef-building corals and pteropods, and how do bleaching, disease, and local pollution interact with ocean acidification to modify these thresholds?", "status": "open", "domain": "oceanography", "systematic_gaps": [ "Long-term continuous pH and alkalinity monitoring at coral reefs is sparse and methodologically inconsistent", "Laboratory acidification experiments use unrealistically rapid pH changes that may overestimate calcification sensitivity compared to gradual natural change", "Species-level calcification thresholds have been measured for fewer than 50 of the ~800 reef-building coral species" ], "suggested_hypotheses": [], "file": "unknowns-catalog/oceanography/u-ocean-acidification-carbonate-threshold.yaml" }, { "id": "u-ocean-color-phytoplankton-remote-sensing", "title": "Can satellite ocean-color retrievals distinguish phytoplankton functional types (diatoms, cyanobacteria, coccolithophores) at sufficient accuracy to close the global marine carbon budget, and what improvements to radiative transfer inversion algorithms are needed to separate CDOM, detritus, and phytoplankton absorption contributions?", "status": "open", "domain": "oceanography", "systematic_gaps": [ "In-situ hyperspectral absorption measurements with co-registered phytoplankton taxonomy are sparse outside research cruises", "Atmospheric correction residuals in coastal turbid waters dominate ocean-color retrieval error", "Phytoplankton-specific absorption spectra show large inter- and intra-species variability not captured by fixed PFT endmembers" ], "suggested_hypotheses": [], "file": "unknowns-catalog/oceanography/u-ocean-color-phytoplankton-remote-sensing.yaml" }, { "id": "u-redfield-ratio-variability-drivers", "title": "What biological and chemical mechanisms drive systematic deviations from the Redfield C:N:P ratio across ocean basins, seasons, and phytoplankton functional groups?", "status": "open", "domain": "oceanography", "systematic_gaps": [ "Single-cell stoichiometry measurements at ocean-basin scale are unavailable", "Separating plasticity from adaptation in field populations requires controlled experiments not feasible at sea", "Earth system models use fixed Redfield ratios, introducing systematic bias in nutrient cycle projections" ], "suggested_hypotheses": [], "file": "unknowns-catalog/oceanography/u-redfield-ratio-variability-drivers.yaml" }, { "id": "u-estimating-jump-moments-for-tumor-phenotypic-plasticity-models", "title": "What failure boundaries determine when `b-kramers-moyal-expansion-x-tumor-phenotype-transition-modeling` remains decision-useful?", "status": "open", "domain": "oncology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-kramers-moyal-surrogates-improve-tumor-state-transition-forecast-calibration" ], "file": "unknowns-catalog/oncology/u-estimating-jump-moments-for-tumor-phenotypic-plasticity-models.yaml" }, { "id": "u-therapy-driven-transition-rate-estimation-in-cell-state-markov-models", "title": "What failure boundaries determine when `b-markov-jump-processes-x-cell-state-switching-therapy-design` remains decision-useful?", "status": "open", "domain": "oncology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-markov-jump-therapy-policies-reduce-relapse-prone-cell-state-occupancy" ], "file": "unknowns-catalog/oncology/u-therapy-driven-transition-rate-estimation-in-cell-state-markov-models.yaml" }, { "id": "u-heavy-traffic-thresholds-for-ed-crowding-intervention-policies", "title": "What validation boundary conditions determine when `b-heavy-traffic-queueing-x-emergency-department-flow` remains decision-useful?", "status": "open", "domain": "operations-research", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-diffusion-queueing-threshold-policies-reduce-ed-boarding-time-variance" ], "file": "unknowns-catalog/operations-research/u-heavy-traffic-thresholds-for-ed-crowding-intervention-policies.yaml" }, { "id": "u-ribosome-kinetics-queuing", "title": "What are the rate-limiting bottleneck codons in human mRNA translation, and does codon-traffic-jam theory correctly predict protein yield and ribosome density profiles from ribosome profiling data?", "status": "open", "domain": "operations-research", "systematic_gaps": [ "Direct measurement of codon-specific elongation rates by ribosome profiling is confounded by nuclease bias, requiring new experimental approaches.", "TASEP model parameters (initiation rate α, termination rate γ) are not independently measured for most transcripts.", "Whether codon-optimization-induced protein yield increases are additive across multiple slow codons (as TASEP theory predicts) has not been tested systematically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/operations-research/u-ribosome-kinetics-queuing.yaml" }, { "id": "u-supply-chain-network-topology-resilience", "title": "What supply chain network topologies maximize resilience to both random failures and targeted disruptions simultaneously, and how can firms redesign their supplier networks to achieve this?", "status": "open", "domain": "operations-research", "systematic_gaps": [ "Empirical supply chain network data is proprietary; most studies use aggregated trade data not firm-level networks", "Recovery dynamics after disruption (time to find alternative suppliers) are poorly modeled", "Multi-tier supply chains (Tier 1, 2, 3 suppliers) have not been mapped for most industries" ], "suggested_hypotheses": [], "file": "unknowns-catalog/operations-research/u-supply-chain-network-topology-resilience.yaml" }, { "id": "u-optogenetics-human-therapeutic-scale-delivery", "title": "What are the barriers to scaling optogenetic therapies from proof-of-concept (retinitis pigmentosa) to broader neurological conditions (Parkinson's, epilepsy, depression) ΓÇö specifically the challenges of viral vector delivery, light penetration through tissue, and long-term immune tolerance?\n", "status": "open", "domain": "optogenetics", "systematic_gaps": [ "Long-term (years) immune response to opsin expression in human neurons has not been studied; primate data suggests some tolerance but human immune systems differ.", "Light delivery devices for deep brain stimulation (DBS replacement with optogenetics) that meet the size/power/biocompatibility requirements of chronic implants have not been demonstrated.", "Promoter specificity in human brain tissue differs from rodents; cell-type specific targeting reliability in humans is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/optogenetics/u-optogenetics-human-therapeutic-scale-delivery.yaml" }, { "id": "u-antibiotic-synergy-surfaces", "title": "Can pharmacodynamic interaction surfaces for antibiotic combinations be predicted from drug-target network topology before experimental measurement, and which network features are the best predictors of synergy?", "status": "open", "domain": "pharmacology", "systematic_gaps": [ "No genome-scale map of antibiotic pairwise synergy exists for a single bacterial species — most data are fragmentary (<100 pairs in any organism).", "The mapping from drug-target network topology metrics (synthetic lethality score, pathway distance) to synergy magnitude has not been calibrated quantitatively.", "Time-kill kinetics of combination antibiotics are rarely measured, leaving the temporal dynamics of synergy (early vs late killing) uncharacterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/pharmacology/u-antibiotic-synergy-surfaces.yaml" }, { "id": "u-cyp450-xenobiotic-metabolic-prediction", "title": "Can in silico machine learning models trained on CYP450 crystal structures and metabolomics databases quantitatively predict drug metabolic stability, metabolite identity, and drug-drug interaction K_i values for novel chemical entities before first-in-human studies?", "status": "open", "domain": "pharmacology", "systematic_gaps": [ "CYP450 crystal structures are solved with inhibitor-bound conformations; the induced-fit dynamics for novel substrates are difficult to model", "Training data for CYP prediction models is biased toward drug-like compounds; natural products and unusual scaffolds are underrepresented", "Metabolic reactions involving two CYP enzymes sequentially (sequential metabolism) are not captured by single-enzyme prediction models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/pharmacology/u-cyp450-xenobiotic-metabolic-prediction.yaml" }, { "id": "u-fitness-landscape-drug-resistance-prediction", "title": "Can deep mutational scanning fitness landscapes measured in vitro predict the order, timing, and combination of resistance mutations that evolve clinically in patients treated with antibiotics or antivirals?", "status": "open", "domain": "pharmacology", "systematic_gaps": [ "Complete DMS landscapes are available for only ~20 drug targets; most resistance surveillance relies on clinical observation", "In vitro vs. in vivo fitness discordance is well-known but not systematically quantified for most pathogens", "Multi-drug fitness landscapes (epistasis between resistance mutations for different drugs) are rarely measured" ], "suggested_hypotheses": [], "file": "unknowns-catalog/pharmacology/u-fitness-landscape-drug-resistance-prediction.yaml" }, { "id": "u-neural-ode-pk-identifiability-under-sparse-sampling", "title": "What identifiability limits arise when neural ODE PK surrogates are fit to sparse therapeutic-drug monitoring data?", "status": "open", "domain": "pharmacology", "systematic_gaps": [ "No shared benchmark combining sparse dosing records with gold-standard compartment parameters.", "Unclear tradeoff between forecast accuracy and mechanistic interpretability under patient heterogeneity.", "Limited calibration audits of uncertainty intervals used for dose adjustment decisions." ], "suggested_hypotheses": [ "h-neural-ode-priors-improve-pk-state-forecasting" ], "file": "unknowns-catalog/pharmacology/u-neural-ode-pk-identifiability-under-sparse-sampling.yaml" }, { "id": "u-pharmacokinetic-interindividual-variability", "title": "What fraction of interindividual variability in drug pharmacokinetics is attributable to CYP genetic polymorphisms versus non-genetic sources (age, disease, drug interactions, microbiome), and can multi-omics integration predict individual PK parameters more accurately than population PK models?", "status": "open", "domain": "pharmacology", "systematic_gaps": [ "Large-scale PK variability studies typically measure few pharmacogenomic markers; genome-wide rare variant contributions are uncharacterized", "Microbiome composition changes with disease, antibiotic treatment, and diet — making microbiome PK contributions dynamic and hard to model", "Most PBPK models were built for healthy adults; pediatric and geriatric PBPK models lack validation data" ], "suggested_hypotheses": [], "file": "unknowns-catalog/pharmacology/u-pharmacokinetic-interindividual-variability.yaml" }, { "id": "u-bayesian-convergence-prior-dependence", "title": "How strongly do Bayesian posterior convergence rates depend on the choice of prior in finite-sample scientific inference, and when does prior sensitivity violate the practical dissolution of Hume's problem of induction?\n", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Formal analysis of convergence rates for realistic scientific model classes (time series, regression, structural equation models) is largely confined to the theoretical statistics literature, inaccessible to practising scientists", "Empirical studies of prior sensitivity in published Bayesian meta-analyses (psychology, medicine) show large sensitivity in 30-50% of cases, but systematic documentation is lacking", "The connection between Doob consistency and Solomonoff induction (both resolve Hume) is rarely made explicit in either statistics or philosophy" ], "suggested_hypotheses": [ "h-doob-convergence-rate-scientific-inference" ], "file": "unknowns-catalog/philosophy-of-science/u-bayesian-convergence-prior-dependence.yaml" }, { "id": "u-bayesian-old-evidence-problem", "title": "How can the Bayesian account of confirmation handle the old evidence problem — where evidence known prior to hypothesis formulation (like Mercury's perihelion for GR) cannot update posteriors — without abandoning either Bayesianism or the historical practice of science?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No formal Bayesian framework provides a complete solution to the old evidence problem that (a) is consistent with standard probability theory, (b) correctly handles the Mercury-GR case, and (c) does not require subjective counterfactual probability assignments.", "The relationship between the old evidence problem and p-hacking / post-hoc hypothesis formation in science has not been formally analyzed — scientists often design hypotheses to fit known data, making all their evidence \"old\" in Glymour's sense.", "Whether incremental confirmation measures (Bayes factor, likelihood ratio) provide a scientifically adequate replacement for the posterior update is contested philosophically and has not been empirically validated against scientific practice." ], "suggested_hypotheses": [ "The old evidence problem is resolved by adopting a two-stage framework — confirmation of H by E requires both (1) likelihood ratio P(E|H)/P(E|¬H) > 1 (computable even with P(E)=1) and (2) independent novel prediction confirmed by H — the conjunction of backward-looking and forward-looking confirmation.\n" ], "file": "unknowns-catalog/philosophy-of-science/u-bayesian-old-evidence-problem.yaml" }, { "id": "u-bayesian-prior-objectivity", "title": "Is there an objective, uniquely determined prior probability distribution for scientific hypotheses, or is Bayesian confirmation theory irreducibly subjective — and if the latter, does this undermine its normative status as the logic of science?\n", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No agreed procedure for assigning priors to qualitative scientific theories (as opposed to parameter estimation within a fixed model class).", "The Bernstein-von Mises convergence theorem requires regularity conditions that may not hold for all scientific hypothesis spaces.", "The relationship between Bayesian priors and frequentist calibration (are Bayesian credible intervals well-calibrated?) is not settled for all prior choices.", "Whether expert elicitation of priors (structured expert judgment) produces coherent and reproducible results in scientific practice is an open empirical question." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-bayesian-prior-objectivity.yaml" }, { "id": "u-causation-vs-correlation", "title": "Under what observational study designs and statistical assumptions can causal conclusions be reliably drawn without experimental intervention?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The predictive validity of observational causal estimates against RCT results has been assessed in only a few fields, and the generalization is contested.", "Sensitivity analyses for unmeasured confounding (E-values, Rosenbaum bounds) are rarely reported even when observational studies are published in top journals.", "Whether large sample sizes in observational studies compensate for unmeasured confounding or merely reduce sampling uncertainty around biased estimates is not systematically evaluated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-causation-vs-correlation.yaml" }, { "id": "u-citizen-science-quality", "title": "Under what conditions does citizen science generate data of sufficient quality for peer-reviewed scientific conclusions?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Systematic comparisons of citizen science and professional data quality use different standards for \"quality\" that are not always comparable.", "The geographic and demographic biases of citizen science participation (urban, English-speaking, educated volunteers) have not been fully characterized for their effects on scientific conclusions.", "Long-term volunteer retention and skill development curves are poorly characterized, affecting quality predictions for ongoing projects." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-citizen-science-quality.yaml" }, { "id": "u-demarcation-problem", "title": "What is the correct criterion for demarcating science from non-science, and is a universal criterion possible?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No proposed criterion simultaneously handles historical sciences, mathematical physics, and clearly pseudoscientific fields without counterexamples.", "The relationship between demarcation criteria and scientific methodology (replication, peer review) is not formally specified.", "Whether demarcation is a single problem or a family of distinct questions (epistemic, sociological, legal) has not been settled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-demarcation-problem.yaml" }, { "id": "u-emergence-vs-reduction", "title": "Under what conditions are higher-level scientific explanations genuinely autonomous rather than in-principle reducible to lower-level descriptions?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Whether multiple realizability (one functional type, many physical realizations) genuinely blocks reduction or is an artifact of imprecise typing is unresolved.", "The causal exclusion problem (how can mental causes be efficacious if physical causes are sufficient?) has not been solved by existing compatibilist proposals.", "Whether emergence in physics (renormalization group fixed points, phase transitions) is the same concept as biological or cognitive emergence is unclear." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-emergence-vs-reduction.yaml" }, { "id": "u-interdisciplinary-barriers", "title": "What are the structural and epistemic barriers to effective interdisciplinary collaboration, and how can they be systematically reduced?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Controlled comparisons of interdisciplinary vs. monodisciplinary research quality and impact are confounded by selection effects (harder problems are more likely to be studied interdisciplinarily).", "The vocabulary translation problem between disciplines has not been formalized; no metric exists for cross-disciplinary conceptual distance.", "Career outcome data for researchers who pursued interdisciplinary careers early vs. later are available but insufficiently analyzed." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-interdisciplinary-barriers.yaml" }, { "id": "u-measurement-theory-foundations", "title": "What is the ontological status of measurement scales, and under what conditions do psychometric measurements quantify genuine psychological attributes?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The axiomatic conditions for psychological measurement (conjoint measurement) have been tested empirically in fewer than 20 studies.", "The relationship between construct validity (a psychological concept) and the representational theory of measurement (a formal concept) has not been systematically specified.", "Whether the success of psychometric prediction (IQ predicting income) implies that IQ is a genuine quantity is a contested philosophical inference." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-measurement-theory-foundations.yaml" }, { "id": "u-model-selection-validity", "title": "Are AIC, BIC, and MDL genuinely measuring predictive accuracy or model simplicity, and when do they give misleading guidance?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The performance of AIC/BIC in model selection degrades in unknown ways when the true generating model is not in the candidate set.", "The relationship between BIC and Bayes factors (which BIC approximates) breaks down in cases where BIC is routinely applied.", "Whether AIC or BIC is more appropriate for a given scientific question has not been formalized beyond the asymptotic theory." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-model-selection-validity.yaml" }, { "id": "u-open-science-incentives", "title": "What incentive structures and institutional reforms would sustainably increase open data sharing, preregistration, and replication in science?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Field-level comparisons of open science adoption rates are confounded by disciplinary culture, data sensitivity, and funding source.", "Whether preregistration adoption increases replication rates at the field level (not just within individual studies) has not been demonstrated.", "The effect of data sharing mandates on the quality (usability, completeness) vs. quantity of shared data has not been measured." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-open-science-incentives.yaml" }, { "id": "u-paradigm-shift-prediction", "title": "Are Kuhnian paradigm shifts predictable from anomaly accumulation patterns, and can science-of-science methods detect pre-revolutionary conditions?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No prospective method has been validated for predicting field-level paradigm shifts before they occur.", "The operationalization of \"anomaly\" in a scientific literature is not standardized; different operationalizations give different historical narratives.", "Whether Kuhnian revolutionary science is genuinely distinct from normal cumulative science, or is simply rapid normal science, is contested in the science studies literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-paradigm-shift-prediction.yaml" }, { "id": "u-peer-review-validity", "title": "Does peer review reliably filter low-quality and incorrect science, and what alternative gatekeeping mechanisms might perform better?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The inter-rater reliability of peer review has been measured in only a handful of controlled experiments, mostly in biomedicine.", "Whether high-impact journals accept more errors than lower-tier journals (due to novelty bias) has not been systematically measured across fields.", "The counterfactual quality of papers that were rejected and then published elsewhere has not been tracked." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-peer-review-validity.yaml" }, { "id": "u-preregistration-effectiveness", "title": "Does preregistration of hypotheses and analysis plans improve the validity of scientific conclusions, and what are its limits?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The effect of preregistration on effect size inflation has been measured in psychology but not across all sciences.", "Whether preregistration reduces genuine discovery (by over-constraining analysis) or only reduces false positives has not been separated empirically.", "Compliance with preregistration plans is imperfect; the rate of undisclosed deviations from preregistered analyses is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-preregistration-effectiveness.yaml" }, { "id": "u-publication-bias-correction", "title": "Can publication bias be corrected post-hoc in meta-analyses, and what methods are valid under realistic distributions of true effects?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Simulation studies of bias correction methods use idealized distributions; performance under realistic heterogeneous-effect conditions is unknown.", "The selection function for publication (exactly what combination of p-value, sample size, and novelty drives publication) has not been empirically characterized for most fields.", "Registration-based meta-analyses (including all preregistered studies regardless of results) are too rare to estimate the magnitude of bias in existing literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-publication-bias-correction.yaml" }, { "id": "u-reproducibility-crisis-causes", "title": "What are the root causes of the reproducibility crisis across sciences, and what interventions reliably improve replication rates?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Replication rates vary widely by field and subfield; what predicts replication success (effect size, sample size, prediction market price) is only partially understood.", "Whether preregistration eliminates or merely reduces QRP (questionable research practices) has not been tested with sufficient statistical power.", "The optimal balance between exploratory and confirmatory research in a scientific discipline is not formally characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-reproducibility-crisis-causes.yaml" }, { "id": "u-science-communication-effectiveness", "title": "What communication strategies reliably improve public understanding of scientific evidence and reduce belief in scientific misinformation?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Long-term follow-up of science communication experiments beyond weeks is rare; behavior change (not belief change) is almost never measured.", "The relative effectiveness of expert communication vs. peer communication vs. institutional communication has not been tested in randomized field experiments.", "Whether the same communication strategy that increases acceptance of climate science decreases acceptance of vaccine safety (value-concordance backfire) has not been systematically examined." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-science-communication-effectiveness.yaml" }, { "id": "u-scientific-consensus-formation", "title": "What are the epistemic and social mechanisms by which scientific consensus forms, and under what conditions can consensus be mistaken?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No prospective study has tracked the formation of scientific consensus in a field from initial evidence to settled agreement.", "The conditions under which non-expert consensus trackers (journalists, policymakers) reliably identify genuine vs. manufactured consensus are not well characterized.", "Formal models of consensus formation do not incorporate power asymmetries (senior scientist authority, prestige journal gatekeeping) that are empirically important." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-scientific-consensus-formation.yaml" }, { "id": "u-scientific-method-cross-domain-falsifiability", "title": "What are the necessary and sufficient conditions for a cross-domain structural analogy to constitute a genuinely falsifiable scientific prediction, rather than a post hoc descriptive metaphor, and how should Bayesian confirmation theory quantify the epistemic contribution of each independent domain confirmation?\n", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No formal operational definition of bridge falsifiability exists in the philosophy of science literature.", "Bayesian confirmation quantification for structural analogies requires specifying a prior over possible analogy depths — this prior has not been formally elicited.", "The distinction between progressive and degenerative bridges (Lakatos) has not been operationalised into measurable criteria applicable to USDR bridges." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-scientific-method-cross-domain-falsifiability.yaml" }, { "id": "u-scientific-progress-measure", "title": "How should scientific progress be measured, and do citation counts, replication rates, or predictive accuracy provide valid progress indicators?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "No study has directly compared theoretical progress accounts against empirical trajectories of specific scientific fields over century-long timescales.", "The relationship between short-term replication rates and long-term theoretical progress has not been modeled.", "Whether technological application success (engineering from physics, drugs from biochemistry) is a valid proxy for theoretical progress in basic science is philosophically contested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-scientific-progress-measure.yaml" }, { "id": "u-scientific-realism-debate", "title": "Should we believe that successful scientific theories are approximately true descriptions of unobservable entities, or merely empirically adequate?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The structural realist position faces the \"Newman problem\"—that structure alone, without intrinsic properties, is trivially satisfiable.", "The no-miracles argument has not been formalized in a way that survives the base-rate problem from Bayesian epistemology.", "Whether approximate truth is a coherent concept for theories involving radical ontological discontinuity (e.g., classical to quantum) is unresolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-scientific-realism-debate.yaml" }, { "id": "u-theory-ladenness-observation", "title": "In what sense and to what degree are scientific observations theory-laden, and does this threaten the independence of evidence from theory?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "Cognitive science evidence on perceptual learning shows top-down theory effects on perception, but their magnitude in expert scientific observation is unmeasured.", "Whether the theory-ladenness of observation is problematic for inter-theory comparison depends on whether the \"contaminating\" theories are shared across the competing paradigms.", "The theory-ladenness of computational data processing pipelines (astronomy image reduction, neuroscience fMRI preprocessing) has not been analyzed philosophically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-theory-ladenness-observation.yaml" }, { "id": "u-underdetermination-theory", "title": "Does the underdetermination of theory by evidence imply that scientific theory choice is inevitably non-rational?", "status": "open", "domain": "philosophy-of-science", "systematic_gaps": [ "The formal version of strong underdetermination has been questioned (empirically equivalent theories may be logically related), but no definitive refutation exists.", "Whether theoretical virtues (parsimony, unification) are a priori or empirically grounded features of good theories is not resolved.", "The relationship between underdetermination and the success of scientific realism (the no-miracles argument) has not been made formally rigorous." ], "suggested_hypotheses": [], "file": "unknowns-catalog/philosophy-of-science/u-underdetermination-theory.yaml" }, { "id": "u-optical-frequency-metamaterial-loss-limits-superlens", "title": "Can optical-frequency metamaterials achieve sufficiently low loss to realise a practical superlens with sub-diffraction resolution, and what fabrication strategies or gain-assisted designs can overcome the fundamental ohmic loss in metallic split-ring resonator arrays at visible and near-infrared frequencies?\n", "status": "open", "domain": "photonics", "systematic_gaps": [ "The maximum achievable FOM at visible wavelengths (400-700 nm) for any metamaterial architecture has not been computed from fundamental material constraints (Kramers-Kronig bounds on permittivity).", "Gain-assisted loss compensation in negative-index media has been demonstrated in simulations but experimental validation at optical frequencies with sufficient gain bandwidth has not been achieved.", "The tradeoff between spatial resolution enhancement and contrast in gain-assisted superlenses (amplification vs. noise figure) has not been analytically characterised." ], "suggested_hypotheses": [ "All-dielectric resonant metamaterials based on high-refractive-index particles (silicon or germanium nanoparticles, Mie resonances) can achieve FOM > 5 in the near-infrared (1300-1550 nm) with Re(n) between -0.5 and -1.5, enabling hyperlens operation with ~lambda/4 resolution in this window.\n" ], "file": "unknowns-catalog/photonics/u-optical-frequency-metamaterial-loss-limits-superlens.yaml" }, { "id": "u-vcsel-silicon-photonics-integration-limit", "title": "What is the fundamental limit to integrating III-V semiconductor laser sources (VCSELs, DFB lasers) onto silicon photonics platforms, and can heterogeneous integration achieve the wall-plug efficiency and modulation bandwidth required for co-packaged optics in hyperscale data centers?\n", "status": "open", "domain": "photonics", "systematic_gaps": [ "Threading dislocation density threshold below which III-V-on-Si laser lifetime exceeds 10⁷ hours", "Thermal resistance modeling for monolithically integrated laser arrays at CPO densities", "Whether 2D materials (GaN, GaAs) quantum dot active layers can achieve lower threshold currents with reduced temperature sensitivity", "Fundamental coupling efficiency limit between monolithic III-V source and Si waveguide without mode mismatch" ], "suggested_hypotheses": [ "h-silicon-photonics-dfb-laser-integration" ], "file": "unknowns-catalog/photonics/u-vcsel-silicon-photonics-integration-limit.yaml" }, { "id": "u-phylogenetic-placement-long-branch-attraction-correction", "title": "What is the best method for correcting long-branch attraction (LBA) artefacts in maximum likelihood and Bayesian phylogenetic inference, and when do model violations (rate heterogeneity, compositional heterogeneity, saturation) produce systematic biases that cannot be corrected by more complex substitution models?\n", "status": "open", "domain": "phylogenetics", "systematic_gaps": [ "A principled statistical test for whether a specific phylogenetic inference suffers from LBA (not relying on simulation with assumed true tree) has not been developed.", "The conditions under which CAT mixture models (Lartillot & Philippe 2004) eliminate LBA vs. merely reduce it have not been empirically characterised across diverse taxonomic groups.", "The interaction between compositional heterogeneity (non-stationarity of base frequencies across the tree) and LBA has not been systematically mapped." ], "suggested_hypotheses": [ "Topological incongruence between partitioned analyses (nuclear vs. mitochondrial genes vs. retrotransposon markers) provides a quantitative indicator of LBA severity that correlates with branch-length contrast ratio across taxon pairs — testable across a benchmark set of known phylogenies with varying rate heterogeneity.\n" ], "file": "unknowns-catalog/phylogenetics/u-phylogenetic-placement-long-branch-attraction-correction.yaml" }, { "id": "u-human-expansion-routes-coalescent-ancient-dna", "title": "What were the precise routes, timing, and population sizes of the initial human dispersal out of Africa ΓÇö specifically the number of founding bottlenecks, the extent of archaic admixture (Neanderthal, Denisovan) at each stage, and the fate of early-dispersing populations replaced by later waves?\n", "status": "open", "domain": "phylogeography", "systematic_gaps": [ "Ancient DNA from the Arabian Peninsula, South Asia, and Southeast Asia (key OoA corridors) is lacking due to poor preservation in tropical climates.", "The number and timing of archaic admixture events (Neanderthal, Denisovan, and potentially other unknown archaics) has not been fully characterized.", "The fate of pre-AMH populations in Eurasia (archaic humans who did not interbreed with AMH) is poorly constrained genetically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/phylogeography/u-human-expansion-routes-coalescent-ancient-dna.yaml" }, { "id": "u-anharmonic-spectroscopy-matrix-models-convergence", "title": "When does harmonic normal-mode diagonalization fail predictably for soft modes, hydrogen bonds, and large-amplitude torsions — and what matrix perturbation schemes converge?", "status": "open", "domain": "physical-chemistry", "systematic_gaps": [ "Benchmark suites linking gas-phase high-resolution spectra with anharmonic calculations across conformers", "Uncertainty quantification on eigenvalue corrections under finite basis truncation" ], "suggested_hypotheses": [ "h-molecular-spectroscopy-x-matrix-diagonalization" ], "file": "unknowns-catalog/physical-chemistry/u-anharmonic-spectroscopy-matrix-models-convergence.yaml" }, { "id": "u-critical-exponents-non-mean-field", "title": "Why do critical exponents deviate from mean-field predictions in low dimensions, and can renormalization group predictions be extended to all universality classes?", "status": "open", "domain": "physical-chemistry", "systematic_gaps": [ "Non-perturbative RG for 3D systems remains technically challenging; many universality classes lack high-precision exponent calculations.", "The classification of all possible universality classes in 2D is complete (conformal field theory), but in 3D remains an open mathematical problem." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physical-chemistry/u-critical-exponents-non-mean-field.yaml" }, { "id": "u-kramers-turnover-solvent-friction", "title": "What is the correct theory of the Kramers turnover regime (intermediate friction), and can it explain anomalous reaction rates observed in viscous and cryogenic solvents?", "status": "open", "domain": "physical-chemistry", "systematic_gaps": [ "Experimental measurements of reaction rates across a full range of solvent viscosities (several orders of magnitude) are available for only a handful of reactions.", "Non-Markovian friction (viscoelastic solvents) changes the effective friction frequency dependence; the theory for this case is not complete.", "Quantum corrections to Kramers theory in the turnover regime are only approximately treated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physical-chemistry/u-kramers-turnover-solvent-friction.yaml" }, { "id": "u-md-thermostat-sde-equivalence-and-ergodicity", "title": "For a given complex biomolecular potential, which thermostat–integrator pairs yield ergodic sampling of slow degrees of freedom within feasible wall-clock budgets?", "status": "open", "domain": "physical-chemistry", "systematic_gaps": [ "Rigorous non-asymptotic mixing rates are unknown for practical biomolecular systems.", "Constraint algorithms coupled with stochastic thermostats need unified stability theory." ], "suggested_hypotheses": [ "h-nose-hoover-chains-match-target-kinetic-spectra-when-tuned" ], "file": "unknowns-catalog/physical-chemistry/u-md-thermostat-sde-equivalence-and-ergodicity.yaml" }, { "id": "u-partition-function-anharmonic-correction", "title": "How accurately can anharmonic corrections to the molecular partition function be computed for large polyatomic molecules, and when do they qualitatively change predicted equilibrium constants or rate constants compared to the harmonic approximation?\n", "status": "open", "domain": "physical-chemistry", "systematic_gaps": [ "No benchmark dataset comparing harmonic vs anharmonic equilibrium constants for >30-atom molecules.", "Quantum tunneling contributions to partition functions for H-transfer reactions remain poorly characterized at 300 K.", "Conformational entropy contributions to binding free energies are systematically underestimated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physical-chemistry/u-partition-function-anharmonic-correction.yaml" }, { "id": "u-acoustic-metamaterials-x-negative-refraction", "title": "Can acoustic superlensing (sub-diffraction focusing using double-negative acoustic metamaterials) be achieved at biologically relevant frequencies (1-20 MHz ultrasound) with sufficient bandwidth and resolution to image sub-cellular structures in living tissue?", "status": "open", "domain": "physics", "systematic_gaps": [ "Double-negative acoustic metamaterials demonstrated only at narrow frequency bands (<1% fractional bandwidth); clinical ultrasound requires >50% bandwidth", "Tissue inhomogeneity (fat, bone interfaces) scatters evanescent waves required for superlensing; no compensation method exists", "Fabrication of 3D biocompatible acoustic metamaterials at 10 MHz scale (unit cell ~10 μm) is at the limit of current 3D printing resolution" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-acoustic-metamaterials-x-negative-refraction.yaml" }, { "id": "u-active-matter-chiral-renormalization", "title": "What are the renormalization group fixed points and universality class of polar chiral active matter, and do they differ from achiral active matter?", "status": "open", "domain": "physics", "systematic_gaps": [ "The universality class (critical exponents) of polar chiral active matter has not been computed to two-loop order in the renormalization group.", "Whether chirality is a relevant or irrelevant perturbation at the Toner-Tu fixed point has not been established.", "The crossover between chiral and achiral active matter universality classes as a function of chirality magnitude has not been mapped." ], "suggested_hypotheses": [ "Chiral symmetry is a relevant perturbation at the Toner-Tu fixed point, so polar chiral active matter belongs to a distinct universality class with anomalous scaling exponents differing from Toner-Tu by O(epsilon) corrections." ], "file": "unknowns-catalog/physics/u-active-matter-chiral-renormalization.yaml" }, { "id": "u-active-matter-percolation", "title": "How does self-propulsion fundamentally change percolation transitions in active biological networks?", "status": "open", "domain": "physics", "systematic_gaps": [ "Classical percolation theory underpins the b-percolation-oncology bridge but assumes passive networks; the validity of this assumption for living tumour vasculature is untested.", "The \"unpercolated active solid\" phase (arXiv 2504.18362) has no mapped equivalent in any biological system; tumour vascular networks are a prime candidate.", "Active matter models of tumour cell migration and vascular remodelling have not been connected to the percolation-threshold framing used in adaptive therapy design.", "It is unknown whether the activity parameter in active percolation models can be independently tuned by existing drugs (cytoskeletal inhibitors, motility suppressors)." ], "suggested_hypotheses": [ "Active tumour vascular remodelling can drive the network into an \"unpercolated active solid\" phase that is distinct from, and more fragile than, classical percolation collapse — making adaptive therapy more effective than passive models predict.", "Cytoskeletal inhibitors that reduce cell motility shift the tumour vascular network toward the passive percolation regime, allowing classical threshold-targeting dosing protocols to apply." ], "file": "unknowns-catalog/physics/u-active-matter-percolation.yaml" }, { "id": "u-active-matter-topological-defect-biology", "title": "What is the causal role of topological defects in active nematics (±½ defects) in driving biological tissue remodelling and morphogenetic events?", "status": "open", "domain": "physics", "systematic_gaps": [ "Causal manipulation of defect position in living tissue has not been achieved", "Whether defect-driven mechanical forces are sufficient to specify cell fate is untested", "The timescale hierarchy of defect motion vs. cell fate commitment is unknown" ], "suggested_hypotheses": [ "Active nematic +½ defects causally direct epithelial cell extrusion and apoptosis through compressive stress concentration above a threshold" ], "file": "unknowns-catalog/physics/u-active-matter-topological-defect-biology.yaml" }, { "id": "u-anderson-localization-biological-systems", "title": "Does Anderson localization of vibrational modes in disordered protein networks affect protein allostery and signal propagation, and can it be detected experimentally?", "status": "open", "domain": "physics", "systematic_gaps": [ "The disorder strength required for Anderson localization in protein elastic networks has not been computed", "Whether allosteric proteins have more delocalized normal modes than non-allosteric proteins is not established", "The relationship between B-factors (crystallographic disorder) and mode localization length has not been quantified" ], "suggested_hypotheses": [ "Allosteric proteins show a higher fraction of delocalized normal modes (participation ratio > 0.1 N) than non-allosteric proteins of similar size, predictable from elastic network models using only B-factor data from crystal structures" ], "file": "unknowns-catalog/physics/u-anderson-localization-biological-systems.yaml" }, { "id": "u-arrow-of-time-low-entropy-origin", "title": "Why did the universe begin in an extraordinarily low-entropy state, and which physical mechanism (quantum gravity, anthropic selection, or cyclic cosmology) explains the thermodynamic arrow?", "status": "open", "domain": "physics", "systematic_gaps": [ "No mechanism derivable from time-symmetric fundamental laws explains why the initial condition was low entropy rather than high entropy.", "Boltzmann's fluctuation hypothesis predicts an overwhelmingly probable universe of Boltzmann brains rather than the observed ordered cosmos.", "Penrose's Weyl curvature hypothesis is geometrically motivated but has no derivation from quantum gravity.", "Landauer's principle connects information erasure to entropy but does not explain the low-entropy boundary condition.", "CMB tests of CCC (Penrose) claim both positive and negative results with disputed statistical significance." ], "suggested_hypotheses": [ "h-landauer-cosmological-arrow" ], "file": "unknowns-catalog/physics/u-arrow-of-time-low-entropy-origin.yaml" }, { "id": "u-atmospheric-convection-x-rayleigh-benard", "title": "Does the Rayleigh-Bénard scaling law for heat flux (Nu ~ Ra^β with β ≈ 1/3 in the ultimate regime) apply to atmospheric convection, and can this inform a universal parameterization of cumulus convection in climate models?", "status": "open", "domain": "physics", "systematic_gaps": [ "The transition Ra to the ultimate regime has not been conclusively measured; theoretical predictions range over two orders of magnitude", "Atmospheric RB is complicated by moisture (latent heat), rotation, and wind shear not present in laboratory RB", "No climate model uses RB scaling laws directly; parameterizations are tuned empirically rather than derived from first principles" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-atmospheric-convection-x-rayleigh-benard.yaml" }, { "id": "u-bgs-conjecture-general-proof", "title": "Can the Bohigas-Giannoni-Schmit conjecture be proved in full generality for all quantum systems with classically ergodic dynamics, and what is the precise boundary between GOE and Poisson statistics?", "status": "open", "domain": "physics", "systematic_gaps": [ "The Sieber-Richter diagrammatic expansion has not been shown to converge or to reproduce RMT results to all orders.", "For mixed-phase-space systems, the interpolation between GOE and Poisson statistics (Berry-Robnik distribution) is phenomenological, not derived from first principles.", "The Montgomery-Odlyzko conjecture (Riemann zeros ~ GUE) has no known physical system whose Hamiltonian has the Riemann zeros as eigenvalues." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-bgs-conjecture-general-proof.yaml" }, { "id": "u-boltzmann-machine-x-ising-model", "title": "What is the maximum expressive power of energy-based models trained by contrastive divergence, and how does the spin glass phase structure of the Ising model constrain the representational capacity of deep Boltzmann machines?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Theoretical storage capacity of deep Boltzmann machines has not been derived analytically", "Phase structure of the training landscape (glassy vs paramagnetic vs ferromagnetic) is not characterized for modern architectures", "Connection between replica symmetry breaking and overfitting / memorization in deep learning has not been rigorously established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-boltzmann-machine-x-ising-model.yaml" }, { "id": "u-boltzmann-shannon-nonequilibrium-bridge", "title": "How does the Boltzmann-Shannon entropy equivalence extend to non-equilibrium systems, and what is the information-theoretic interpretation of entropy production in driven dissipative systems?", "status": "open", "domain": "physics", "systematic_gaps": [ "No general MaxEnt principle selects the non-equilibrium steady-state distribution; multiple variational principles (maximum entropy production, minimum entropy production) give contradictory predictions in different regimes.", "The relationship between trajectory-level entropy production (Crooks fluctuation theorem) and macroscopic entropy production rate is not fully characterized for complex networks (biochemical, neural).", "Information-thermodynamic bounds on biological computation (DNA replication, neural signaling) have been derived for idealized models but not validated in vivo." ], "suggested_hypotheses": [ "Non-equilibrium steady states are selected by a MaxCal (maximum caliber, maximum path entropy) principle — the trajectory-level generalization of MaxEnt — and this principle recovers known fluctuation theorems as special cases." ], "file": "unknowns-catalog/physics/u-boltzmann-shannon-nonequilibrium-bridge.yaml" }, { "id": "u-cardiac-criticality-synchronization", "title": "Does the heart operate near a criticality transition, and does cardiac synchronization exploit the same Kuramoto-oscillator physics as neural criticality?", "status": "open", "domain": "physics", "systematic_gaps": [ "It is unknown whether healthy resting cardiac dynamics exhibit the power-law correlations and maximal susceptibility characteristic of a system at or near criticality.", "The Kuramoto order parameter (global phase coherence) has not been measured in real cardiac tissue from single-cell electrophysiology recordings during arrhythmia onset.", "If the heart is at criticality, the universality class of the transition is unknown — which determines whether interventions designed for one critical system will generalise.", "The coupling between neural criticality (brain) and cardiac criticality (heart) via the autonomic nervous system is unstudied from a dual-criticality perspective." ], "suggested_hypotheses": [ "The onset of atrial fibrillation corresponds to the heart crossing from the synchronised (ordered) to the desynchronised (disordered) phase of a Kuramoto-type transition; the critical point is measurable as a diverging susceptibility in ECG power spectra.", "Antiarrhythmic drugs that restore sinus rhythm act by shifting the effective coupling constant in the cardiac Kuramoto system back above its critical threshold, rather than through purely ionic channel-blocking mechanisms." ], "file": "unknowns-catalog/physics/u-cardiac-criticality-synchronization.yaml" }, { "id": "u-cardiomyocyte-synchronization-criticality", "title": "Is synchronization of cardiomyocytes governed by a critical phase transition in an elastic coupling network, and does this predict arrhythmia onset as a loss of criticality?", "status": "open", "domain": "physics", "systematic_gaps": [ "Whether the heart operates near criticality in its synchronization phase diagram has not been established by measuring critical slowing-down indicators in healthy cardiac tissue.", "The universality class of the elastic synchronization transition (Ising, XY, Kuramoto) has not been determined.", "Pre-arrhythmic early-warning indicators derived from elastic synchronization theory have not been tested against clinical ECG data." ], "suggested_hypotheses": [ "Arrhythmia onset is preceded by measurable critical slowing-down (rising AR1 coefficient of inter-beat intervals) within 2-5 minutes, consistent with proximity to the synchronization critical point." ], "file": "unknowns-catalog/physics/u-cardiomyocyte-synchronization-criticality.yaml" }, { "id": "u-cavity-method-x-belief-propagation", "title": "Can the cavity method (replica symmetry breaking) predict exact thresholds for computational phase transitions in random graphical inference problems, and do these thresholds match information-theoretic limits?", "status": "open", "domain": "physics", "systematic_gaps": [ "The RSB prediction for random 3-SAT threshold (≈4.267) is unproven; upper and lower bounds are still separated", "Whether the algorithmic hardness threshold coincides with the information-theoretic threshold for random CSPs is open", "The cavity method is non-rigorous; its predictions require independent mathematical proof for each problem class" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-cavity-method-x-belief-propagation.yaml" }, { "id": "u-chaos-synchronization-noise-robustness-threshold", "title": "How much additive noise in the coupling channel degrades Pecora-Carroll synchronization quality, and is there a noise threshold above which synchronization fails completely?\n", "status": "open", "domain": "physics", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-chaos-synchronization-noise-robustness-threshold.yaml" }, { "id": "u-cherenkov-mach-cone-unified-demo-transfer", "title": "Does side-by-side laboratory demonstration of optical Cherenkov light and hydrodynamic Mach cones measurably improve student transfer performance on cone-angle quantitative problems versus teaching either phenomenon alone?", "status": "open", "domain": "physics", "systematic_gaps": [ "Controlled education studies isolating visualization modality effects on cone-angle problem solving", "Cross-cultural replication where sonic boom pedagogy differs from optics sequencing" ], "suggested_hypotheses": [ "h-cherenkov-mach-prerequisite-transfer-diagnostic" ], "file": "unknowns-catalog/physics/u-cherenkov-mach-cone-unified-demo-transfer.yaml" }, { "id": "u-chromatic-aberration-broadband-metalens", "title": "Can metasurface metalenses achieve achromatic focusing across the full visible spectrum at high numerical aperture simultaneously, and what material and geometric constraints govern the fundamental trade-off between aperture, efficiency, and achromatic bandwidth in phase-gradient metasurfaces?", "status": "open", "domain": "physics", "systematic_gaps": [ "Fabrication of high-aspect-ratio nanostructures for dispersion engineering introduces systematic phase errors not captured in simulation", "The relationship between local resonance dispersion and global point-spread function achromatism is not analytically tractable for large apertures", "Efficiency measurements of metalenses rarely report absolute efficiency vs theoretical bound, making progress tracking difficult" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-chromatic-aberration-broadband-metalens.yaml" }, { "id": "u-climate-ew-indicator-universality", "title": "Do climate tipping element early-warning indicators (AR1, variance, spatial correlation length) follow the universal scaling exponents predicted by their respective bifurcation class, and which statistical test is most sensitive for detecting approach to each tipping point in available satellite and instrumental data?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Bifurcation class has not been formally assigned to each IPCC tipping element using dynamical systems analysis", "AR1 and variance scaling exponents approaching tipping have not been measured from climate data and compared to bifurcation-class predictions", "Spatial correlation length of Amazon NDVI and Arctic sea ice has not been computed as a time series to test for divergence", "Optimal statistical detection theory has not been applied to determine minimum detectable warning time for each tipping element" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-climate-ew-indicator-universality.yaml" }, { "id": "u-concert-hall-acoustic-quality-metrics", "title": "Which measurable physical acoustic parameters of concert halls most reliably predict subjective listener quality ratings, and how do individual differences in perception affect universality of acoustic design criteria?", "status": "open", "domain": "physics", "systematic_gaps": [ "Large-scale (N > 500) listener preference studies using blind evaluation across a controlled range of acoustic conditions have not been conducted due to the practical difficulty of varying hall acoustics at scale.", "Neuroimaging studies of concert hall acoustic quality perception are absent — the neural correlates of \"spaciousness\" (IACC) and \"warmth\" (bass ratio) are unmapped.", "The effect of visual experience of the hall on acoustic quality ratings (architecture-acoustic interaction) is systematically uncontrolled in existing studies." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-concert-hall-acoustic-quality-metrics.yaml" }, { "id": "u-conformal-field-theory-x-critical-phenomena", "title": "Does every second-order phase transition in 3D correspond to a well-defined unitary CFT, and can the conformal bootstrap classify all 3D universality classes analogously to the BPZ classification in 2D?", "status": "open", "domain": "physics", "systematic_gaps": [ "No complete classification of unitary 3D CFTs analogous to the 2D ADE classification", "Bootstrap computations scale poorly with operator spin; higher-spin constraints not fully explored", "Disordered systems (random-bond Ising) may require non-unitary CFTs outside the standard bootstrap framework" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-conformal-field-theory-x-critical-phenomena.yaml" }, { "id": "u-cosmological-constant-fine-tuning", "title": "Why is the cosmological constant (dark energy density) 10^120 times smaller than quantum field theory predicts — is this a fine-tuning problem, an anthropic selection effect, or evidence of new physics?", "status": "open", "domain": "physics", "systematic_gaps": [ "No known mechanism cancels QFT vacuum energy to the observed precision without fine-tuning", "The anthropic/landscape explanation requires a multiverse with no direct observational test", "Whether SUSY or other BSM physics provides a technically natural solution is unknown" ], "suggested_hypotheses": [ "A new scalar field with negative vacuum energy contribution and coupling to Standard Model particles (quintessence) partially cancels QFT vacuum energy dynamically, leaving a residual Lambda(t) that varies slowly with cosmic time, detectable as w(z) ≠ -1 in DESI baryon acoustic oscillation measurements at z < 2" ], "file": "unknowns-catalog/physics/u-cosmological-constant-fine-tuning.yaml" }, { "id": "u-crystallography-x-group-theory", "title": "Can the complete set of topological invariants for all 230 space groups and 1651 magnetic space groups be systematically computed to predict all topological crystalline insulators and semimetals, and what fraction of known materials harbor topologically non-trivial electronic structures?", "status": "open", "domain": "physics", "systematic_gaps": [ "Topological classification for all 1651 magnetic space groups is computationally complete but not validated against experiment for most groups", "Correlated topological insulators (Mott topological insulators) require beyond-DFT methods not yet systematized", "The fraction of synthesizable materials with topological properties is unknown because synthesis feasibility constraints are not included in database searches" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-crystallography-x-group-theory.yaml" }, { "id": "u-diffusion-limited-aggregation-x-fractal-growth", "title": "Is the fractal dimension of DLA clusters in 3D exactly 2.5, and how does adding surface tension or noise to DLA change the universality class of biological branching structures?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Analytical proof of DLA fractal dimension does not exist; only numerical estimates with ~1% error", "Crossover between DLA and Eden (reaction-limited) growth universality classes in biological systems is not quantified", "Effect of flow (advection) on DLA fractal dimension is known to change universality class but biological analogs have not been systematically studied" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-diffusion-limited-aggregation-x-fractal-growth.yaml" }, { "id": "u-emergence-quantification-integrated-information-empirical-test", "title": "Can Tononi's Integrated Information Theory (Φ) be computed for real neural systems at scale, and does Φ increase monotonically with commonly accepted indicators of consciousness (wakefulness vs. sleep vs. anaesthesia vs. vegetative state)?", "status": "open", "domain": "physics", "systematic_gaps": [ "An efficient algorithm for computing Φ exactly for systems with N > 50 elements does not exist; all empirical tests use approximations whose validity is unestablished relative to the true Φ.", "The predicted ordering Φ(vegetative state) < Φ(sleep) < Φ(wakefulness) < Φ(psychedelic state) has not been empirically validated with any single consistent Φ approximation across all four states in the same subjects.", "Whether any local network motif or structural property of neural connectivity reliably predicts high Φ without full computation has not been established; this is the key question for using IIT as a predictive framework rather than a post-hoc measure." ], "suggested_hypotheses": [ "Φ (approximated by spectral complexity measures on EEG data) follows the ordering vegetative < deep sleep < light sleep ≈ anaesthesia < wakefulness < REM < psychedelics for a single consistent measure across states, with the spectral approximation error bounded by a computable factor that scales as N^(1/2)." ], "file": "unknowns-catalog/physics/u-emergence-quantification-integrated-information-empirical-test.yaml" }, { "id": "u-entropy-production-x-living-systems", "title": "Can entropy production rate serve as a universal thermodynamic fitness measure across all scales of biological organisation, from metabolic networks to ecosystems?", "status": "open", "domain": "physics", "systematic_gaps": [ "No rigorous derivation of maximum entropy production as a biological fitness criterion from first principles of natural selection", "Minimum vs. maximum entropy production principles give contradictory predictions at different scales; no unifying criterion has been established", "Empirical measurements of entropy production across phylogenetic diversity are sparse" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-entropy-production-x-living-systems.yaml" }, { "id": "u-ergodic-theory-x-statistical-mechanics", "title": "What is the criterion for a many-body quantum system to thermalize (obey the eigenstate thermalization hypothesis) vs. many-body localize (fail to thermalize), and is there a sharp phase transition between these behaviors?", "status": "open", "domain": "physics", "systematic_gaps": [ "Numerical studies of MBL are limited to ~20 qubits; finite-size effects may mimic a sharp transition", "Classical ergodic theory does not directly apply to quantum systems; quantum ergodicity (ETH) is a stronger requirement", "No experimental system has demonstrated a sharp MBL transition with controlled disorder in thermodynamic limit" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-ergodic-theory-x-statistical-mechanics.yaml" }, { "id": "u-fluctuation-theorem-biological-motors", "title": "How close are biological molecular motors (kinesin, ATP synthase) to thermodynamic optimality as defined by fluctuation theorems, and how do they navigate the efficiency-speed tradeoff?", "status": "open", "domain": "physics", "systematic_gaps": [ "Single-molecule fluctuation measurements in physiological crowded environments are limited", "Thermodynamic uncertainty relation predictions for motor arrays in cells are untested", "The full trajectory distribution P(W) for motor steps has not been measured with sufficient resolution" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-fluctuation-theorem-biological-motors.yaml" }, { "id": "u-gauge-field-epidemic-nonlocality", "title": "Does the QED gauge-field formalism make quantitatively better predictions for non-local epidemic spreading (superspreader dynamics, long-range transmission) than classical SIR/SEIR models, and does the \"behavioral shielding\" derived from stochastic field theory match empirical contact-reduction data?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "The gauge-field epidemic equations have not been solved numerically and compared to classical SIR on the same contact network", "No empirical superspreading dataset has been fit to both the gauge-field and classical SIR models to test predictive superiority", "It is unclear whether \"behavioral shielding\" (derived from the field theory) corresponds to any measurable intervention effect in real outbreaks", "The connection to the percolation framework (b-percolation-epidemiology) has not been explored — does the gauge-field approach recover the percolation threshold as a special case?" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-gauge-field-epidemic-nonlocality.yaml" }, { "id": "u-geometric-phase-calibration-across-polarization-optics", "title": "How accurately can polarization-optics experiments calibrate Berry-phase holonomy concepts for quantum-physics education and device metrology across lossy, nonideal optical paths?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Shared protocols measuring loop area, loss, and phase error for polarization paths.", "Quantified learning transfer between optical and quantum geometric-phase representations." ], "suggested_hypotheses": [ "h-pancharatnam-loop-area-predicts-interferometric-phase-shifts" ], "file": "unknowns-catalog/physics/u-geometric-phase-calibration-across-polarization-optics.yaml" }, { "id": "u-gravitational-wave-memory-effect", "title": "Has the gravitational wave memory effect (permanent spacetime displacement after a wave passes) been detected, and does it match general relativistic predictions?", "status": "open", "domain": "physics", "systematic_gaps": [ "Individual GW memory events have not been detected; only upper limits from LIGO", "Whether NANOGrav's stochastic GW background contains memory contributions is not analyzed", "The nonlinear (Christodoulou) memory contribution to binary merger signals has not been separated from the linear memory" ], "suggested_hypotheses": [ "The cumulative gravitational wave memory from 3rd-generation detector (Einstein Telescope) detections at z<1 will produce a detectable low-frequency stochastic background with strain amplitude h_c ~ 10^{-18} at 10^{-4} Hz, distinguishable from astrophysical noise by its spectral shape" ], "file": "unknowns-catalog/physics/u-gravitational-wave-memory-effect.yaml" }, { "id": "u-grokking-phase-transition", "title": "Is the \"grokking\" phenomenon in deep neural networks a genuine second-order phase transition, and what is its universality class?", "status": "open", "domain": "physics", "systematic_gaps": [ "The universality class of the grokking transition is unknown; critical exponents have not been measured systematically across architectures and task families.", "It is unknown whether grokking is the same phase transition as the \"lazy-to-rich learning\" transition observed in NTK vs feature-learning regimes.", "Finite-size scaling analysis (borrowed from condensed-matter physics) has not been applied to determine how grokking scales with model size, dataset size, and training time simultaneously.", "The connection to biological learning is entirely unexplored: does synaptic consolidation (memory consolidation during sleep) represent an analogous criticality transition in biological neural networks?" ], "suggested_hypotheses": [ "The grokking transition belongs to the same universality class as the 2D Ising ferromagnetic transition; critical exponents (ν, η, β) measured from representation-dimension scaling should match known Ising values.", "Renormalisation-group flow of the learned weight matrices during training converges to a fixed point at grokking; the approach to this fixed point obeys the same scaling laws as thermodynamic systems approaching T_c." ], "file": "unknowns-catalog/physics/u-grokking-phase-transition.yaml" }, { "id": "u-hawking-channel-capacity", "title": "What is the quantum channel capacity of black hole evaporation, and can the full quantum information content of infalling matter be reconstructed from the Hawking radiation after the Page time?", "status": "open", "domain": "physics", "systematic_gaps": [ "Island formula reproduces the Page curve but provides no explicit decoding protocol for extracting information from radiation", "Decoding complexity may be exponential in black hole entropy, making information recovery computationally intractable even if theoretically possible", "The Hayden-Preskill protocol assumes maximally scrambled black holes; deviations from maximal scrambling are unconstrained", "Sub-AdS locality and the Python's lunch geometry obstruct explicit reconstruction of operators deep inside the black hole" ], "suggested_hypotheses": [ "The quantum channel capacity of a black hole is strictly positive after the Page time, with capacity equal to (S_radiation - S_BH) / 2 qubits per unit time", "Decoding Hawking radiation requires quantum computational resources exponential in black hole entropy, making information recovery thermodynamically impossible in practice even if unitarity is preserved" ], "file": "unknowns-catalog/physics/u-hawking-channel-capacity.yaml" }, { "id": "u-hawking-unruh-experimental-detection", "title": "Can Hawking radiation or the Unruh effect be detected experimentally in accessible laboratory systems — including analog gravity systems in BEC, sonic black holes, or laser-accelerated electrons — and would such a detection confirm the key quantum field theory predictions without requiring a true gravitational horizon?", "status": "open", "domain": "physics", "systematic_gaps": [ "BEC analog experiments observe Hawking-like correlations but cannot confirm entanglement across the horizon due to finite system size", "The required laser intensity for Unruh effect detection in electron spin experiments is at the boundary of current and near-future facility capabilities", "The Bogoliubov transformation derivation of Hawking radiation relies on trans-Planckian frequencies whose physics is unknown" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-hawking-unruh-experimental-detection.yaml" }, { "id": "u-higgs-mode-high-tc-superconductors", "title": "Has the Higgs amplitude mode been unambiguously detected in high-Tc cuprate superconductors, and what does its mass tell us about the pairing mechanism?", "status": "open", "domain": "physics", "systematic_gaps": [ "The Higgs mode in conventional superconductors (NbN) is well-established, but in cuprates the strong damping and d-wave symmetry make it extremely hard to observe", "No consensus on whether the 'Higgs mode' signals seen in Raman and THz pump-probe experiments in cuprates are the true amplitude mode or a competing charge-density-wave excitation", "The Higgs mass in a superconductor is proportional to the gap — if measured precisely in cuprates, it could constrain competing theories of high-Tc pairing" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-higgs-mode-high-tc-superconductors.yaml" }, { "id": "u-high-tc-pairing-mechanism", "title": "What is the pairing mechanism in cuprate and iron-based high-temperature superconductors, and why does it produce d-wave rather than s-wave symmetry?", "status": "open", "domain": "physics", "systematic_gaps": [ "The pairing glue (mediating boson) in cuprates has not been identified experimentally — ARPES, neutron scattering, and STM give competing interpretations.", "The pseudogap phase above T_c in underdoped cuprates may represent preformed pairs or a competing order; its role in superconductivity is unknown.", "The iron-based superconductors have multiband (multiple Fermi surfaces) structure; whether s± wave or orbital-selective pairing governs T_c is contested.", "Room-temperature superconductors (hydrides H₃S, LaH₁₀ under >100 GPa pressure) have conventional phonon-mediated BCS pairing; extrapolating to ambient pressure is unknown." ], "suggested_hypotheses": [ "Antiferromagnetic spin fluctuation exchange (paramagnon pairing) with d-wave symmetry accounts for the T_c vs. doping phase diagram in cuprates without free parameters." ], "file": "unknowns-catalog/physics/u-high-tc-pairing-mechanism.yaml" }, { "id": "u-hopfield-capacity-cortex", "title": "Does the human hippocampal CA3 operate near the replica-theory Hopfield capacity limit alpha_c = 0.138?", "status": "open", "domain": "physics", "systematic_gaps": [ "No direct measurement of effective neural assembly size N_eff in human CA3 that would allow computing alpha = memories / N_eff", "Memory interference statistics (confusion errors vs omission errors) have not been systematically separated in clinical AD studies", "The continuous-variable extension of the Hopfield model applicable to rate-coded neurons has not been fitted to in-vivo CA3 data" ], "suggested_hypotheses": [ "h-hopfield-alzheimers-glass-transition" ], "file": "unknowns-catalog/physics/u-hopfield-capacity-cortex.yaml" }, { "id": "u-ion-pump-landauer-thermodynamics", "title": "Do biological ion pumps (Na/K-ATPase, Ca-ATPase) operate as Landauer information-erasure engines, and how close are they to the thermodynamic efficiency limit?", "status": "open", "domain": "physics", "systematic_gaps": [ "The information-theoretic contribution to ATP consumption in Na/K-ATPase (distinguishing Na+ from K+) has not been isolated from the mechanical work contribution.", "Whether ion pump efficiency is limited by kinetic proofreading error rates (Hopfield 1974) or by other physical constraints is unknown.", "The efficiency of Ca2+-ATPase and H+-ATPase relative to their respective Landauer limits has not been computed." ], "suggested_hypotheses": [ "The ATP consumption of Na/K-ATPase exceeds the mechanical work minimum by exactly the amount predicted by the kinetic proofreading thermodynamic cost for 99.99% ion specificity." ], "file": "unknowns-catalog/physics/u-ion-pump-landauer-thermodynamics.yaml" }, { "id": "u-jamming-transition-biological-tissues", "title": "Do biological tissues undergo a jamming transition from fluid-like to solid-like behavior, and is the vertex model or the Voronoi model the correct description of epithelial mechanics?", "status": "open", "domain": "physics", "systematic_gaps": [ "The universality class of tissue jamming (vertex model) vs. granular jamming (J-point) has not been determined", "Whether p0 is the only control parameter or whether active tension and division rates are relevant has not been tested quantitatively", "The molecular switches (E-cadherin, myosin) that set p0 in vivo have not been identified from the vertex model predictions" ], "suggested_hypotheses": [ "The tissue jamming transition belongs to the mean-field universality class (critical exponents beta=0.5, nu=0.5) because cell shape fluctuations are independent in 3D, testable by finite-size scaling of tissue rigidity across cell cluster sizes in 3D organoids" ], "file": "unknowns-catalog/physics/u-jamming-transition-biological-tissues.yaml" }, { "id": "u-kelvin-helmholtz-growth-rate-transfer-cloud-plasma-shear", "title": "Can Kelvin-Helmholtz growth-rate normalizations transfer between stratified atmospheric cloud billows and magnetized plasma shear layers once field-aligned tension, compressibility, and diagnostic resolution are explicitly modeled?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Paired nondimensional parameter sweeps with comparable shear thickness and density contrast.", "Image-to-mode extraction methods that report uncertainty on billow wavelength and growth rate." ], "suggested_hypotheses": [ "h-kh-growth-rate-normalization-predicts-billow-plasma-onset" ], "file": "unknowns-catalog/physics/u-kelvin-helmholtz-growth-rate-transfer-cloud-plasma-shear.yaml" }, { "id": "u-kibble-zurek-embryo", "title": "Does embryonic symmetry breaking obey Kibble-Zurek scaling?", "status": "open", "domain": "physics", "systematic_gaps": [ "No published experiment has deliberately varied C. elegans fertilisation or CDK1 activation speed and recorded polarity-domain statistics", "The PAR correlation length near the symmetry-breaking transition has not been measured experimentally — it is inferred from steady-state images", "The dynamic critical exponent z for PAR phase separation is unknown; existing models give z≈2 (diffusive) but coupling to actomyosin flow could alter this substantially", "It is unresolved whether KZ applies only to thermal phase transitions or extends to active/driven systems (embryos are far from equilibrium)" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-kibble-zurek-embryo.yaml" }, { "id": "u-kleiber-pulsatile-waves", "title": "Is Kleiber's 3/4 metabolic scaling law a signature of pulsatile wave physics rather than fractal network geometry, and does this reframe the entire theory of biological allometry?", "status": "open", "domain": "physics", "systematic_gaps": [ "The wave-physics derivation of the 3/4 exponent has not been tested against the full 27-order-of-magnitude dataset with the same statistical rigour as the fractal-network model.", "It is unknown whether unicellular organisms (where there is no cardiovascular tree) obey the same 3/4 exponent for the same physical reason, or whether they follow a different mechanism that happens to produce the same exponent.", "The transition between wave-physics scaling (large animals with pulsatile circulation) and diffusion-limited scaling (very small organisms) has not been characterised as a phase transition in the scaling law itself.", "Other allometric exponents (bone strength 2/3, lifespan, growth rate) have not been re-derived under the wave-physics framework — it is unknown which are also wave-physics signatures and which remain geometric." ], "suggested_hypotheses": [ "The 3/4 exponent in Kleiber's Law is uniquely derivable from impedance matching in pulsatile arterial trees; the fractal-network model produces the same exponent but through a different physical mechanism that can be distinguished by measuring deviations from 3/4 in organisms with non-pulsatile circulation (e.g. fish with gill ventilation).", "Other fundamental allometric exponents (1/4 power laws in biological time) are co-derived from the same wave-physics constraint, not independently from fractal geometry." ], "file": "unknowns-catalog/physics/u-kleiber-pulsatile-waves.yaml" }, { "id": "u-landau-theory-neural-criticality-order-parameter", "title": "What is the order parameter for neural phase transitions — is it population firing rate, synaptic strength distribution, or a topological quantity — and which Landau universality class does it belong to?", "status": "open", "domain": "physics", "systematic_gaps": [ "No consensus on the neural order parameter; four competing candidates with different experimental signatures", "Whether neural criticality belongs to equilibrium universality classes (Ising, XY) or non-equilibrium classes (directed percolation, KPZ) is unresolved", "Whether the neural \"critical point\" is a true fixed point or a crossover region has not been tested with finite-size scaling" ], "suggested_hypotheses": [ "The neural order parameter is the variance of population firing rate fluctuations, and neural criticality belongs to the mean-field Ising universality class, with susceptibility chi ~ |T-T_c|^{-1} where T = E/I ratio (excitation-to-inhibition balance)" ], "file": "unknowns-catalog/physics/u-landau-theory-neural-criticality-order-parameter.yaml" }, { "id": "u-landauer-bound-experimental-verification", "title": "Can the Landauer bound kT ln 2 per erased bit be approached within one order of magnitude in a solid-state device, and what are the practical barriers to thermodynamically reversible computation?", "status": "open", "domain": "physics", "systematic_gaps": [ "The minimum energy per bit operation in a scalable solid-state device (MOSFET, memristor, quantum dot) at practical operating speeds has not been measured within 3 orders of magnitude of the Landauer limit.", "The thermodynamic cost per error-corrected logical qubit operation in a fault-tolerant quantum computer has not been calculated from first principles.", "Whether room-temperature Brownian computing (using thermal fluctuations as a resource) can be made practically useful is unknown.", "The relationship between the Landauer bound and the minimum energy for neural computation (per synaptic operation) has not been measured experimentally." ], "suggested_hypotheses": [ "Adiabatic CMOS logic at 1 GHz clock frequency can approach 10² k_B T per bit operation (vs. current ~10⁶) through slow-ramp charging of gate capacitances, provably lower-bounded by the RC time constant." ], "file": "unknowns-catalog/physics/u-landauer-bound-experimental-verification.yaml" }, { "id": "u-landauer-limit-biological-computation", "title": "How close to the Landauer limit do biological information-processing systems (synapses, ribosomes, DNA repair) operate?", "status": "open", "domain": "physics", "systematic_gaps": [ "Synaptic vesicle release involves resetting ion channel states — the thermodynamic cost per bit erased has not been measured and compared to k_B*T*ln(2)", "Ribosomal proofreading during translation erases incorrect amino-acid states; the energy cost per corrected error is known (~2 GTP) but not expressed per bit", "DNA mismatch repair erases and rewrites nucleotides; the per-bit thermodynamic cost relative to the Landauer limit has not been calculated", "No systematic comparison of Landauer efficiency across biological vs artificial computing substrates exists" ], "suggested_hypotheses": [ "h-brain-landauer-efficiency" ], "file": "unknowns-catalog/physics/u-landauer-limit-biological-computation.yaml" }, { "id": "u-landauer-limit-nonhelical-resonator", "title": "What is the minimum energy dissipated per logically irreversible bit operation when storing or resetting classical electromagnetic state in high-Q non-helical cavity resonators at temperature T?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Few protocols that explicitly count bits erased vs logically reversible steps in RF hardware.", "Difficulty isolating Landauer-scale heat from larger refrigerator load and amplifier noise.", "Limited cryogenic RF thermometry tied to computational primitives." ], "suggested_hypotheses": [ "h-nonhelical-resonator-adiabatic-quantum-memory" ], "file": "unknowns-catalog/physics/u-landauer-limit-nonhelical-resonator.yaml" }, { "id": "u-laser-cooling-sub-doppler-quantum-limit", "title": "What is the fundamental quantum thermodynamic limit to laser cooling beyond the single-photon recoil limit, and can quantum measurement feedback (Maxwell's demon protocols) achieve sub-recoil temperatures without evaporative cooling?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Quantum thermodynamic efficiency of laser cooling has not been calculated using quantum information theory", "Sub-recoil cooling via VSCPT and Raman cooling approaches the limit empirically but derivation is incomplete", "Maxwell's demon interpretation of sub-Doppler cooling is not formalised in quantum thermodynamics literature" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-laser-cooling-sub-doppler-quantum-limit.yaml" }, { "id": "u-leptogenesis-cp-scale", "title": "Is the CP-violating phase measured in neutrino oscillation experiments (delta_CP in the PMNS matrix) sufficient and consistent with generating the observed baryon asymmetry via leptogenesis?", "status": "open", "domain": "physics", "systematic_gaps": [ "The Davidson-Ibarra bound requires heavy Majorana neutrino masses above ~10^9 GeV for minimal leptogenesis, far beyond collider reach", "The connection between low-energy leptonic CP violation (delta_CP measurable at DUNE) and high-energy leptogenesis CP violation is model-dependent", "Resonant leptogenesis can lower the scale to ~TeV but requires nearly degenerate heavy neutrino masses with no independent motivation", "Washout processes (inverse decays, scatterings) can erase the lepton asymmetry if not carefully balanced" ], "suggested_hypotheses": [ "If the PMNS phase delta_CP is near -pi/2 (as current T2K data hints), minimal leptogenesis via type-I seesaw is viable for heavy neutrino masses consistent with the seesaw relation m_nu ~ v^2/M_R", "Resonant leptogenesis at the TeV scale is testable at future lepton colliders if the quasi-degenerate heavy neutrino spectrum is explained by a flavor symmetry" ], "file": "unknowns-catalog/physics/u-leptogenesis-cp-scale.yaml" }, { "id": "u-liquid-crystal-x-cell-membrane", "title": "How do lipid raft phase separation and curvature coupling in cell membranes influence protein sorting, signaling, and membrane-mediated interactions between proteins?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "In vivo raft size is below optical diffraction limit (~10-200 nm) and hard to measure directly", "The role of cytoskeleton-membrane coupling in defining raft domains is not quantified", "Curvature-composition coupling constants are not measured in biological membranes" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-liquid-crystal-x-cell-membrane.yaml" }, { "id": "u-lorenz-attractor-universality-class", "title": "Is the Lorenz attractor in a distinct universality class from other strange attractors, and what determines the route to chaos (period-doubling vs. intermittency vs. quasiperiodicity) in physical fluid systems?", "status": "open", "domain": "physics", "systematic_gaps": [ "No rigorous proof exists that the physical Rayleigh-Bénard system (PDE) exhibits the Lorenz attractor in any parameter regime — the truncation may be qualitatively misleading.", "The universality class of the Lorenz attractor (critical exponents, dimension) relative to other strange attractors is not fully classified.", "Predicting the route to chaos (period-doubling vs. intermittency) from fluid parameters (Prandtl number, aspect ratio) without simulation remains an open theoretical problem." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-lorenz-attractor-universality-class.yaml" }, { "id": "u-maxwell-shannon-channel-near-capacity", "title": "What physical limits prevent real electromagnetic communication channels from reaching Shannon capacity, and can they be systematically overcome through advanced modulation and coding?", "status": "open", "domain": "physics", "systematic_gaps": [ "The Shannon capacity of wideband fading channels with realistic Maxwell propagation (multipath, Doppler) is not achievable with known codes — the gap between outage capacity and ergodic capacity is not fully characterized.", "Nonlinear Shannon capacity of optical fiber (Kerr nonlinearity + noise) remains an active research problem; the Nonlinear Shannon Limit is not tight for all practical modulation formats.", "Massive MIMO spatial multiplexing (many-antenna systems) approaches the degrees-of-freedom limit set by electromagnetic wave theory (spatial sampling theorem); the fundamental limit for 3D MIMO in realistic propagation environments is not established." ], "suggested_hypotheses": [ "Nonlinear compensation in optical fiber using digital back-propagation can approach within 10% of the nonlinear Shannon capacity in WDM systems with realistic amplifier noise.", "Massive MIMO with holographic apertures can achieve capacity scaling proportional to antenna area rather than antenna count, reflecting a fundamental electromagnetic degree-of-freedom bound." ], "file": "unknowns-catalog/physics/u-maxwell-shannon-channel-near-capacity.yaml" }, { "id": "u-minimum-dissipation-network-topology", "title": "Do biological transport networks (vascular, neural, mycorrhizal) self-organize to minimize dissipation through the same symmetry-breaking mechanism as physical minimum-dissipation networks?", "status": "open", "domain": "physics", "systematic_gaps": [ "The existence of sharp symmetry-breaking transitions in biological vascular network topology as a function of metabolic demand has not been measured.", "Murray's law derivation assumes minimum dissipation but does not predict topology; the connection between dissipation minimization and loop formation is unknown biologically.", "No cross-species comparison of vascular topology as a function of body mass has been performed using the minimum-dissipation framework." ], "suggested_hypotheses": [ "Leaf venation networks switch from tree to loopy topology at a critical mechanical damage probability that matches the symmetry-breaking threshold in minimum-dissipation theory." ], "file": "unknowns-catalog/physics/u-minimum-dissipation-network-topology.yaml" }, { "id": "u-minority-game-market-microstructure-universality", "title": "Does the minority game phase transition at alpha_c have a universal critical exponent shared with real financial market microstructure, and can alpha be measured empirically from order book data?", "status": "open", "domain": "physics", "systematic_gaps": [ "No method exists to empirically estimate alpha = P/N (strategies per trader) from order book or trade data", "Critical exponents of MG transition have not been compared to empirical volatility scaling exponents", "Whether MG phase transition maps to known market regimes (normal vs turbulent) has not been tested" ], "suggested_hypotheses": [ "High-frequency order book imbalance kurtosis diverges as |alpha - alpha_c|^{-gamma_MG} near the MG critical point, with gamma_MG measurable from intraday data across multiple market conditions" ], "file": "unknowns-catalog/physics/u-minority-game-market-microstructure-universality.yaml" }, { "id": "u-neutron-star-core-qcd-constraints", "title": "Do observed mass–radius posteriors require a strong first-order phase transition in the core, or can pure hadronic EOS remain consistent within uncertainties?", "status": "open", "domain": "physics", "systematic_gaps": [ "Limited simultaneous constraints from multiple stars with different masses.", "Uncertainties in pasta phases and pasta–crust thermal conductivity affect cooling interpretations." ], "suggested_hypotheses": [ "h-tidal-deformability-tightens-symmetry-energy-slope" ], "file": "unknowns-catalog/physics/u-neutron-star-core-qcd-constraints.yaml" }, { "id": "u-neutron-star-x-nuclear-matter", "title": "Does a quark-hadron phase transition occur in the cores of massive neutron stars (M > 1.8 solar masses), and if so, is it a first-order transition (with a mixed phase) or a crossover, as constrained by gravitational wave tidal deformability measurements?", "status": "open", "domain": "physics", "systematic_gaps": [ "QCD lattice calculations cannot access finite baryon density (sign problem); perturbative QCD applies only above ~40ρ₀", "The composition of dense matter between 2-5 ρ₀ (hyperons vs. quarks vs. pions) is experimentally unconstrained", "No gravitational wave post-merger detection has been achieved to test quark matter signatures in neutron star mergers" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-neutron-star-x-nuclear-matter.yaml" }, { "id": "u-noether-quantum-gravity-symmetry", "title": "Does Noether's theorem extend to quantum gravity, and what conservation laws (if any) survive the breakdown of spacetime symmetry at the Planck scale?", "status": "open", "domain": "physics", "systematic_gaps": [ "No consensus on whether energy is conserved in a closed quantum universe (quantum cosmology).", "The relationship between gauge symmetry, Noether charges, and holographic entropy (Bekenstein-Hawking) is not fully understood — boundary symmetries (BMS supertranslations) may encode information about the interior.", "Whether CPT symmetry (the combination of charge, parity, time-reversal) is an exact symmetry of quantum gravity, or is violated at the Planck scale, is unknown." ], "suggested_hypotheses": [ "BMS supertranslation charges (infinite-dimensional asymptotic symmetries of flat spacetime) are the Noether charges that resolve the black hole information paradox — information is stored in soft photon/graviton correlations at the horizon." ], "file": "unknowns-catalog/physics/u-noether-quantum-gravity-symmetry.yaml" }, { "id": "u-nonextensive-entropy-turbulence", "title": "Does the non-extensive Tsallis entropy (with index q ≠ 1) correctly characterize the statistical mechanics of quantum turbulence, and is q a universal constant for all superfluid turbulence?", "status": "open", "domain": "physics", "systematic_gaps": [ "The Tsallis q-parameter has been measured only for Vinen turbulence; its value for Kolmogorov turbulence in superfluid He-4 is unknown.", "Whether q is a universal constant or depends on temperature, vortex density, or driving frequency has not been established.", "The relationship between q and the multifractal spectrum f(alpha) of superfluid turbulence has not been derived." ], "suggested_hypotheses": [ "The Tsallis q-parameter for quantum turbulence equals 1 + 1/D_f, where D_f is the fractal dimension of the vortex tangle, unifying non-extensive entropy with fractal geometry." ], "file": "unknowns-catalog/physics/u-nonextensive-entropy-turbulence.yaml" }, { "id": "u-nonhelical-turing-wavelength-scaling", "title": "Under what conditions does the dominant spatial scale of coupled electromagnetic modes in non-helical cavity resonator arrays match a Turing-like instability prediction (and how does it scale with insulation and loss)?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Absence of peer-reviewed linear stability analysis treating coupled resonators inside finite cavities as activator–inhibitor-like dynamics.", "No agreed mapping from geometry (meander pitch, bifilar spacing, cavity Q) to effective D_u, D_v analog parameters.", "Uncertainty whether observed mode clustering is purely forced by periodic lithography vs spontaneous symmetry breaking." ], "suggested_hypotheses": [ "h-nonhelical-turing-cloaking-adaptation" ], "file": "unknowns-catalog/physics/u-nonhelical-turing-wavelength-scaling.yaml" }, { "id": "u-nonlinear-optics-soliton-stability", "title": "What determines the stability of optical solitons against perturbations from higher-order dispersion, stimulated Raman scattering, and pump noise in photonic crystal fibers, and can inverse-designed fiber dispersion profiles guarantee soliton stability across specified bandwidth and power ranges?", "status": "open", "domain": "physics", "systematic_gaps": [ "Higher-order dispersion coefficients β_3 and beyond are hard to measure accurately and propagate large errors through GNLSE simulations", "The boundary between soliton-like and dispersive-wave propagation regimes for high-power pumping is not analytically defined", "Inverse design of fiber dispersion profiles for soliton stability has been demonstrated for specific cases but lacks general guarantees" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-nonlinear-optics-soliton-stability.yaml" }, { "id": "u-primordial-nucleosynthesis-reaction-networks", "title": "What nuclear physics uncertainties in the ⁷Be(n,p)⁷Li and d(p,γ)³He reaction rates explain the cosmological Lithium-7 problem, and can next-generation underground accelerators (LUNA-MV) resolve it?", "status": "open", "domain": "physics", "systematic_gaps": [ "The ⁷Be(n,p)⁷Li cross section at BBN energies (0.01–1 MeV) is known only to ±15%; a factor-2 reduction is needed to solve the Li problem and requires new indirect measurements.", "Stellar depletion of Li by atomic diffusion in metal-poor stars could reduce the Spite plateau Li abundance by 0.1–0.3 dex, partially reconciling prediction with observation — but the diffusion efficiency is uncertain.", "BBN codes disagree at the 1–2% level on D/H predictions due to different treatments of the d+p→³He+γ rate; resolution requires LUNA-MV data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-primordial-nucleosynthesis-reaction-networks.yaml" }, { "id": "u-qcd-ew-phase-transition-relics", "title": "What are the quantitative constraints on dark matter relic densities from the QCD and electroweak phase transitions, and can lattice QCD precision measurements of the QCD equation of state distinguish between axion, WIMP, and primordial black hole dark matter scenarios?", "status": "open", "domain": "physics", "systematic_gaps": [ "The QCD transition is a smooth crossover (not first-order) in the Standard Model, suppressing PBH formation enhancement — but a first-order QCD transition remains possible with BSM physics", "Lattice QCD calculations of the topological susceptibility chi_top(T) near the QCD crossover have large systematic uncertainties affecting axion mass predictions", "The electroweak phase transition in the SM is also a crossover, requiring BSM physics for first-order transition needed by electroweak baryogenesis and WIMP scenarios", "Distinguishing PBH dark matter from WIMP or axion dark matter requires combined GW, CMB, and gravitational lensing data not yet available" ], "suggested_hypotheses": [ "A first-order QCD phase transition, if induced by BSM quark flavor content, would enhance primordial black hole formation at the solar mass scale and explain LIGO's unexpectedly high merger rate at 30-100 solar masses", "Improved lattice QCD measurements of chi_top(T) at T ~ 150 MeV will constrain the axion dark matter window to a factor-of-2 precision by 2030, enabling definitive comparison with ADMX and CASPEr axion search results" ], "file": "unknowns-catalog/physics/u-qcd-ew-phase-transition-relics.yaml" }, { "id": "u-quantum-biology-decoherence", "title": "How does a warm, wet, noisy biological protein maintain quantum coherence long enough to perform a functional quantum measurement — and what does it reveal about decoherence suppression in open quantum systems?", "status": "open", "domain": "physics", "systematic_gaps": [ "The T2 (transverse relaxation) time of the radical pair in cryptochrome under physiological conditions is not precisely known — estimates range from 1–100 microseconds; the precision limit of the compass depends critically on this value.", "It is unknown which features of the cryptochrome protein scaffold (amino-acid geometry, electrostatic shielding, hydrogen-bond network, protein dynamics) are responsible for extending T2 beyond the thermal bath prediction.", "NV-center coherence times in diamond at room temperature (T2 ~ 1ms) are longer than cryptochrome estimates, yet achieved by a completely different mechanism (lattice phonon coupling vs. protein dynamics) — a direct comparison has not been made.", "No quantum error-correction or decoherence-suppression strategy from quantum information theory has been analysed for applicability to the biological radical-pair system.", "The evolutionary path by which cryptochrome acquired near-optimal quantum sensing performance is entirely unknown — it is not clear whether quantum optimality was selected for directly or emerged as a by-product of other biochemical functions." ], "suggested_hypotheses": [ "The protein scaffold of cryptochrome acts as a \"vibrational filter\" — suppressing high-frequency thermal fluctuations that cause decoherence while preserving low-frequency motions that modulate the exchange interaction and thus sensitivity. This is testable by mutagenesis of specific residues and measurement of T2.", "The decoherence-suppression mechanism in cryptochrome is analogous to dynamical decoupling in quantum control — periodic protein conformational motions effectively refocus spin dephasing in a manner equivalent to a biological Hahn echo sequence." ], "file": "unknowns-catalog/physics/u-quantum-biology-decoherence.yaml" }, { "id": "u-quantum-decoherence-x-classical-emergence", "title": "Does quantum decoherence fully solve the measurement problem, or does the emergence of definite outcomes from quantum superpositions require a physical collapse mechanism beyond unitary evolution and environmental entanglement?", "status": "open", "domain": "physics", "systematic_gaps": [ "No experiment can currently distinguish between decoherence + Many Worlds and objective collapse models", "The Born rule has not been derived from first principles without circularity in any interpretation", "Quantum Darwinism (redundant environmental encoding) has been demonstrated in toy models but not in realistic mesoscopic systems" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-quantum-decoherence-x-classical-emergence.yaml" }, { "id": "u-quantum-error-correction-x-topological-codes", "title": "What physical platforms can host non-abelian anyons at scales sufficient for fault-tolerant topological quantum computation, and what is the minimum system size needed to achieve meaningful logical error rate suppression?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "No experimental demonstration of non-abelian anyon braiding with sufficient fidelity for logical gate implementation", "Theoretical threshold theorems assume idealized noise models that may not match realistic correlated noise in solid-state systems", "Relationship between bulk energy gap and logical error rate in finite-size topological codes is not precisely known" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-quantum-error-correction-x-topological-codes.yaml" }, { "id": "u-quantum-field-theory-x-combinatorics", "title": "Is the Feynman diagram series in QED (quantum electrodynamics) Borel summable, and if not, what non-perturbative contributions (instantons, renormalons) dominate the remainder?", "status": "open", "domain": "physics", "systematic_gaps": [ "Feynman diagram coefficients at order > 10 are computationally inaccessible for QED; renormalon behavior is extrapolated", "Instanton contributions to QED (Lipatov instantons) are known but not summed to all orders; the instanton series itself may diverge", "The relationship between combinatorial graph asymptotics and physical renormalon singularities is not proven rigorously" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-quantum-field-theory-x-combinatorics.yaml" }, { "id": "u-quantum-glass-learning-efficiency", "title": "Does quantum glassiness impose fundamental computational hardness limits on machine learning that no classical statistical mechanics framework can predict?", "status": "open", "domain": "physics", "systematic_gaps": [ "The computational complexity class of sampling from quantum glass phases has not been established (is it in BQP, QMA, or beyond?).", "Whether classical replica theory predicts the wrong phase boundary for quantum spin glasses (due to quantum tunneling between replicas) has not been verified numerically.", "The connection between quantum glassiness and trainability (barren plateaus) in quantum neural networks has not been established." ], "suggested_hypotheses": [ "Quantum spin glasses exhibiting RSB have barren plateau-free training landscapes despite classical spin-glass analogues being computationally intractable to sample.", "The quantum glass transition corresponds to a transition from BQP-easy to QMA-hard in the learning complexity landscape." ], "file": "unknowns-catalog/physics/u-quantum-glass-learning-efficiency.yaml" }, { "id": "u-quantum-noise-figure-silicon-mm-wave-cryo-vs-room", "title": "At mm-wave frequencies, when does the Caves/Haus quantum-added noise floor materially alter achievable noise figure in silicon LNAs relative to classical Johnson–Nyquist budgets — as a function of temperature, gain, and bandwidth?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Sparse vendor data separating correlated substrate noise from quantum noise floors in packaged arrays.", "Nonlinear distortion versus quantum noise in multi-carrier mm-wave links remains empirically tangled." ], "suggested_hypotheses": [ "h-josephson-paramp-nears-quantum-noise-floor-with-rimp-matched-array" ], "file": "unknowns-catalog/physics/u-quantum-noise-figure-silicon-mm-wave-cryo-vs-room.yaml" }, { "id": "u-quantum-turbulence-simulation-limit", "title": "Can end-to-end quantum simulation of turbulence reveal universality classes or transport mechanisms that are computationally inaccessible to classical methods?", "status": "open", "domain": "physics", "systematic_gaps": [ "No quantum algorithm has demonstrated advantage for computing turbulence statistics above Re ~ 10^3 in 3D.", "The encoding of continuous turbulence fields into qubit registers without exponential overhead remains an open problem.", "It is unknown whether the Kolmogorov -5/3 spectrum has a quantum information interpretation (e.g., as entanglement entropy scaling).", "Quantum error correction overhead for fluid simulation at practical Reynolds numbers has not been estimated." ], "suggested_hypotheses": [ "The Kolmogorov energy cascade corresponds to a specific entanglement growth pattern in the quantum state representation of the velocity field.", "Quantum simulation of the Euler equations at Re ~ 10^6 requires fewer qubits than classical DNS requires floating-point operations." ], "file": "unknowns-catalog/physics/u-quantum-turbulence-simulation-limit.yaml" }, { "id": "u-quantum-walk-x-classical-random-walk", "title": "Can continuous-time quantum walks on arbitrary graphs be efficiently simulated classically for graphs with special structure, and for which graph families does quantum walk provide provable (not just conjectured) exponential speedup over classical random walk?", "status": "open", "domain": "physics", "systematic_gaps": [ "No complete characterization of graph families for which quantum walk search achieves provable exponential speedup", "Classical simulation complexity of quantum walk on random graphs with small treewidth is not established", "Experimental demonstration of quantum walk speedup on actual quantum hardware for problem sizes beyond classical simulation has not been achieved" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-quantum-walk-x-classical-random-walk.yaml" }, { "id": "u-radiocarbon-calibration-plateau-dating-precision", "title": "Can radiocarbon dates falling on calibration plateaus be resolved to calendar year precision using multi-isotope approaches or wiggle-matching, and what are the fundamental limits of radiocarbon chronology?", "status": "open", "domain": "physics", "systematic_gaps": [ "High-precision AMS measurements (< 5 yr) are expensive and not widely available", "Multi-isotope chronologies for the Hallstatt plateau period are not yet systematic", "Solar particle events (Miyake events 774 CE, 993 CE) provide 1-year anchors but only for post-800 CE" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-radiocarbon-calibration-plateau-dating-precision.yaml" }, { "id": "u-rbm-training-critical-slowdown-near-phase-boundaries", "title": "When does contrastive divergence training of RBMs exhibit critical slowing analogous to poor mixing near spin-glass-like regions of energy landscapes induced by data distributions?", "status": "open", "domain": "physics", "systematic_gaps": [ "Limited standardized reporting linking RBM training divergence to mixing times of associated Gibbs samplers.", "Sparse comparisons across temperatures / regularizers interpreted as noise scales.", "Under-studied finite-sample effects obscuring phase metaphors." ], "suggested_hypotheses": [ "h-annealed-rbm-pretraining-improves-phase-diagram-discovery" ], "file": "unknowns-catalog/physics/u-rbm-training-critical-slowdown-near-phase-boundaries.yaml" }, { "id": "u-renormalization-x-compression", "title": "Is there a rigorous mathematical isomorphism between Shannon rate-distortion theory and Wilson's renormalization group, and if so, does it provide new computational algorithms for either?", "status": "open", "domain": "physics", "systematic_gaps": [ "The RG operates on field theories (continuous systems) while rate-distortion theory is discrete; the continuous-limit correspondence is not fully worked out", "RG universality classes have no obvious counterpart in rate-distortion theory (the distortion measure is not physically motivated from RG)", "Numerical tests of the RG-compression correspondence are limited to simple spin models; interacting field theories have not been studied" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-renormalization-x-compression.yaml" }, { "id": "u-replica-boltzmann-machine-glass", "title": "Does replica symmetry breaking in spherical Boltzmann machine ensembles predict the same generalization-to-memorization transition as in spin glasses, with the same critical exponents?", "status": "open", "domain": "physics", "systematic_gaps": [ "The critical exponents of the RSB transition in spherical Boltzmann machines have not been computed and compared to the SK spin glass.", "Whether the RSB transition persists in non-spherical (sigmoid, ReLU) Boltzmann machines, or is an artifact of the spherical constraint, is unknown.", "The relationship between RSB onset and the grokking transition in deep networks has not been established." ], "suggested_hypotheses": [ "The RSB transition in the spherical Boltzmann machine belongs to the same universality class as the SK spin glass, with Gardner transition exponents.", "The memorization threshold in deep neural networks is predicted by the SK spin-glass capacity formula with an effective temperature equal to the inverse learning rate." ], "file": "unknowns-catalog/physics/u-replica-boltzmann-machine-glass.yaml" }, { "id": "u-replica-symmetry-breaking-algorithmic-hardness", "title": "Can the degree of replica-symmetry breaking in a random optimization problem be used to quantitatively predict the running time of specific algorithms such as DPLL, belief propagation, or simulated annealing?", "status": "open", "domain": "physics", "systematic_gaps": [ "No rigorous mathematical proof connects RSB phase structure to algorithm complexity classes", "Empirical running times of CDCL SAT solvers near the phase transition are poorly predicted by any physics-derived quantity", "The replica method is non-rigorous; results have been confirmed by the cavity method but full mathematical proofs are limited to specific cases" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-replica-symmetry-breaking-algorithmic-hardness.yaml" }, { "id": "u-rg-fixed-points-non-wilson-fisher-universality-classes", "title": "What determines the complete landscape of RG fixed points beyond the Gaussian and Wilson-Fisher fixed points, and are there as-yet-unknown universality classes in systems with long-range interactions, fractal lattices, or non-equilibrium driving that lack a known Lax pair or epsilon-expansion treatment?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Non-perturbative fixed point structure in d=3 O(N) models beyond N=1,2,3 (Ising, XY, Heisenberg) — are there fixed points at non-integer N?", "Fixed point classification for non-equilibrium universality classes (DP, KPZ, voter model) — is there a complete analog of the equilibrium table?", "The long-range to short-range crossover fixed point in O(N) models with power-law interactions — exact location in (d,σ,N) space not fully mapped.", "Conformal field theory (CFT) methods provide exact constraints (conformal bootstrap) on operator dimensions at 3d fixed points — systematic exploration not complete for all universality classes." ], "suggested_hypotheses": [ "Conformal bootstrap constraints (Kos-Poland-Simmons-Duffin 2014) applied systematically to all c-theorem-allowed 3d CFTs will enumerate the complete landscape of RG fixed points in 3d scalar field theories, finding new multicritical fixed points between Ising and mean-field that are currently unknown.\n" ], "file": "unknowns-catalog/physics/u-rg-fixed-points-non-wilson-fisher-universality-classes.yaml" }, { "id": "u-rg-layerwise-flow-identifiability-across-architectures", "title": "Under what conditions can layerwise representations in trained networks be mapped quantitatively to an explicit coarse-graining operator sequence analogous to an RG transform across architectures?", "status": "open", "domain": "physics", "systematic_gaps": [ "Few falsifiable protocols linking measured layer Jacobians to contraction properties interpretable as irrelevant-operator suppression.", "Limited cross-architecture comparability under identical tasks.", "Sparse separation between empirical scaling laws and RG universality claims." ], "suggested_hypotheses": [ "h-beta-scheduled-layer-wise-training-mimics-rg-stability" ], "file": "unknowns-catalog/physics/u-rg-layerwise-flow-identifiability-across-architectures.yaml" }, { "id": "u-scale-free-brain-connectome-criticality", "title": "Is the brain connectome's scale-free topology a consequence of preferential attachment during development, and does the critical gamma exponent predict hub-targeted disease vulnerability?", "status": "open", "domain": "physics", "systematic_gaps": [ "Developmental origin of connectome scale-free topology: preferential attachment vs spatial embedding not distinguished", "Disease vulnerability predicted by network criticality (targeted vs random attack) not quantitatively tested", "Whether connectome gamma changes with age, disease, or cognitive training remains poorly characterized" ], "suggested_hypotheses": [ "Alzheimer's disease hub-node atrophy follows targeted-attack percolation theory: connectivity loss scales as k^{-gamma_attack} with exponent determined by the structural connectome gamma ≈ 2.1" ], "file": "unknowns-catalog/physics/u-scale-free-brain-connectome-criticality.yaml" }, { "id": "u-simulated-annealing-x-statistical-mechanics", "title": "What cooling schedule guarantees that quantum annealing finds the global optimum faster than classical simulated annealing, and for which problem classes does quantum tunneling provide exponential speedup?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "No provable exponential quantum speedup over classical SA has been demonstrated for practical optimization problems", "Optimal annealing schedule depends on the spectral gap of the problem Hamiltonian, which is generically intractable to compute", "Threshold theorems for quantum annealing convergence analogous to the classical SA convergence proof are not established" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-simulated-annealing-x-statistical-mechanics.yaml" }, { "id": "u-soc-universality-class-brain", "title": "Does the cortex belong to the BTW universality class (exponent -3/2) or a distinct SOC universality class?", "status": "open", "domain": "physics", "systematic_gaps": [ "Beggs & Plenz (2003) measured -3/2 in cortical slice — but in vivo measurements show exponents ranging from -1.5 to -2.1 depending on recording method and brain state", "The BTW model is defined on a regular lattice; cortical connectivity is heterogeneous — the universality class may differ", "No systematic test of finite-size scaling of neuronal avalanches has been performed in vivo to extract the exponent to better than +/- 0.2", "The relationship between the SOC universality class and the functional benefits of criticality (dynamic range, information transmission) has not been worked out for non-BTW classes" ], "suggested_hypotheses": [ "h-criticality-conscious-integration" ], "file": "unknowns-catalog/physics/u-soc-universality-class-brain.yaml" }, { "id": "u-social-ising-universality", "title": "Do empirical social tipping events — norm cascades, political phase transitions, market crashes — exhibit early-warning indicators and scaling exponents consistent with the Ising universality class, and which universality class best describes opinion dynamics on real social networks?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "AR1 and variance have not been computed from longitudinal attitude surveys to detect EWIs before documented social tipping events", "The Ising universality class exponents have not been measured from empirical social tipping data", "The universality class of opinion dynamics on real social network topologies (Facebook, Twitter, ANES geographic networks) has not been empirically determined", "The coupled social-physical tipping point system (climate action social tipping coupled to climate physical tipping) has not been modelled with a shared bifurcation framework" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-social-ising-universality.yaml" }, { "id": "u-solar-cell-efficiency-practical-loss-mechanisms", "title": "What is the practical efficiency ceiling for silicon solar cells under the best achievable surface passivation and light-trapping conditions, and which specific loss mechanism (Auger recombination, free-carrier absorption, contact resistance) is the dominant remaining gap below the SQ limit?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Auger recombination coefficients in silicon are measured to 10-20% precision; improvement would tighten the practical limit estimate.", "The best achievable surface recombination velocity with hydrogen-passivated SiO₂/Si interfaces has not been measured below 0.1 cm/s.", "The practical efficiency achievable with ideal carrier-selective contacts (no metal-silicon interface) has not been demonstrated." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-solar-cell-efficiency-practical-loss-mechanisms.yaml" }, { "id": "u-solid-mechanics-x-topology-optimization", "title": "Does topology optimization with fine mesh resolution converge to the true Michell truss solution in the continuum limit, and can this convergence be proven mathematically with explicit convergence rates for SIMP and level-set methods?", "status": "open", "domain": "physics", "systematic_gaps": [ "No convergence proof for SIMP to Michell truss in h→0 limit for multi-load case problems", "The effect of penalization exponent p and filter radius on the quality of the continuum limit is only empirically understood", "Topology optimization for non-linear materials (plasticity, hyperelasticity) lacks the mathematical foundation of the linear case" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-solid-mechanics-x-topology-optimization.yaml" }, { "id": "u-soliton-x-integrable-systems", "title": "Are all physically relevant nonlinear wave equations with stable solitary wave solutions exactly integrable in the sense of possessing a Lax pair, or do approximate solitons exist in non-integrable systems?", "status": "open", "domain": "physics", "systematic_gaps": [ "No general criterion exists for determining whether a PDE admits a Lax pair without finding one explicitly", "Approximate soliton stability in near-integrable systems lacks a systematic perturbation theory", "3D solitons (skyrmions, vortex rings) are not described by IST and require different mathematical frameworks" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-soliton-x-integrable-systems.yaml" }, { "id": "u-sonoluminescence-emission-mechanism-state-resolved", "title": "Which microscopic emission pathway dominates single-bubble sonoluminescence—collisional thermal plasma bremsstrahlung, molecular recombination chemiluminescence, or dissolved noble-gas chemistry — when state-resolved spectra and timing are measured across diverse driving gases and dissolved species?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Joint streak cameras + spectrometers + synchronized radius interferometry on identical bubbles", "Noble-gas isotope sweeps isolating chemistry versus thermal pathways" ], "suggested_hypotheses": [ "h-spectral-linewidth-scales-with-collapse-shock-mach-estimate" ], "file": "unknowns-catalog/physics/u-sonoluminescence-emission-mechanism-state-resolved.yaml" }, { "id": "u-spin-waves-x-magnons", "title": "Can magnons in antiferromagnets or frustrated magnets exhibit topologically non-trivial band structures (magnon Hall effect, topological magnon insulators) and be used as information carriers in spintronic devices without dissipation?", "status": "open", "domain": "physics", "systematic_gaps": [ "Topological magnon band theory for frustrated magnets with strong quantum fluctuations is incomplete", "Magnon-phonon coupling destroys topological protection at finite temperature; the temperature scale for protection is unknown", "No experimental demonstration of magnon edge states with propagation lengths comparable to electronic topological systems" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-spin-waves-x-magnons.yaml" }, { "id": "u-standard-model-beyond-hierarchy-dark-matter-identity", "title": "What lies beyond the Standard Model — what resolves the hierarchy problem, what is dark matter, and what mechanism generates the matter-antimatter asymmetry of the universe?", "status": "open", "domain": "physics", "systematic_gaps": [ "The LHC has found no supersymmetric particles up to ~2 TeV — but the full SUSY parameter space extends to much higher masses inaccessible to current colliders.", "Direct dark matter detection has excluded the canonical WIMP cross-section by 3 orders of magnitude but cannot exclude all viable dark matter candidates.", "The source of CP violation needed for baryogenesis has not been identified in any experiment — neutrino CP violation measurement (T2K, NOvA, DUNE) is the most promising near-term probe." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-standard-model-beyond-hierarchy-dark-matter-identity.yaml" }, { "id": "u-standard-model-representation-completeness", "title": "Are the representation-theoretic assignments of the Standard Model uniquely determined by anomaly cancellation, or do other consistent representations exist?", "status": "open", "domain": "physics", "systematic_gaps": [ "A complete classification of anomaly-free representations of SU(3)×SU(2)×U(1) with a small number of generations has not been published.", "Whether the three-generation structure of the Standard Model follows from any mathematical consistency condition or is purely empirical is unresolved.", "The relationship between anomaly cancellation constraints and string theory landscape selection (which representations are realised in the string landscape) is not established at the level of the observed Standard Model." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-standard-model-representation-completeness.yaml" }, { "id": "u-tensor-networks-x-quantum-states", "title": "What is the minimum tensor network ansatz that can efficiently represent all topological quantum states in 2D, and can PEPS contraction be made polynomial-time for physically relevant classes of quantum states?", "status": "open", "domain": "physics", "systematic_gaps": [ "PEPS contraction complexity for topological (non-trivial) states has not been separately characterised", "The entanglement structure of non-Abelian anyon models in PEPS language is not fully developed", "No polynomial-time PEPS algorithm has been demonstrated for any non-trivial 2D gapped state" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-tensor-networks-x-quantum-states.yaml" }, { "id": "u-thermoacoustic-engine-efficiency-scaling", "title": "What limits the thermodynamic efficiency of practical thermoacoustic engines relative to the Carnot limit, and how does efficiency scale with operating frequency and temperature gradient?", "status": "open", "domain": "physics", "systematic_gaps": [ "Efficiency scaling with machine size (acoustic power) is not empirically characterised", "Optimal regenerator geometry for combined heat transfer and minimal flow resistance is unresolved", "Streaming suppression techniques (acoustic streaming suppressors) need experimental validation" ], "suggested_hypotheses": [ "Thermoacoustic efficiency scales as (1 - T_cold/T_hot) × (1 - f_streaming/f_work) where streaming fraction is a universal function of drive ratio" ], "file": "unknowns-catalog/physics/u-thermoacoustic-engine-efficiency-scaling.yaml" }, { "id": "u-topological-defect-classification-nonequilibrium-condensed-matter", "title": "Which topological invariants best predict defect persistence and coarsening rates in nonequilibrium condensed matter systems?", "status": "open", "domain": "physics", "systematic_gaps": [ "Shared datasets connecting defect topology labels to long-time coarsening trajectories are scarce.", "Experimental uncertainty in defect identification often exceeds differences between candidate scaling laws.", "Coupling between conserved quantities and topological charge is not consistently modeled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-topological-defect-classification-nonequilibrium-condensed-matter.yaml" }, { "id": "u-topological-defects-x-homotopy", "title": "What is the complete classification of topological defects in active matter and non-equilibrium ordered phases where homotopy theory applies only approximately?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Homotopy classification does not account for defect dynamics and kinetics in driven systems far from equilibrium", "Non-Abelian defect fusion rules have not been experimentally verified in accessible condensed matter systems", "Topological defects in systems with multiple competing order parameters (spin-orbit coupled magnets) remain poorly classified" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-topological-defects-x-homotopy.yaml" }, { "id": "u-topological-insulator-majorana-qubit-scalability", "title": "Can Majorana zero modes at topological insulator-superconductor interfaces be scaled to a fault-tolerant topological qubit with error rates below the surface code threshold, and what materials platform minimizes quasiparticle poisoning?", "status": "open", "domain": "physics", "systematic_gaps": [ "No experimental platform has unambiguously demonstrated a pair of spatially separated MZMs with non-local correlations (simultaneous zero-bias peaks at both ends of a wire with correlated noise) meeting the topological gap protocol criteria without alternative trivial explanations.", "The quasiparticle poisoning rate in the most advanced InAs/Al platforms has not been measured below the threshold required for topological qubit coherence (T_poison > T_braid ~ 100 ns); current estimates suggest poisoning rates 100-1000x too high at achievable temperatures.", "No braiding operation has been demonstrated experimentally in any topological platform; the only evidence for non-Abelian statistics comes from fractional quantum Hall systems (ν=5/2), not the semiconductor Majorana platforms, leaving the fault-tolerance claim unverified experimentally." ], "suggested_hypotheses": [ "Epitaxial InAs/Al heterostructures with Al film thickness 3–7 nm and In-face InAs (111) orientation will exhibit topological gap protocol-compliant signatures with topological gap Δ_topo > 100 μeV and quasiparticle poisoning time T_poison > 10 μs at 20 mK, sufficient for demonstration of a non-local Majorana qubit." ], "file": "unknowns-catalog/physics/u-topological-insulator-majorana-qubit-scalability.yaml" }, { "id": "u-topological-insulator-x-band-theory", "title": "Can K-theory topological invariants be extended to non-Hermitian band structures (open quantum systems with gain and loss) to predict protected surface states in photonic and acoustic topological insulators?", "status": "open", "domain": "physics", "systematic_gaps": [ "Non-Hermitian K-theory classification is incomplete for non-Abelian symmetry classes", "The bulk-boundary correspondence for non-Hermitian systems fails in the standard form due to the skin effect", "Experimental demonstration of topologically protected non-Hermitian surface states in 3D photonic systems is lacking" ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-topological-insulator-x-band-theory.yaml" }, { "id": "u-topological-qec-physical-realization", "title": "Which condensed-matter systems currently in the laboratory are in the toric-code (Z2 topological) phase, and can their topological entanglement entropy be measured to confirm they function as physical quantum error-correcting codes?", "status": "open", "domain": "physics", "systematic_gaps": [ "Topological entanglement entropy measurement requires preparing large-scale entangled states — current platforms cannot unambiguously measure gamma = ln 2 for candidate spin liquids.", "Anyon braiding experiments (confirming fractional statistics) require controlling individual anyon positions, which no current platform has demonstrated.", "The alpha-RuCl3 Kitaev spin liquid candidate has contested neutron scattering signatures; the fractionalized excitation interpretation remains disputed.", "Fracton topological phases (Haah code) have no known physical realization and no predicted condensed-matter Hamiltonian." ], "suggested_hypotheses": [ "h-topological-phase-qec-threshold-correspondence" ], "file": "unknowns-catalog/physics/u-topological-qec-physical-realization.yaml" }, { "id": "u-turbulence-anomalous-scaling-intermittency-origin", "title": "What is the mathematical origin of anomalous scaling (intermittency corrections) in fully developed turbulence, and can the multifractal exponents ζ_p be derived analytically from the Navier-Stokes equations?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "No rigorous derivation of the anomalous exponents ζ_p from the 3D Navier-Stokes equations exists.", "The relationship between Navier-Stokes solutions and the Kolmogorov refined similarity hypothesis (RSH) has not been proven.", "Whether the 3D Euler equations (ν → 0) exhibit anomalous scaling is not established analytically or numerically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics/u-turbulence-anomalous-scaling-intermittency-origin.yaml" }, { "id": "u-turbulence-market-reynolds-analogue", "title": "Is there a financial market analogue of the Reynolds number that predicts the onset of 'turbulent' crash dynamics?", "status": "open", "domain": "physics", "systematic_gaps": [ "The turbulence-finance analogy is well-developed for the cascade structure but has no formal correspondence for the onset parameter (Re in turbulence)", "No dimensionless ratio of market quantities (liquidity, leverage, volatility) has been shown to predict the transition from calm to crash-like dynamics", "The dissipation scale of the market cascade (microstructure noise) has not been formally mapped to the Kolmogorov dissipation scale eta" ], "suggested_hypotheses": [ "h-market-crash-turbulent-transition" ], "file": "unknowns-catalog/physics/u-turbulence-market-reynolds-analogue.yaml" }, { "id": "u-turbulence-onset-subcritical-transition", "title": "Why does pipe flow transition to turbulence subcritically (no continuous bifurcation), and what determines the critical Reynolds number Re_c ≈ 2300 from first principles?", "status": "open", "domain": "physics", "systematic_gaps": [ "Re_c ≈ 2300 has not been derived from first principles; only phenomenological estimates exist", "Whether the turbulence transition belongs to directed percolation universality class is debated", "The edge state (saddle point separating laminar and turbulent basins) has no analytical characterization" ], "suggested_hypotheses": [ "The turbulence transition Reynolds number in pipe flow scales as Re_c ~ (L/r)^{1/2} * nu where L is the viscous length scale and r is the pipe radius, derived from the condition that transient amplification exceeds the laminar attractor basin radius" ], "file": "unknowns-catalog/physics/u-turbulence-onset-subcritical-transition.yaml" }, { "id": "u-turbulence-symmetry-breaking-cascade", "title": "Does turbulent transition in shear flows proceed as a succession of distinct symmetry-breaking events, each belonging to a different universality class?", "status": "open", "domain": "physics", "systematic_gaps": [ "Critical exponents of the temporal symmetry-breaking step in boundary layer transition have not been measured.", "Whether the spatial symmetry-breaking step belongs to directed percolation (as in pipe flow) or a different universality class is unknown.", "No RG calculation exists for the successive symmetry-breaking route to turbulence." ], "suggested_hypotheses": [ "Each successive symmetry-breaking step in shear-flow transition belongs to the directed percolation universality class in d+1 dimensions, where d is the spatial symmetry dimension." ], "file": "unknowns-catalog/physics/u-turbulence-symmetry-breaking-cascade.yaml" }, { "id": "u-vegetation-pattern-tipping-universality", "title": "Do vegetation spatial self-organization patterns belong to different universality classes before versus after a desertification tipping point, and can this classify the transition type?", "status": "open", "domain": "physics", "systematic_gaps": [ "The spatial correlation function and scaling exponents of dryland vegetation patterns near the desertification transition have not been measured at sufficient resolution to identify universality class.", "Whether the spatial pattern universality class changes discontinuously at the tipping point or continuously has not been established.", "The connection between vegetation patterning universality class and Early Warning Indicators (EWIs) such as AR(1) and spatial variance has not been theoretically derived." ], "suggested_hypotheses": [ "The pre-tipping spatial patterns belong to the Turing-Hopf universality class; post-tipping patterns belong to the directed percolation class, and this class change can be detected from spatial Fourier spectra." ], "file": "unknowns-catalog/physics/u-vegetation-pattern-tipping-universality.yaml" }, { "id": "u-zeeman-spectrum-unfolding-rmt-quantitative-test", "title": "For which atomic/molecular series and magnetic-field ranges does Zeeman-resolved high-lying spectra show GOE/GUE spacing statistics after unfolding, and where do deviations signal regularity or mixed phase space?\n", "status": "open", "domain": "physics", "systematic_gaps": [ "Limited community-wide standards for unfolding Zeeman-crowded spectra near ionization thresholds.", "Cross-talk between radiative widths and spacing statistics is not always separated in published analyses." ], "suggested_hypotheses": [ "h-zeeman-multiplet-spacing-shows-quantum-chaos-statistics" ], "file": "unknowns-catalog/physics/u-zeeman-spectrum-unfolding-rmt-quantitative-test.yaml" }, { "id": "u-arrhenius-prefactor-molecular-basis", "title": "Whether the Arrhenius pre-exponential factor A can be predicted from first principles for arbitrary reactions, and to what degree A encodes steric, entropic, and quantum tunnelling contributions distinguishable from experiment alone\n", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "The pre-exponential A = (kBT/h) exp(ΔS‡/R) in transition state theory conflates entropic and steric effects that are experimentally inseparable from rate measurements alone.", "Quantum tunnelling contributes to A at low temperatures (H-atom transfer reactions) but the magnitude is calculable only with high-level quantum chemistry (multidimensional tunnelling corrections).", "Ab initio computation of A requires accurate knowledge of the full potential energy surface along the reaction coordinate, feasible only for small molecules with CCSD(T) methods.", "Experimental Arrhenius plots often show curved (non-linear) ln k vs 1/T, indicating multiple reaction mechanisms or tunnelling, but interpretation is model-dependent." ], "suggested_hypotheses": [ "h-activation-energy-mb-tail-universality" ], "file": "unknowns-catalog/physics-chemistry/u-arrhenius-prefactor-molecular-basis.yaml" }, { "id": "u-crystallography-phase-problem-ab-initio", "title": "Can the crystallographic phase problem be solved ab initio for large macromolecules (>100 kDa) using only measured intensities |F_{hkl}|², without experimental phasing or molecular replacement, through computational approaches combining direct methods, charge flipping, and machine learning?\n", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "Fundamental information-theoretic limit on ab initio phasing as a function of data completeness and resolution", "Whether deep learning can generalize phase prediction to genuinely novel topologies not in the PDB", "Combination of cryo-EM density envelopes with crystallographic amplitudes to provide phase priors", "Phase problem difficulty as a function of crystal symmetry (space group) and non-crystallographic symmetry" ], "suggested_hypotheses": [ "h-cryo-em-supersedes-xray-membrane-proteins" ], "file": "unknowns-catalog/physics-chemistry/u-crystallography-phase-problem-ab-initio.yaml" }, { "id": "u-dft-exchange-correlation-exact-functional", "title": "What are the exact constraints that the exchange-correlation functional E_xc[rho] must satisfy, and can a functional satisfying all known exact constraints (non-empirical, fully ab initio) achieve chemical accuracy for arbitrary molecular and materials systems?\n", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "Complete list of exact constraints on E_xc[rho] is not known.", "Whether chemical accuracy is achievable with a constraint-satisfying non-empirical functional is unproven.", "Strong-correlation regime (transition metal oxides, f-electron systems) has no reliable DFT approximation." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics-chemistry/u-dft-exchange-correlation-exact-functional.yaml" }, { "id": "u-high-tc-superconductor-pairing-mechanism", "title": "What is the electron pairing mechanism in cuprate and iron-based high-temperature superconductors — phonon, spin-fluctuation, charge-density-wave, or something else entirely?", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "The symmetry of the order parameter in iron-based superconductors (s±, d-wave, or mixed) is not definitively established across the diverse family of materials.", "The relationship between the pseudogap and superconductivity in underdoped cuprates is unresolved — is the pseudogap a competing order or a precursor of superconductivity?", "No theory quantitatively predicts T_c for cuprates from first principles (DFT + pairing theory).", "The mechanism of ambient-pressure high-T_c superconductivity, if achievable, is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics-chemistry/u-high-tc-superconductor-pairing-mechanism.yaml" }, { "id": "u-pem-fuel-cell-pt-catalyst-degradation-mechanism", "title": "What are the dominant atomic-scale degradation mechanisms of Pt/C oxygen reduction catalysts in PEM fuel cells under drive-cycle conditions — and can they be suppressed to achieve 150,000-hour durability targets for heavy-duty transportation?\n", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "Atomic-scale operando imaging of Pt dissolution and re-precipitation during realistic drive-cycle voltage protocols has not been achieved.", "The relative contributions of all four degradation mechanisms under realistic conditions (humidity, temperature, contamination) have not been quantified simultaneously in a single system.", "Whether the durability of Pt-alloy catalysts in real stacks matches accelerated stress test (AST) extrapolations remains uncertain due to non-linear degradation kinetics." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics-chemistry/u-pem-fuel-cell-pt-catalyst-degradation-mechanism.yaml" }, { "id": "u-polymer-entanglement-topology", "title": "What is the topological mechanism of polymer entanglement, and can entanglement constraints be derived from first principles without the tube model assumption?", "status": "open", "domain": "physics-chemistry", "systematic_gaps": [ "The tube diameter (entanglement length M_e) cannot yet be predicted from chemical structure without empirical fitting.", "Constraint release (CR) and contour-length fluctuation (CLF) corrections to reptation are empirically fitted, not derived.", "Ring polymer dynamics (no chain ends) shows anomalous diffusion unexplained by reptation, suggesting the tube model is incomplete even for simple architectures." ], "suggested_hypotheses": [], "file": "unknowns-catalog/physics-chemistry/u-polymer-entanglement-topology.yaml" }, { "id": "u-glymphatic-csf-clearance-sleep-deprivation-rate", "title": "What is the quantitative relationship between sleep deprivation duration and glymphatic CSF clearance rate, and what is the minimum sleep dose needed to prevent net amyloid-β accumulation?", "status": "open", "domain": "physics-neuroscience", "systematic_gaps": [ "Quantitative dose-response curve of CSF amyloid-β accumulation as a function of sleep deprivation hours is not established in humans (ethical constraints on prolonged deprivation and lack of real-time CSF sampling methods).", "Whether recovery sleep fully restores accumulated clearance deficit (\"sleep debt payoff\" for amyloid) or whether repeated cycles of deprivation cause irreversible accumulation has not been resolved.", "The relative contributions of slow-wave sleep (SWS) vs. REM sleep to glymphatic clearance are not quantified; current data suggest SWS dominates but the mechanism (slow oscillation-driven CSF pulsatility) is incompletely validated in humans." ], "suggested_hypotheses": [ "CSF amyloid-β clearance is linearly proportional to SWS duration above a threshold, with each hour of SWS loss causing ~X% deficit that accumulates irreversibly over timescales > 1 week." ], "file": "unknowns-catalog/physics-neuroscience/u-glymphatic-csf-clearance-sleep-deprivation-rate.yaml" }, { "id": "u-hopfield-modern-attention-biological-plausibility", "title": "Whether the mathematical equivalence between dense Hopfield networks and transformer self-attention (Ramsauer et al. 2020) implies that biological memory retrieval in the hippocampus operates via a biologically plausible version of the attention mechanism\n", "status": "open", "domain": "physics-neuroscience", "systematic_gaps": [ "The Ramsauer et al. (2020) equivalence is mathematical -- softmax attention = dense Hopfield retrieval. Whether this implies hippocampal CA3 autoassociative circuits literally implement attention is a separate, poorly constrained question.", "Biological Hebbian plasticity (STDP) differs from the gradient-based weight updates used in transformers; a biologically plausible update rule that converges to the dense Hopfield weights has not been demonstrated.", "The exponential storage capacity of dense Hopfield networks requires exponential interaction functions (polynomial, softmax) that may not be biologically realistic at individual neuron level.", "Catastrophic forgetting in Hopfield networks (α > 0.14 for classical) vs. continual learning in biology -- how the hippocampus avoids catastrophic forgetting during continuous experience-dependent plasticity is unknown." ], "suggested_hypotheses": [ "h-dense-hopfield-transformer-attention-unified" ], "file": "unknowns-catalog/physics-neuroscience/u-hopfield-modern-attention-biological-plausibility.yaml" }, { "id": "u-quantum-zeno-measurement-neural-interruption", "title": "When, if ever, does frequent cognitive sampling of an internal variable produce measurement-induced stabilization analogous to the quantum Zeno effect, and what experimental designs falsify the analogy?", "status": "open", "domain": "physics-neuroscience", "systematic_gaps": [ "Few behavioral datasets jointly manipulate sampling rate and fit generative switching models.", "Literature rarely states falsifiable scalings (e.g., hazard vs. interval) implied by projection-chain models.", "Boundary between classical Bayesian updates and projection-like readouts is seldom operationalized." ], "suggested_hypotheses": [ "h-quantum-zeno-like-slowing-in-attention-networks" ], "file": "unknowns-catalog/physics-neuroscience/u-quantum-zeno-measurement-neural-interruption.yaml" }, { "id": "u-lymphatic-valve-gating-pressure-threshold", "title": "What is the minimum interstitial hydrostatic pressure required to open primary lymphatic capillary valves, and how does this threshold change with tissue inflammation or fibrosis?\n", "status": "open", "domain": "physiology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/physiology/u-lymphatic-valve-gating-pressure-threshold.yaml" }, { "id": "u-loss-aversion-neural-substrate", "title": "What neural computation implements loss aversion (λ ≈ 2.25), and is it a single mechanism or the product of multiple systems with different evolutionary origins?", "status": "open", "domain": "psychology", "systematic_gaps": [ "Single-unit recording in human OFC/amygdala during economic loss tasks is technically limited — most data comes from fMRI with poor temporal resolution.", "Whether the λ coefficient is stable across decision contexts within individuals (financial, physical risk, social) has not been systematically tested.", "Cross-species comparison of loss aversion magnitude with phylogenetic control has not been done rigorously.", "The developmental trajectory of loss aversion (does it increase with experience?) has not been quantified." ], "suggested_hypotheses": [ "Loss aversion is implemented by asymmetric dopamine/serotonin balance: losses suppress dopamine more than gains enhance it, by a ratio that determines λ." ], "file": "unknowns-catalog/psychology/u-loss-aversion-neural-substrate.yaml" }, { "id": "u-agent-surrogate-policy-optimization-behavioral-fidelity", "title": "How much behavioral-fidelity loss is acceptable when optimizing interventions with agent-based surrogates?", "status": "open", "domain": "public-health", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-agent-surrogate-optimization-reduces-intervention-regret" ], "file": "unknowns-catalog/public-health/u-agent-surrogate-policy-optimization-behavioral-fidelity.yaml" }, { "id": "u-frailty-model-biological-age-calibration", "title": "Can a frailty model fitted to longitudinal biomarker data identify a latent biological age variable that predicts mortality better than chronological age alone, and what is the minimum biomarker panel needed for robust frailty variance estimation in a population cohort?", "status": "open", "domain": "public-health", "systematic_gaps": [ "Longitudinal cohorts with dense biomarker panels and complete mortality follow-up spanning > 20 years are rare", "Statistical identifiability of the frailty distribution (gamma vs. log-normal vs. positive stable) from empirical data is difficult with moderate sample sizes", "The mapping from methylation-clock biological age to the frailty Z variable has not been formally derived" ], "suggested_hypotheses": [], "file": "unknowns-catalog/public-health/u-frailty-model-biological-age-calibration.yaml" }, { "id": "u-photosynthesis-quantum-coherence-physiological-function", "title": "Does quantum electronic coherence in photosynthetic light-harvesting complexes at physiological temperature (300K) provide any functional enhancement of energy transfer efficiency beyond what classical Förster/Redfield theory predicts, or is the ~95% quantum efficiency of primary charge separation achievable by purely classical mechanisms?\n", "status": "open", "domain": "quantum-biology", "systematic_gaps": [ "2D electronic spectroscopy at 300K in vivo (in living chloroplasts, not isolated protein in buffer) has not been achieved with sufficient signal/noise to definitively separate vibrational from electronic coherence.", "Genetic/spectroscopic comparison of organisms with different antenna architectures (FMO-containing green sulfur bacteria vs. LHC-containing plants vs. phycobilisomes in cyanobacteria) in terms of quantum efficiency vs. coherence lifetime has not been done with matched methodology.", "Isotope substitution (¹²C → ¹³C in chromophores) shifts vibrational frequencies without changing electronic energy levels — a tool to distinguish electronic from vibrational coherence in 2DES that has not been systematically applied." ], "suggested_hypotheses": [ "Electronic quantum coherence at 300K in FMO and LHCII is functionally irrelevant: energy transfer rates calculated by Redfield theory (secular approximation, Markovian bath) match measured energy transfer rates to within 5%, and genetic modification of pigment-protein coupling to eliminate coherence does not decrease quantum yield of charge separation — demonstrating that classical mechanisms achieve near-unity efficiency.\n" ], "file": "unknowns-catalog/quantum-biology/u-photosynthesis-quantum-coherence-physiological-function.yaml" }, { "id": "u-quantum-coherence-biological-sensing", "title": "Does quantum coherence play a functional role in biological sensory systems (olfaction, magnetoreception, photosynthesis) beyond the classical noise floor?", "status": "open", "domain": "quantum-biology", "systematic_gaps": [ "No in-vivo measurement of coherence lifetimes in cryptochrome under physiological conditions at body temperature has been reported.", "The frequency-dependence of avian compass disorientation (RF sensitivity pattern) matches radical pair predictions but has not been falsified against classical alternatives." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-biology/u-quantum-coherence-biological-sensing.yaml" }, { "id": "u-quantum-coherence-biological-systems-nmr-detectable", "title": "Is quantum coherence (superposition, entanglement, or tunnelling) functionally relevant in biological systems at physiological temperature — in photosynthesis energy transfer, avian magnetoreception, or enzyme catalysis — and could solid-state NMR or dynamic nuclear polarisation techniques detect coherence lifetimes long enough to be biologically functional?\n", "status": "open", "domain": "quantum-biology", "systematic_gaps": [ "Room-temperature 2D electronic spectroscopy experiments on FMO and other photosynthetic complexes have not definitively resolved whether quantum beats represent excitonic coherence or vibrational contributions (ground state wavepackets).", "DNP-enhanced solid-state NMR has not been applied to measure spin coherence lifetimes in cryptochrome radical pairs in situ — existing EPR studies use isolated proteins or model radicals.", "The kinetic isotope effect in enzyme tunnelling has not been connected to measurable NMR observables that would distinguish quantum from classical H-transfer mechanisms." ], "suggested_hypotheses": [ "Solid-state DNP-NMR of intact avian cryptochrome Cry4 at 37°C will reveal radical-pair spin coherence times T₂* > 100 ns — sufficient for geomagnetic field-sensitive spin dynamics — distinguishable from diamagnetic protein by field-dependent ¹H spin relaxation anisotropy.\n" ], "file": "unknowns-catalog/quantum-biology/u-quantum-coherence-biological-systems-nmr-detectable.yaml" }, { "id": "u-quantum-decoherence-microtubule-physiological-temperature-measured", "title": "What is the actual quantum decoherence timescale of tubulin dimer conformational superpositions in neuronal microtubules at physiological temperature (310 K), measured directly in situ, and how does it compare to Tegmark's theoretical prediction of ~10⁻¹³ s?\n", "status": "open", "domain": "quantum-biology", "systematic_gaps": [ "2D electronic spectroscopy of purified tubulin in aqueous solution has not been performed to measure quantum beat signatures.", "In situ measurements within intact neurons (where ordered water, MAPs, and membrane potential could influence coherence) have not been attempted.", "The specific tubulin GTP-hydrolysis conformational transition proposed as the quantum state by Hameroff has not been characterised by quantum chemical calculation to determine if it supports superposition.", "Anesthetic binding to tubulin in microtubules vs. other cellular targets (GABA receptors, ion channels) has not been quantitatively compared for dose-response at clinically relevant concentrations." ], "suggested_hypotheses": [ "h-orch-or-quantum-consciousness-decoherence-timescale-refutes" ], "file": "unknowns-catalog/quantum-biology/u-quantum-decoherence-microtubule-physiological-temperature-measured.yaml" }, { "id": "u-ctqw-grover-geometry-transferability", "title": "Which graph families encountered in hardware layouts preserve continuous-time quantum walk spatial-search speedups under realistic connectivity constraints, decoherence, and oracle compilation overhead relative to discrete Grover circuits?\n", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "Benchmark suites tying compilation overhead + decoherence to end-to-end speedup thresholds on identical graph instances.", "Empirical spectral-gap distributions for ion-trap / superconducting connectivity graphs compared with spatial-search proofs." ], "suggested_hypotheses": [ "h-johnson-graph-spectral-gap-predicts-ctqw-search-plateau" ], "file": "unknowns-catalog/quantum-computing/u-ctqw-grover-geometry-transferability.yaml" }, { "id": "u-non-abelian-anyons-topological-qc", "title": "Have non-Abelian anyons been experimentally realized with sufficient fidelity to demonstrate braiding-based topological quantum gates, and what material systems provide the best platform for scalable topological qubits resistant to local decoherence?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "Topological gap protection of Majorana modes requires the system to be in the true topological phase; distinguishing topological from trivial Andreev bound states requires careful spectroscopy", "Braiding experiments require moving Majorana modes adiabatically, which demands extremely low temperatures and fast gate operations not yet simultaneously achieved", "Fractional quantum Hall states at ν = 5/2 and 12/5 have not been unambiguously assigned to the Pfaffian or anti-Pfaffian universality class" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-computing/u-non-abelian-anyons-topological-qc.yaml" }, { "id": "u-quantum-annealing-simulated", "title": "Does quantum annealing provide a provable computational advantage over classical simulated annealing for any practically relevant optimization problem class, and on what problem instances?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "Rigorous asymptotic complexity comparison between QA and SA for specific problem classes (MAX-CUT, graph coloring, protein folding on lattice) has not been established.", "The minimum spectral gap Δ(n) as a function of problem size for practically relevant QUBO instances is unknown; this determines the required coherence time for QA advantage.", "Fair benchmarking (same hardware quality, same time budget) between D-Wave and state-of-the-art classical solvers has been contested in the literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-computing/u-quantum-annealing-simulated.yaml" }, { "id": "u-quantum-speedup-optimization-boundary", "title": "What is the precise boundary between optimization problems where quantum annealing offers speedup over classical simulated annealing?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "No benchmark suite distinguishes problems that favor quantum vs. classical annealing based on landscape geometry rather than just instance hardness.", "The connection between problem graph structure (topology of variable interactions) and quantum speedup has not been theoretically characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-computing/u-quantum-speedup-optimization-boundary.yaml" }, { "id": "u-quantum-supremacy-hardness-noise-boundary", "title": "What is the precise noise threshold below which classical simulation of random quantum circuits becomes exponentially hard, and does Google's supremacy claim survive improved classical simulation algorithms?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "The classical simulation complexity at specific (n, d, ε) points is not established", "Whether anti-concentration is necessary for hardness is unresolved", "The role of mid-circuit measurement in changing the hardness boundary is open" ], "suggested_hypotheses": [ "Classical simulation hardness threshold occurs at fidelity F* ~ exp(-c·n) where c depends only on circuit geometry, not gate set" ], "file": "unknowns-catalog/quantum-computing/u-quantum-supremacy-hardness-noise-boundary.yaml" }, { "id": "u-quantum-walk-decoherence-practical-speedup", "title": "At what decoherence rate does the quadratic quantum walk speedup over classical random walks disappear, and can noise-tolerant quantum walk algorithms recover polynomial speedup on near-term hardware?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "The decoherence threshold for quantum walk speedup loss has not been characterized for realistic noise models (T1/T2 coherence)", "Experimental demonstrations of quantum walk search speedup on quantum processors are limited to small graphs", "The transition from quantum to classical walk dynamics under decoherence is not fully characterized for non-Markovian noise" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-computing/u-quantum-walk-decoherence-practical-speedup.yaml" }, { "id": "u-spectral-gap-quantum-phase-transitions", "title": "Can the spectral gap of a local Hamiltonian be computed efficiently, and does its vanishing exactly predict quantum phase transition locations?", "status": "open", "domain": "quantum-computing", "systematic_gaps": [ "The decidability boundary between systems where spectral gap is computable vs. undecidable has not been mapped for physically realistic Hamiltonians.", "Topological quantum phase transitions (e.g., TKNN invariant changes in topological insulators) can occur while the gap remains open — the gap-phase transition relation is not universal." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-computing/u-spectral-gap-quantum-phase-transitions.yaml" }, { "id": "u-bell-loophole-free-implications", "title": "What are the full physical implications of loophole-free Bell inequality violations, and do they definitively rule out all local hidden variable theories?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Superdeterminism cannot be ruled out in principle; quantitative constraints on fine-tuning required are weak.", "Non-local hidden variable theories (Bohmian mechanics) remain consistent with all Bell test results.", "The transition from fundamental nonlocality to practical quantum cryptography security proofs requires additional assumptions." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-bell-loophole-free-implications.yaml" }, { "id": "u-decoherence-timescales-warm-systems", "title": "What determines quantum decoherence timescales in warm, wet biological systems, and can coherence survive long enough to be functionally relevant?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Distinguishing quantum from vibronic coherence in 2D spectroscopy is technically difficult and disputed.", "No causal experiment has shown that disrupting quantum coherence degrades biological function.", "Theoretical models of decoherence in structured protein environments do not agree on coherence timescales." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-decoherence-timescales-warm-systems.yaml" }, { "id": "u-entanglement-entropy-area-law-exceptions", "title": "What are the conditions under which quantum systems violate the entanglement entropy area law, and what do violations imply for classical simulability?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "A complete classification of which Hamiltonians satisfy area law in 2D and higher dimensions does not exist.", "The relationship between area-law violations at excited states and thermal phase transitions is not fully understood.", "No algorithm exploits area-law-adjacent structure for general 2D quantum systems as efficiently as DMRG does in 1D." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-entanglement-entropy-area-law-exceptions.yaml" }, { "id": "u-entanglement-tensor-network-complexity", "title": "What is the computational complexity of contracting arbitrary tensor networks, and which physical entanglement structures admit efficient classical simulation versus those that are fundamentally classically intractable?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Exact complexity of PEPS contraction on planar graphs is unresolved for non-uniform lattices", "The relationship between physical entanglement (thermal, topological) and tensor contraction complexity is not fully characterized", "Efficient MERA algorithms for 2D critical systems have not been demonstrated despite theoretical promise" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-entanglement-tensor-network-complexity.yaml" }, { "id": "u-holographic-entanglement-bulk-reconstruction-limits", "title": "What are the precise limits of bulk reconstruction from boundary entanglement data, and can the entanglement wedge reconstruction be extended beyond semiclassical gravity to full quantum gravity?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "RT formula derivation from first principles in string theory is incomplete", "Entanglement wedge reconstruction for bulk operators near black hole singularities is not understood", "The island formula requires replica wormholes whose physical interpretation in non-gravitational theories is unclear" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-holographic-entanglement-bulk-reconstruction-limits.yaml" }, { "id": "u-many-worlds-copenhagen-experimental", "title": "Is there any experiment that could empirically distinguish many-worlds from Copenhagen or other single-outcome interpretations of quantum mechanics?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No agreed operationalisation of what constitutes a \"world\" in MWI makes experimental test design impossible.", "Frauchiger-Renner thought experiment reveals logical consistency issues but does not distinguish interpretations empirically.", "Wigner's friend realisations with quantum agents remain beyond current technology." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-many-worlds-copenhagen-experimental.yaml" }, { "id": "u-measurement-problem-interpretation", "title": "What physical process constitutes quantum measurement, and which interpretation of quantum mechanics is empirically correct?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Objective collapse theories make predictions quantitatively different from standard QM but experiments are not yet sensitive enough.", "Many-worlds interpretation has no agreed measure for probability.", "Decoherence explains why interference is not observed but does not explain why only one outcome is experienced." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-measurement-problem-interpretation.yaml" }, { "id": "u-neutral-atom-qubit-fidelity", "title": "What limits neutral atom qubit gate fidelities, and can they reach the error thresholds required for fault-tolerant quantum computing?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Rydberg excitation crosstalk and leakage to unintended states limits gate fidelity and has not been fully characterised at scale.", "Mid-circuit measurement fidelity and speed do not yet meet error correction requirements.", "Clock qubit coherence during atom shuttling degrades in ways not fully modelled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-neutral-atom-qubit-fidelity.yaml" }, { "id": "u-perturbation-series-borel-summability-qft", "title": "What is the complete non-perturbative structure of QED and QCD that makes their perturbation series Borel summable (or not), and can resurgence theory systematically reconstruct the full answer from the divergent perturbative expansion?\n", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Borel summability of the QED series has not been rigorously proven; the renormalon singularities on the positive Borel axis obstruct naive Borel resummation.", "The connection between perturbative renormalon ambiguities and non-perturbative condensates (OPE, operator product expansion) is known qualitatively but not systematically exploited for precision predictions.", "The resurgence program has been applied to quantum mechanics (exact WKB) and matrix models; its extension to four-dimensional QFT is incomplete." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-perturbation-series-borel-summability-qft.yaml" }, { "id": "u-photon-antibunching-sub-poissonian", "title": "What limits g⁽²⁾(0) from reaching zero in solid-state single-photon emitters at room temperature, and can photon indistinguishability be simultaneously maximized with high brightness?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The physical mechanisms limiting g⁽²⁾(0) in hBN defect emitters at room temperature — charge noise vs. spectral diffusion vs. background fluorescence — are not dissociated.", "No scalable fabrication process exists for deterministically placing single emitters into nanophotonic cavities with Purcell factor > 10 at room temperature.", "The relationship between the HOM visibility and g⁽²⁾(0) for emitters with non-Lorentzian lineshapes has not been derived analytically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-photon-antibunching-sub-poissonian.yaml" }, { "id": "u-photonic-qc-scalability", "title": "Can photonic quantum computing achieve fault-tolerant scalability given current photon loss rates and deterministic gate requirements?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Integrated photonic circuits achieving less than 1 percent loss per component at scale have not been demonstrated.", "Deterministic single-photon sources with more than 99.9 percent efficiency and indistinguishability are not yet available.", "The resource overhead of fusion-based quantum computing has not been validated experimentally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-photonic-qc-scalability.yaml" }, { "id": "u-post-quantum-cryptography-transition", "title": "What is the timeline and risk profile of the transition to post-quantum cryptography, and which current systems are most vulnerable to harvest-now-decrypt-later attacks?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The timeline to CRQC is uncertain by a factor of 2-5x depending on error rate assumptions.", "The volume of harvested encrypted traffic being stored for future decryption is not known.", "Implementation vulnerabilities in post-quantum algorithms continue to be discovered." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-post-quantum-cryptography-transition.yaml" }, { "id": "u-qaoa-depth-generalization-vs-classical-baselines", "title": "Under realistic hardware noise, when do finite-depth QAOA instances generalize better than strong classical combinatorial baselines on matched problem ensembles?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Sparse apples-to-apples benchmarks against updated classical solvers on identical graph ensembles.", "Prospective reporting of noise calibration drift across experimental sessions.", "Limited standardized metrics linking surrogate prediction error to outer-loop optimization regret." ], "suggested_hypotheses": [ "h-qaoa-parameter-transfer-improves-surrogate-warm-starts" ], "file": "unknowns-catalog/quantum-physics/u-qaoa-depth-generalization-vs-classical-baselines.yaml" }, { "id": "u-qft-non-perturbative-regimes", "title": "What analytical or computational methods can access the non-perturbative regimes of quantum field theories, particularly strongly coupled gauge theories?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The sign problem in lattice QCD at finite baryon density prevents simulation of dense nuclear matter relevant to neutron stars.", "Confinement in QCD has no rigorous proof; the Yang-Mills mass gap Millennium Problem remains unsolved.", "AdS/CFT duality provides tools for strongly coupled QFTs but only in the large-N limit and for specific theories." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-qft-non-perturbative-regimes.yaml" }, { "id": "u-qkd-practical-limits", "title": "What are the practical security limits of quantum key distribution against quantum computer attacks, side channels, and photonic implementation imperfections?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No comprehensive security analysis exists for commercial QKD systems including all known side-channel attack vectors.", "Finite-key security bounds become very conservative for short transmission distances and low photon rates.", "Device-independent QKD has not been demonstrated at distances or rates practical for real-world use." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-qkd-practical-limits.yaml" }, { "id": "u-quantum-advantage-classical-boundary", "title": "For which computational problems does quantum hardware achieve asymptotic speedup that is robust to realistic noise and classical simulation advances?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No NISQ device has demonstrated quantum advantage on a practically useful problem that classical computers cannot simulate.", "The classical simulation complexity of random circuit sampling has not been formally resolved.", "Variational quantum algorithms have not demonstrated quantum speedup on chemistry or optimisation instances." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-advantage-classical-boundary.yaml" }, { "id": "u-quantum-annealing-qaoa-comparison", "title": "Under what conditions does quantum annealing outperform QAOA or classical optimisation methods for structured combinatorial problems?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The energy landscape structure of practically relevant NP-hard instances is poorly characterised for quantum annealing analysis.", "QAOA performance scaling with circuit depth p for specific problem classes has not been determined analytically.", "Head-to-head benchmark comparisons controlling for hardware noise have not been published for competitive classical baselines." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-annealing-qaoa-comparison.yaml" }, { "id": "u-quantum-chaos-scrambling-rates", "title": "What determines quantum information scrambling rates in chaotic systems, and does the Maldacena-Shenker-Stanford bound saturate in black holes and quantum matter?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "OTOC measurements in condensed matter systems are difficult; no clean saturation of MSS bound has been demonstrated experimentally.", "The connection between scrambling rates in quantum processors and thermodynamic properties of black holes remains speculative.", "Whether linear-T resistivity in strange metals implies MSS-saturating scrambling is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-chaos-scrambling-rates.yaml" }, { "id": "u-quantum-darwinism-evidence", "title": "Does quantum Darwinism explain the emergence of classical objectivity from quantum mechanics, and what experimental evidence would confirm it?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Pointer states predicted by quantum Darwinism and those from decoherence alone are difficult to distinguish experimentally.", "The quantum-to-classical transition timescale as a function of system-environment coupling has not been measured systematically.", "Quantum Darwinism in interacting non-Markovian environments is not well understood theoretically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-darwinism-evidence.yaml" }, { "id": "u-quantum-darwinism-redundancy-threshold-classicality", "title": "What minimum redundancy in environmental information encoding is required for a quantum system to appear classical, and has quantum Darwinism been experimentally verified in a controlled system?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No experiment has demonstrated quantum Darwinism in a system where all environment degrees of freedom are accessible", "The transition from quantum to classical as redundancy increases has not been quantitatively characterized", "The role of quantum Darwinism in biological decoherence (e.g., retinal photoisomerization) is speculative" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-darwinism-redundancy-threshold-classicality.yaml" }, { "id": "u-quantum-dot-blinking-power-law-mechanism", "title": "What is the physical mechanism that generates strictly power-law (rather than log-normal or stretched-exponential) on/off time distributions in quantum dot blinking, and why are the exponents universal across QD compositions?\n", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Trap energy distributions have not been directly measured by single-QD spectroscopy with energy resolution below kT", "Universality of exponent across QD compositions is empirical; mechanistic explanation is lacking", "Effect of surface passivation on trap distribution vs. blinking rate is not disentangled" ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-dot-blinking-power-law-mechanism.yaml" }, { "id": "u-quantum-error-correction-overhead", "title": "What is the minimum physical-to-logical qubit overhead required for fault-tolerant quantum computing, and can it be reduced below current theoretical estimates?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The minimum achievable physical-to-logical qubit ratio has no tight lower bound.", "Concatenated codes, surface codes, and LDPC codes have different tradeoffs not yet achievable in hardware.", "Magic state distillation overhead for universal quantum computation remains a significant resource bottleneck." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-error-correction-overhead.yaml" }, { "id": "u-quantum-gravity-unification", "title": "What is the correct theory unifying quantum mechanics and general relativity, and what are its experimentally distinguishable predictions?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No experimental signature of quantum gravity has been confirmed.", "The renormalisability of gravity as a quantum field theory remains unresolved beyond effective field theory.", "String theory landscape has ~10^500 vacua with no selection principle." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-gravity-unification.yaml" }, { "id": "u-quantum-memory-coherence-limits", "title": "What are the fundamental limits on quantum memory coherence times in solid-state, atomic, and photonic systems, and how close are current implementations?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Which decoherence mechanism dominates in each platform has not been definitively established.", "Dynamic decoupling approaching the fundamental coherence limit has only been demonstrated in a few systems.", "The tradeoff between coherence time and coupling efficiency is poorly characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-memory-coherence-limits.yaml" }, { "id": "u-quantum-metrology-heisenberg-limit", "title": "Can quantum metrology routinely achieve Heisenberg-limited sensitivity in practical measurement contexts, overcoming decoherence and photon loss?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "The crossover loss rate at which Heisenberg-limited sensing fails to outperform the standard quantum limit has not been experimentally mapped for all sensor types.", "Entangled probe states (NOON states) are extremely fragile; creating them for large N at photon frequencies relevant to atomic imaging is not feasible.", "Multi-parameter quantum metrology (simultaneous sensing of multiple fields) is theoretically incomplete." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-metrology-heisenberg-limit.yaml" }, { "id": "u-quantum-random-number-true-randomness", "title": "Can quantum random number generators produce certifiably true randomness, and what are the practical limits of device-independent randomness certification?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Practical device-independent QRNGs generate randomness at rates orders of magnitude below application requirements.", "The relationship between Bell violation strength and randomness certification tightness has not been experimentally validated in practical devices.", "Side-channel attacks on QRNGs based on implementation imperfections are not comprehensively characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-random-number-true-randomness.yaml" }, { "id": "u-quantum-repeater-distance-limit", "title": "What is the maximum distance over which quantum entanglement can be distributed using quantum repeaters, and what are the fundamental rate-distance tradeoffs?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "No quantum repeater has demonstrated repeater-assisted entanglement distribution with higher rate than direct transmission.", "Quantum memories with sufficiently long coherence time and high coupling efficiency for repeater operation have not been co-integrated.", "Multi-node repeater chains with entanglement swapping have only been demonstrated with two nodes." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-repeater-distance-limit.yaml" }, { "id": "u-quantum-sensing-biological-limits", "title": "Can quantum sensing technologies achieve the sensitivity required to probe biological processes at the single-molecule level in living systems?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Achieving Heisenberg-limited sensitivity in solid-state sensors at room temperature in the presence of biological noise has not been demonstrated.", "Spin squeezing beyond the standard quantum limit in NV centre ensembles has not been demonstrated in nanoscale volumes.", "Biocompatibility of diamond nanoparticles for in-vivo sensing is poorly characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-sensing-biological-limits.yaml" }, { "id": "u-quantum-simulation-classical-hardness", "title": "For which quantum systems is classical simulation provably hard, and where does the quantum-classical hardness boundary lie in practice?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Worst-case hardness proofs for quantum simulation do not imply typical-case hardness for specific Hamiltonians of interest.", "Classical algorithms continue to push the boundary of simulable system sizes; the moving frontier is not tracked systematically.", "Proof of classical hardness for the Fermi-Hubbard model at intermediate coupling remains open." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-simulation-classical-hardness.yaml" }, { "id": "u-quantum-speedup-optimization-np", "title": "Can quantum algorithms provide polynomial or superpolynomial speedups for NP-hard combinatorial optimisation problems?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "QAOA requires circuit depth exponential in problem size for near-optimal solutions on hard instances.", "Quantum annealing on D-Wave hardware has not demonstrated speedup over simulated annealing on any tested problem class.", "Complexity-theoretic barriers prevent quantum computers from solving NP-complete problems in polynomial time." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-speedup-optimization-np.yaml" }, { "id": "u-quantum-thermodynamics-arrow", "title": "Does quantum thermodynamics provide a microscopic derivation of the second law, and does quantum coherence generate or suppress thermodynamic irreversibility?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Whether quantum coherence provides thermodynamic advantage beyond classical stochastic engines is not settled theoretically or experimentally.", "Landauer principle at the quantum limit has been partially tested but not at the coherence-relevant regime.", "The connection between quantum scrambling and thermodynamic entropy production lacks experimental validation." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-quantum-thermodynamics-arrow.yaml" }, { "id": "u-topological-qc-fault-tolerance-threshold", "title": "Can topological quantum error correction achieve fault-tolerant thresholds in physical systems, and what are the minimum hardware requirements?", "status": "open", "domain": "quantum-physics", "systematic_gaps": [ "Definitive experimental observation of non-Abelian anyons remains contested.", "Surface code requires thousands of physical qubits per logical qubit; topological protection may not reduce overhead sufficiently.", "Decoherence mechanisms specific to Majorana devices are not fully characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/quantum-physics/u-topological-qc-fault-tolerance-threshold.yaml" }, { "id": "u-majorana-zero-mode-experimental-confirmation", "title": "Whether unambiguous Majorana zero modes have been experimentally confirmed in any solid-state system, and whether the retracted Microsoft InAs nanowire results reflect a fundamental challenge to the topological qubit programme\n", "status": "open", "domain": "quantum-physics-materials-science", "systematic_gaps": [ "The 2012 Mourik et al. (Science) InAs nanowire result — widely celebrated as first evidence of Majorana modes — was partially retracted in 2021 (Zhang et al.) after data analysis irregularities were found; this casts doubt on the first generation of MZM claims.", "Distinguishing true topological MZMs from trivial Andreev bound states (ABSs) near zero energy requires signatures beyond zero-bias conductance peaks; non-Abelian braiding statistics have not been demonstrated.", "Alternative platforms (2D TI edges, iron-based superconductors, topological Josephson junctions) show promising signatures but none have demonstrated qubit operations based on braiding.", "Theory predicts that MZMs require very specific material parameter windows (proximity gap, spin-orbit coupling, Zeeman splitting) that are difficult to maintain simultaneously in real materials." ], "suggested_hypotheses": [ "h-topological-qubit-fault-tolerance-threshold" ], "file": "unknowns-catalog/quantum-physics-materials-science/u-majorana-zero-mode-experimental-confirmation.yaml" }, { "id": "u-energy-landscape-mismatch-indicators-for-lesion-segmentation-qc", "title": "What failure boundaries determine when `b-graph-cut-energy-minimization-x-radiology-lesion-segmentation-qc` remains decision-useful?", "status": "open", "domain": "radiology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-graph-cut-energy-residuals-detect-lesion-segmentation-failure-modes-earlier" ], "file": "unknowns-catalog/radiology/u-energy-landscape-mismatch-indicators-for-lesion-segmentation-qc.yaml" }, { "id": "u-resnet-histology-domain-shift-failure-modes", "title": "Which histopathology domain shifts most strongly degrade residual-network diagnostic reliability?", "status": "open", "domain": "radiology", "systematic_gaps": [ "No consensus benchmark with harmonized metadata for stain/scanner factors.", "Rare-subtype error analysis is underpowered in many studies.", "Calibration and abstention behavior under shift are inconsistently reported." ], "suggested_hypotheses": [ "h-residual-feature-normalization-reduces-histology-site-shift-error" ], "file": "unknowns-catalog/radiology/u-resnet-histology-domain-shift-failure-modes.yaml" }, { "id": "u-sampling-pattern-transferability-for-compressed-sensing-mri", "title": "Which acquisition patterns keep `b-compressed-sensing-x-accelerated-mri-protocol-design` robust across scanners and patient cohorts?", "status": "open", "domain": "radiology", "systematic_gaps": [ "Cross-vendor protocol transfer datasets with consistent pathology labels are limited.", "Clinical acceptability thresholds are inconsistently encoded in reconstruction studies." ], "suggested_hypotheses": [ "h-adaptive-kspace-schedules-preserve-diagnostic-mri-quality-at-higher-acceleration" ], "file": "unknowns-catalog/radiology/u-sampling-pattern-transferability-for-compressed-sensing-mri.yaml" }, { "id": "u-ransac-optimal-sampling-strategy-non-uniform-inlier-distribution", "title": "What is the optimal sampling strategy for RANSAC when the inlier distribution is non-uniform (spatially clustered, class-imbalanced, or structured) ΓÇö and can information-theoretic bounds on robust estimation be derived for heterogeneous inlier distributions?\n", "status": "open", "domain": "robust-statistics", "systematic_gaps": [ "The optimal sampling distribution for RANSAC under structured inlier clustering (spatially correlated correspondences) has not been derived theoretically.", "Information-theoretic lower bounds on the number of RANSAC iterations required for a given inlier fraction and minimum subset size under non-iid inliers are not established.", "The relationship between RANSAC's breakdown point and classical robust statistics breakdown points for structured data (time series, images) has not been formalized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/robust-statistics/u-ransac-optimal-sampling-strategy-non-uniform-inlier-distribution.yaml" }, { "id": "u-earthquake-alert-threshold-sprt-under-correlated-noise", "title": "Under spatially correlated seismic noise and aftershock clustering, what sequential decision boundaries achieve bounded false-alarm rates for EEW while preserving detection probability targets — without Wald’s classic i.i.d. guarantees?\n", "status": "open", "domain": "seismology", "systematic_gaps": [ "Few published analyses computing empirical false-alarm exceedance rates versus SPRT nominal α under realistic catalogs.", "Human behavioral responses (alert fatigue) absent from pure statistical objective functions." ], "suggested_hypotheses": [ "h-aftershock-clustering-inflates-sprt-false-alarm-rate-fixed-boundaries" ], "file": "unknowns-catalog/seismology/u-earthquake-alert-threshold-sprt-under-correlated-noise.yaml" }, { "id": "u-earthquake-nucleation-dislocation-slip-weakening", "title": "What is the earthquake nucleation process at the asperity scale, and does rate-and-state friction or slip-weakening dislocation mechanics better describe the transition from quasi-static creep to dynamic rupture?\n", "status": "open", "domain": "seismology", "systematic_gaps": [], "suggested_hypotheses": [], "file": "unknowns-catalog/seismology/u-earthquake-nucleation-dislocation-slip-weakening.yaml" }, { "id": "u-pino-aftershock-forecasting-uncertainty-calibration", "title": "Are PINO aftershock forecasts uncertainty-calibrated for operational hazard use?", "status": "open", "domain": "seismology", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-pino-aftershock-fields-improve-short-term-seismic-hazard-maps" ], "file": "unknowns-catalog/seismology/u-pino-aftershock-forecasting-uncertainty-calibration.yaml" }, { "id": "u-bci-non-stationarity-adaptation", "title": "How can brain-computer interface decoders adapt to non-stationary neural signals (caused by learning, electrode drift, and day-to-day variability) without requiring lengthy daily recalibration?", "status": "open", "domain": "signal-processing", "systematic_gaps": [ "Long-term intracortical recording datasets (>1 year) with high-quality tracking of individual neurons are rare", "The relationship between neural plasticity during BCI learning and decoder non-stationarity is not quantified", "Transfer learning approaches for BCI have not been validated across patients with different neural anatomy" ], "suggested_hypotheses": [], "file": "unknowns-catalog/signal-processing/u-bci-non-stationarity-adaptation.yaml" }, { "id": "u-oxytocin-parochial-altruism-policy-implications", "title": "Are the parochial altruism effects of oxytocin (increased in-group cooperation, decreased out-group trust) large enough, robust enough, and manipulable enough to have policy-relevant implications for inter-group conflict and diversity- cooperation tradeoffs, or are they small-effect laboratory phenomena that do not generalise to real social behaviour?\n", "status": "open", "domain": "social-neuroscience", "systematic_gaps": [ "Large-scale pre-registered replications of the de Dreu parochial altruism effect with real (not artificial) social group identities and ecologically valid cooperation tasks have not been conducted.", "The dose-response relationship between endogenous oxytocin levels (measured by plasma or CSF) and real-world in-group/out-group behaviour has not been established in field studies.", "Whether the parochial altruism effect is moderated by prior inter-group contact (contact hypothesis) has not been tested — the interaction between social history and oxytocin signalling is unknown." ], "suggested_hypotheses": [ "The parochial altruism effect of intranasal oxytocin on real-world ethnic group cooperation is reduced by ~60% when participants have had high-quality prior inter-group contact, measured by standardised contact quality scale — testable in a 2x2 (oxytocin/placebo x high/low contact) design with immigrant-host community cooperation tasks.\n" ], "file": "unknowns-catalog/social-neuroscience/u-oxytocin-parochial-altruism-policy-implications.yaml" }, { "id": "u-abm-calibration-empirical-social-science-validation", "title": "How should agent-based models be calibrated, validated, and falsified against empirical social science data, given that the mapping between ABM agent rules and measurable individual behaviors is underdetermined and emergent outcomes are sensitive to rule specification?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Standard validation protocol for social science ABMs analogous to k-fold cross-validation in machine learning.", "Identifiability analysis: what macro-observables constrain what micro-parameters?", "Behavioral calibration: connecting ABM agent rules to experimentally measured decision-making heuristics from behavioral economics.", "Out-of-sample forecasting track record of ABMs vs. equation-based models for social outcomes (elections, market crashes, civil conflict)." ], "suggested_hypotheses": [ "ABMs calibrated via ABC on pre-2020 US political geography data (county-level vote shares, demographic sorting) will perform worse than structural equation models at predicting 2022 midterm geographic outcomes — demonstrating that ABM flexibility leads to overfitting to calibration data unless strong theoretical constraints are imposed on agent rule specification.\n" ], "file": "unknowns-catalog/social-science/u-abm-calibration-empirical-social-science-validation.yaml" }, { "id": "u-attitude-behavior-gap-pro-environmental", "title": "Why does high environmental concern consistently fail to predict pro-environmental behavior, and which psychological and structural mechanisms most effectively close the attitude-behavior gap at population scale?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Long-run (>2 year) persistence of nudge intervention effects on pro-environmental behavior has not been established for most interventions.", "The contribution of structural vs. psychological barriers to the attitude-behavior gap has not been decomposed in a well-identified natural experiment.", "Whether moral licensing rebound is large enough to offset nudge effectiveness is debated — meta-analyses give contradictory results depending on inclusion criteria." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-attitude-behavior-gap-pro-environmental.yaml" }, { "id": "u-behavioral-immune-system-pathogen-xenophobia-mechanism", "title": "What is the specific cognitive-neural mechanism by which the behavioral immune system generalises from disease-avoidance disgust to anti-outgroup prejudice, and can this mechanism be modulated without impairing genuine pathogen detection — enabling interventions that reduce xenophobia while preserving public-health-relevant disgust?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No neuroimaging study has directly compared insular cortex activation to pathogen disgust cues (maggots, feces) vs. social disgust cues (outgroup images) vs. neutral disgust-irrelevant outgroup images in the same participants with matched image sets.", "The specificity of BIS priming (disease salience → increased outgroup prejudice) for pathogen-relevant cues vs. general threat cues has not been controlled for threat-arousal confounds in published studies.", "Whether individual BIS sensitivity predicts compliance with public health measures (mask wearing, vaccination) but also predicts anti-immigration attitudes in the same population, with the same effect size, has not been tested in a pre-registered study." ], "suggested_hypotheses": [ "Insular cortex connectivity between pathogen disgust and social evaluation networks (amygdala-prefrontal axis) mediates BIS over-generalisation: high trait-disgust individuals show stronger functional coupling between insula and amygdala during outgroup image processing, and this coupling predicts both xenophobia scores and disease-protective behavior compliance — confirming shared neural substrate with dual behavioral consequences.\n" ], "file": "unknowns-catalog/social-science/u-behavioral-immune-system-pathogen-xenophobia-mechanism.yaml" }, { "id": "u-collective-action-without-authority", "title": "Under what conditions can groups solve collective action problems without central authority, and how do informal institutions maintain cooperation?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The minimum group size and cultural conditions for successful self-governance have not been systematically established.", "Scaling Ostrom's principles to large-scale digital commons or global public goods has not been validated.", "The interaction between formal legal institutions and informal self-governance is not modelled dynamically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-collective-action-without-authority.yaml" }, { "id": "u-collective-memory-formation", "title": "How do collective memories of historical events form, persist, and distort across generations, and what factors determine their cultural salience?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The mechanisms by which collective memory is transmitted across generational boundaries are not well characterised.", "The relationship between individual autobiographical memory and collective memory involves unknown aggregation processes.", "State memory management (censorship, commemoration) has heterogeneous effects not captured by current models." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-collective-memory-formation.yaml" }, { "id": "u-complex-contagion-threshold-distribution-estimation", "title": "How can adoption thresholds φ_i be estimated from observational social network data, and does the empirical threshold distribution predict cascade dynamics better than mean-field SIR models for real social behaviours?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Methods for identifying individual adoption thresholds from panel data on social network adoption are not validated against ground truth from controlled experiments.", "The degree to which threshold heterogeneity (wide P(φ)) vs. mean threshold determines cascade dynamics has not been quantified empirically.", "No head-to-head comparison of simple SIR and complex contagion models exists using the same empirical social diffusion dataset with temporal data." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-complex-contagion-threshold-distribution-estimation.yaml" }, { "id": "u-criminal-justice-deterrence", "title": "What is the evidence that criminal punishment deters crime, and which punishment characteristics (certainty, severity, speed) have the largest effects?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Natural experiments that cleanly identify the causal effect of specific deterrence parameters are rare; most evidence is quasi-experimental.", "Deterrence effects vary substantially by crime type, offender type, and context in ways not fully explained.", "The relative effectiveness of deterrence versus incapacitation versus rehabilitation in reducing crime is not established across national contexts." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-criminal-justice-deterrence.yaml" }, { "id": "u-crowd-dynamics-panic-transitions", "title": "What are the measurable precursors of the transition from orderly evacuation to panic-driven crowd turbulence, and can social force model parameters be calibrated in real-time from LiDAR or video tracking to give advance warning of a crowd disaster?", "status": "open", "domain": "social-science", "systematic_gaps": [ "High-density crowd trajectory data from actual disaster events is rarely publicly available for calibration", "Real-time LiDAR-based crowd tracking systems with sufficient resolution for velocity correlation analysis have not been deployed at mass gathering venues", "The transition from ordered to turbulent flow has not been observed experimentally in a controlled high-density setting" ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-crowd-dynamics-panic-transitions.yaml" }, { "id": "u-cultural-drift-vs-selection-detection", "title": "How can we empirically distinguish cultural drift (neutral random variation) from cultural selection (adaptive adoption) in archaeological and digital cultural datasets, given that both produce power-law frequency distributions?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Most archaeological datasets have insufficient temporal resolution and spatial coverage to distinguish drift from selection using existing tests", "Digital cultural datasets (social media) have the resolution but lack longitudinal tracking of individual cultural \"lineages\" needed for Price equation decomposition", "The functional significance of archaeologically-tracked cultural variants (whether they affect fitness) is usually unknown, making selection coefficients unidentifiable from variant frequencies alone" ], "suggested_hypotheses": [ "h-price-equation-cultural-trait-frequency" ], "file": "unknowns-catalog/social-science/u-cultural-drift-vs-selection-detection.yaml" }, { "id": "u-cultural-evolution-rate-prediction", "title": "What determines the rate of cultural evolution, and can formal evolutionary models predict the speed and direction of cultural change?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The neutral model of cultural evolution (random cultural drift) is not consistently distinguishable from selection-driven change in empirical data.", "Gene-culture coevolution models are formally developed but empirically tested only for a few traits (lactase persistence, alcohol metabolism).", "Predicting which cultural variants will spread versus die out in advance has not been demonstrated reliably." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-cultural-evolution-rate-prediction.yaml" }, { "id": "u-dark-patterns-cognitive-bias-exploitation-measurement", "title": "Can the harm potential of dark pattern UI designs be quantified on a principled scale based on cognitive load theory and behavioral economics — and what is the causal effect of specific dark patterns on user decision quality and autonomy?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No randomized controlled trial has measured the causal effect of specific dark patterns on real-world financial harm (unauthorized subscriptions, data sharing decisions) in a nationally representative sample.", "A principled, psychologically-grounded harm scale for dark patterns (analogous to a toxicity dose-response curve) does not exist.", "Automated large-scale auditing of dark patterns across app stores has not been validated against human expert classification at sufficient precision for regulatory use." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-dark-patterns-cognitive-bias-exploitation-measurement.yaml" }, { "id": "u-democracy-stability-conditions", "title": "Under what economic, social, and institutional conditions is democracy stable, and what early warning indicators predict democratic backsliding?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Early warning indicators of democratic backsliding show high false-positive rates when tested prospectively.", "The relative importance of economic versus institutional factors in preventing backsliding is not established.", "Whether democratic backsliding is reversible after a certain point has not been studied systematically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-democracy-stability-conditions.yaml" }, { "id": "u-differential-privacy-utility-tight-bound", "title": "What is the tight tradeoff between privacy budget epsilon and statistical utility for high-dimensional queries, and can tight privacy-utility Pareto frontiers be computed efficiently for arbitrary query workloads beyond counting queries?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No general tight lower bound on utility loss for arbitrary high-dimensional query workloads under DP.", "The relationship between local DP and central DP in terms of achievable accuracy is not tight.", "Composition theorems for approximate DP (δ>0) are not tight in the multi-query regime." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-differential-privacy-utility-tight-bound.yaml" }, { "id": "u-economic-inequality-tipping-points", "title": "At what level of economic inequality do self-reinforcing mechanisms kick in to produce permanently elevated inequality, and can policy reverse this?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The causal relationship between inequality and political influence (the inequality trap) has not been established rigorously.", "Whether inequality is a cause or consequence of institutional quality is not resolved.", "Historical reductions in inequality (interwar period, 1945-1975) do not agree on which mechanisms drove the change." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-economic-inequality-tipping-points.yaml" }, { "id": "u-econophysics-wealth-distribution-mechanism", "title": "Do kinetic exchange econophysics models correctly identify the microscopic mechanism generating Pareto wealth distributions, or are emergent power laws coincidental fits requiring different causal explanations?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Kinetic exchange models have been fitted to cross-sectional data but not to longitudinal wealth dynamics at the individual level", "The Pareto exponent alpha varies across countries and time periods in ways the basic model cannot predict", "Alternative mechanisms (preferential attachment, returns-on-wealth heterogeneity) produce identical distributions" ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-econophysics-wealth-distribution-mechanism.yaml" }, { "id": "u-epigenetic-intergenerational-transmission-social-stress", "title": "To what extent are epigenetic modifications induced by social adversity (poverty, trauma, discrimination) transmitted to offspring via germline epigenetic inheritance in humans — and over how many generations do such marks persist?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Prospective multi-generational human cohort studies with genome-wide methylation data on parents AND children AND grandchildren have not been completed.", "The mechanism for escape from epigenetic reprogramming in the human germline has not been characterized for social-stress-induced methylation marks.", "Causal inference methods (Mendelian randomization, natural experiments) have not been applied to disentangle intergenerational epigenetic transmission from intergenerational environmental persistence of social adversity." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-epigenetic-intergenerational-transmission-social-stress.yaml" }, { "id": "u-fairness-impossibility-optimal-tradeoff", "title": "Given the mathematical impossibility of simultaneously satisfying demographic parity, equalized odds, and calibration, what principles should determine how to navigate the fairness-accuracy tradeoff in high-stakes algorithmic decisions?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No agreed framework exists for translating political-philosophy normative principles (Rawls, Sen, Dworkin) into algorithmic fairness criterion choices.", "The effect of long-run feedback loops (when a classifier's decisions affect future base rates) on fairness-accuracy tradeoffs over time is undercharacterized.", "Participatory approaches to determining the operating point (asking affected communities) have been proposed but not implemented at scale with rigorous outcome evaluation." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-fairness-impossibility-optimal-tradeoff.yaml" }, { "id": "u-gender-gap-stem-causes", "title": "What explains persistent gender gaps in STEM participation, and why do gaps vary so widely across countries, disciplines, and historical periods?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The gender equality paradox (larger gaps in more equal societies) has multiple proposed explanations none of which is empirically resolved.", "Stereotype threat effects in STEM have shown inconsistent replication across studies.", "The relative contribution of interests versus structural barriers to gender gaps cannot be causally disentangled." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-gender-gap-stem-causes.yaml" }, { "id": "u-genocide-early-warning-validity", "title": "Do genocide early warning systems have sufficient predictive validity and response time to enable preventive intervention?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The base rate of genocide is very low, making false positive rates extremely important and difficult to manage.", "Early warning systems have not been prospectively validated on out-of-sample cases with pre-registered predictions.", "The causal effectiveness of early warning + intervention in preventing genocide has not been established; most cases with warning signals do not receive effective intervention." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-genocide-early-warning-validity.yaml" }, { "id": "u-happiness-set-point", "title": "Do individuals have a hedonic set point that pulls subjective wellbeing back to baseline after life events, and can deliberate activities shift it permanently?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Panel attrition in longitudinal happiness studies is non-random, creating selection effects that bias estimates of adaptation.", "The measurement of subjective wellbeing by single survey items versus multi-item scales gives different adaptation patterns.", "Individual differences in adaptation rate are large but the predictors of slow versus fast adapters are poorly characterised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-happiness-set-point.yaml" }, { "id": "u-human-error-organizational-accident-boundary", "title": "Where exactly is the boundary between individual human error and organizational/ systemic causation in accidents, and can a quantitative model assign causal weight to each level (operator, team, organization, regulatory, societal) in a manner that is both empirically valid and legally operable?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No empirically validated quantitative model assigns causal weights across the Reason causal hierarchy", "Incident reporting systems (ASRS, ECORS) do not collect data sufficient to test Swiss Cheese predictions", "Legal attribution requirements (proximate vs. distal cause) are inconsistent with multifactorial accident causation", "Whether organizational culture change (HRO principles) causally reduces accident rate vs. confounded by safety investment" ], "suggested_hypotheses": [ "h-swiss-cheese-alignment-accident-prediction" ], "file": "unknowns-catalog/social-science/u-human-error-organizational-accident-boundary.yaml" }, { "id": "u-inequality-health-pathway", "title": "Does income inequality causally harm population health beyond individual poverty effects, and what are the specific pathways?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Cross-national ecological studies of inequality and health are confounded by correlated country characteristics (culture, institutions, welfare state generosity).", "Within-country studies using local inequality variation find smaller and less consistent effects than cross-national studies.", "The proposed biological mechanisms (chronic stress, cortisol, immune dysregulation) linking relative deprivation to health have not been established causally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-inequality-health-pathway.yaml" }, { "id": "u-institutional-trust-collapse", "title": "What mechanisms drive rapid collapses in institutional trust, and can early warning signs be identified before collapse occurs?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Long-run institutional trust data spanning different countries and institutional types is not comparable across measurement instruments.", "Causal identification of the specific mechanisms driving trust collapse is confounded by simultaneous changes in multiple factors.", "The relationship between measured trust and institutional behaviour (compliance, cooperation, voting) is not stable across contexts." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-institutional-trust-collapse.yaml" }, { "id": "u-intergroup-contact-prejudice-reduction", "title": "Under what conditions does intergroup contact reliably reduce prejudice, and can these conditions be engineered in diverse societies at scale?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The optimal contact conditions are theoretically specified but cannot be engineered reliably in real social settings.", "Meta-analytic effect sizes are inflated by publication bias and include very heterogeneous interventions.", "Long-term durability of contact-induced attitude change beyond the immediate contact situation is not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-intergroup-contact-prejudice-reduction.yaml" }, { "id": "u-matching-markets-dynamic-stability", "title": "Does the Gale-Shapley stable matching persist under dynamic entry/exit of agents, and what mechanism design principles govern real-time matching platforms (gig economy, ride-sharing)?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No polynomial-time algorithm is known for stable matching with dynamic arrivals under general preference structures.", "The welfare impact of dynamic vs. static mechanisms in real labor markets (NRMP, teacher placement) has not been empirically identified.", "Incentive compatibility in dynamic settings (where agents can strategically delay reporting preferences) has not been fully characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-matching-markets-dynamic-stability.yaml" }, { "id": "u-meme-channel-capacity-measurement", "title": "Can the channel capacity for cultural transmission be measured empirically for different media and idea types?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Empirical estimates of mutual information I(X;Y) between transmitted and received cultural variants across different transmission media (oral, written, video, social media) have not been systematically obtained.", "Whether cognitive attractors (Sperber) correspond to ideas with measurably higher channel capacity on the human cognitive channel has not been tested.", "The effect of social media algorithmic amplification on effective channel capacity (versus noise characteristics) has not been quantified information-theoretically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-meme-channel-capacity-measurement.yaml" }, { "id": "u-misinformation-correction-asymmetry", "title": "Why is misinformation often more persistent and spreadable than corrections, and what interventions reliably reduce its effects?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Meta-analyses of correction effectiveness show high heterogeneity; the conditions predicting successful correction are not established.", "Laboratory interventions for misinformation correction often fail to replicate or generalise to real-world misinformation.", "The relationship between misinformation exposure and actual belief change is measured inconsistently across studies." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-misinformation-correction-asymmetry.yaml" }, { "id": "u-moral-intuition-evolutionary-stability-mapping", "title": "Which moral intuitions (Haidt's foundations) map onto evolutionarily stable strategies in iterated social games, and what payoff structures predict the cross-cultural variation in their strength?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No formal derivation links each of Haidt's six moral foundations to a specific ESS or game-theoretic mechanism.", "Cross-cultural variation in moral foundation weights (WEIRD vs. non-WEIRD societies) has not been explained by network topology or relatedness variation.", "The evolutionary stability of costly sanctioning institutions (laws) vs. informal punishment norms is not modelled in the evolutionary game theory literature." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-moral-intuition-evolutionary-stability-mapping.yaml" }, { "id": "u-multilateral-cooperation-failure-modes", "title": "Why do multilateral cooperation arrangements fail for global commons problems, and what institutional designs are most robust to defection?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The relative effectiveness of different institutional design features (trade linkage, financial transfers, verification mechanisms) is not established across cooperation domains.", "Most international relations research on cooperation is case-based; quantitative comparative analysis across all major cooperation attempts is lacking.", "The role of domestic politics in determining a country's international cooperation behaviour is modelled separately from the international level but both levels interact." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-multilateral-cooperation-failure-modes.yaml" }, { "id": "u-network-centrality-temporal-dynamics-influence", "title": "How does temporal variation in social network structure (edge rewiring, link decay, node activity bursts) affect the validity of static centrality measures as predictors of influence, and what dynamic centrality metrics correctly capture time-varying social power?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No temporal centrality measure has been validated against empirical epidemic data with individual-level contact tracing at sufficient resolution to compare static vs. temporal centrality predictions for superspreader identification.", "The computational complexity of dynamic eigenvector centrality on large temporal networks (|V| > 10⁶, |E| > 10⁸) is prohibitive with current algorithms; approximate methods have not been benchmarked for validity.", "The relationship between temporal burstiness (inter-event time distribution P(τ) ∝ τ^(-α)) and the effective centrality ranking stability over time has not been derived analytically." ], "suggested_hypotheses": [ "On social networks with bursty contact patterns (α < 2 power-law inter-event times), static eigenvector centrality overestimates influence by a factor that grows as N^0.5, and a temporal PageRank (computed on the time-ordered edge stream) recovers predictive accuracy." ], "file": "unknowns-catalog/social-science/u-network-centrality-temporal-dynamics-influence.yaml" }, { "id": "u-network-formation-dynamic-stability-real-world", "title": "Do empirical social networks converge to the Nash-stable configurations predicted by Jackson-Wolinsky theory, and how does the Braess paradox manifest in real social and information networks?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No large-scale longitudinal test of Jackson-Wolinsky equilibrium predictions against real network formation data (e.g., co-authorship networks, friendship networks).", "Braess paradox in social networks (e.g., Slack channels, email lists) has not been systematically documented or measured.", "Dynamic network formation with heterogeneous agents and private information is analytically intractable — no results on equilibrium existence or uniqueness." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-network-formation-dynamic-stability-real-world.yaml" }, { "id": "u-opinion-dynamics-critical-homophily", "title": "Is there an empirically measurable critical homophily threshold in real social networks above which opinion distributions undergo a sharp transition from unimodal (pluralism) to bimodal (polarisation), and can this threshold be predicted from network topology using Ising model theory?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "The inverse Ising problem (inferring J_{ij} from opinion correlations) is computationally tractable only for small networks; scalable methods are needed.", "Natural experiments distinguishing the homophily hypothesis from the media-field hypothesis (increasing external field h rather than decreasing T) are lacking.", "Longitudinal data needed: measuring the same opinion network over decades to detect whether polarisation dynamics follow critical slowing-down signatures.", "Cross-national comparison of polarisation dynamics has not been mapped onto differences in estimated Ising parameters." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-opinion-dynamics-critical-homophily.yaml" }, { "id": "u-opinion-dynamics-empirical-calibration-social-media-networks", "title": "Can Ising/bounded-confidence opinion dynamics models be empirically calibrated to social media data (Twitter/X, Reddit), and do their predictions for polarization trajectories and consensus thresholds agree with observed political opinion distributions in longitudinal surveys?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Longitudinal panel studies with sufficient temporal resolution to fit opinion dynamics model parameters (daily or weekly opinion measurements over years).", "Empirical measurement of the confidence bound ε from experimental studies of opinion updating in response to information from ideologically distant sources.", "Quantitative comparison of opinion model predictions vs. long-term political polarization trends in multiple countries with different media environments.", "Network-theoretic extensions of bounded confidence models that account for scale-free topology, echo chambers, and algorithmic curation." ], "suggested_hypotheses": [ "The effective confidence bound ε inferred from Twitter/X retweet network homophily (probability of retweeting across partisan divide as proxy for interaction willingness) predicts the number of opinion clusters observed in Pew Research political polarization surveys within a factor of 2, validating the Deffuant-Weisbuch model as a quantitative predictor of polarization.\n" ], "file": "unknowns-catalog/social-science/u-opinion-dynamics-empirical-calibration-social-media-networks.yaml" }, { "id": "u-opinion-dynamics-phase-transition-prediction", "title": "Can Ising-model-based opinion dynamics models predict real-world political polarization tipping points, and what empirical observables correspond to the social \"temperature\" and \"coupling constant\"?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No empirical measure of \"social temperature\" T and \"coupling constant\" J has been validated against observed polarization outcomes across multiple societies and time periods.", "Critical slowing down (a universal precursor of phase transitions in physics) has been proposed as a social polarization warning signal but not tested in prospective studies.", "Network heterogeneity (scale-free social networks vs Ising lattice) changes the phase diagram qualitatively; most Ising-social models use unrealistic interaction geometries." ], "suggested_hypotheses": [ "The susceptibility of national opinion polls to small external perturbations (sudden news events) diverges near political polarization tipping points, analogous to Ising model divergence of magnetic susceptibility near T_c." ], "file": "unknowns-catalog/social-science/u-opinion-dynamics-phase-transition-prediction.yaml" }, { "id": "u-opioid-prescribing-policy-chemistry-disconnect", "title": "Why does pharmacological evidence about opioid receptor pharmacokinetics and tolerance mechanisms fail to translate into evidence-based prescribing policy, and how can this science-policy gap be closed?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Quantitative models linking receptor pharmacology (tolerance rate, respiratory depression threshold) to population prescribing outcomes have not been validated against epidemic data.", "The relative contributions of physician incentives, patient demand, and regulatory failure to opioid overprescribing have not been causally identified.", "Evidence-based criteria for Schedule I classification (grounded in receptor pharmacology and epidemiology) have never been formally operationalized in U.S. drug law." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-opioid-prescribing-policy-chemistry-disconnect.yaml" }, { "id": "u-political-polarisation-dynamics", "title": "What drives increasing political polarisation in democracies, and are online filter bubbles a primary cause or a symptom?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The relative contribution of social media versus economic and geographic factors to polarisation is not causally established.", "Polarisation in countries with different media ecosystems shows heterogeneous patterns not explained by any single theory.", "The feedback between elite polarisation and mass polarisation is not modelled dynamically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-political-polarisation-dynamics.yaml" }, { "id": "u-prediction-market-thin-market-accuracy-limits", "title": "What are the fundamental accuracy limits of prediction markets with thin trading, and can LMSR automated market makers with subsidized liquidity overcome the no-trade theorem in practice?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No theoretical characterization of prediction market accuracy as a function of trader population size, information heterogeneity, and LMSR subsidy b.", "Optimal combination of prediction markets with other forecasting methods (expert elicitation, model ensembles) has not been derived under a unified framework.", "The no-trade theorem's relevance to modern continuous-trading prediction markets (Metaculus, Polymarket) with real incentives has not been tested empirically." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-prediction-market-thin-market-accuracy-limits.yaml" }, { "id": "u-racial-achievement-gap-mechanisms", "title": "What are the causal mechanisms producing persistent racial achievement gaps in education, and which interventions most reliably close them?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The relative contribution of school quality versus neighbourhood environment versus family resources to the achievement gap is not causally identified.", "Stereotype threat effects on test performance have shown inconsistent replication.", "Interventions effective in controlled settings often fail to scale due to implementation heterogeneity." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-racial-achievement-gap-mechanisms.yaml" }, { "id": "u-replicator-equation-cultural-norm-stability", "title": "Can replicator equation dynamics explain the stability and collapse of cultural norms and social conventions, and when do multiple Nash equilibria coexist as persistent alternative cultures?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No large-scale cultural norm dataset has been fit to replicator equation dynamics", "The selection coefficient for cultural norm copying vs. independent evaluation is unmeasured", "How punishment and reputation systems affect replicator dynamics in human populations is not modelled" ], "suggested_hypotheses": [ "Cultural norm adoption follows S-curve (logistic) dynamics consistent with replicator equations when social learning is conformist-biased" ], "file": "unknowns-catalog/social-science/u-replicator-equation-cultural-norm-stability.yaml" }, { "id": "u-social-capital-measurement", "title": "What is the best way to measure social capital, and do different definitions (bonding, bridging, linking) have different effects on economic and social outcomes?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No agreed measurement instrument for social capital enables cross-national comparison with consistent validity.", "The causal effect of social capital on economic outcomes is confounded by common causes (culture, institutions, geography).", "Whether social capital is generative (communities create it) or inherited (path-dependent from historical institutions) has not been resolved." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-capital-measurement.yaml" }, { "id": "u-social-contagion-vs-homophily", "title": "For any given social behaviour, how much of its clustering in social networks is due to social influence (contagion) versus homophily (assortative mixing)?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No observational study design can perfectly distinguish contagion from homophily and latent variable confounding; the problem is mathematically underidentified without experimental variation.", "Natural experiments exploiting exogenous variation in network formation are rare and specific; generalisation is limited.", "Online social network studies measure self-reported tie formation which may not reflect the ties relevant for social influence." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-contagion-vs-homophily.yaml" }, { "id": "u-social-critical-temperature-empirical", "title": "Can the effective social temperature (disorder parameter in opinion Ising models) be empirically measured from large-scale social media data, and does it predict proximity to opinion cascade tipping points?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No validated method to extract effective Ising temperature from social media time series", "No prospective study testing susceptibility divergence before documented polarization events", "Social network topology effects on critical temperature not mapped to empirical data" ], "suggested_hypotheses": [ "h-social-critical-temperature-empirical" ], "file": "unknowns-catalog/social-science/u-social-critical-temperature-empirical.yaml" }, { "id": "u-social-learning-cultural-transmission-mechanisms", "title": "What cognitive and social mechanisms determine which learning biases (conformist, prestige, content-based) dominate cultural transmission in different contexts, and can population-genetic style models quantitatively predict cross-cultural variation in the stability of cooperative norms?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Natural experiments for measuring conformist bias are rare; most evidence comes from laboratory tasks that may not generalize to high-stakes cultural decisions", "The mapping between individual learning mechanism parameters and population-level cultural change rates requires agent-based modeling that is rarely validated against real data", "Cultural transmission rates vary with ecological context (low-mortality vs high-mortality environments) in ways not predicted by current models" ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-learning-cultural-transmission-mechanisms.yaml" }, { "id": "u-social-media-mental-health-causality", "title": "Does social media use causally increase depression, anxiety, and loneliness in adolescents, and which usage patterns are most harmful?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Natural experiments (Facebook rollout, platform outages) show heterogeneous and often null effects on mental health outcomes.", "The mechanism (social comparison, sleep displacement, cyberbullying, algorithmic amplification) for any harm is not established.", "Effect sizes in longitudinal studies are small (r~0.05) and may not be practically significant even if causal." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-media-mental-health-causality.yaml" }, { "id": "u-social-mobility-measurement", "title": "How should intergenerational social mobility be measured, and what policies reliably increase it across different national contexts?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Different mobility measures give different rankings of countries and different trend assessments; no agreed measure exists.", "The causal pathways from parental income to child outcomes (neighbourhood, school quality, social networks, cultural capital) have not been individually isolated.", "Policies shown to increase mobility in one country often fail to replicate in another." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-mobility-measurement.yaml" }, { "id": "u-social-norm-cascade-tipping-points", "title": "What are the tipping point conditions under which social norms rapidly cascade through populations, and can they be predicted in advance?", "status": "open", "domain": "social-science", "systematic_gaps": [ "No validated early warning indicator of social norm tipping points has been demonstrated prospectively.", "The minimum committed minority fraction required to trigger norm cascade varies widely across empirical cases.", "Online norm change does not reliably predict offline norm change." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-social-norm-cascade-tipping-points.yaml" }, { "id": "u-stereotype-formation-persistence", "title": "How do group stereotypes form, persist, and spread, and under what conditions do accurate versus inaccurate stereotypes prevail?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Measuring stereotype accuracy requires agreed criteria for which group differences are real versus artefactual, which is itself contested.", "The social transmission dynamics of stereotypes in networks have not been formally modelled with empirical validation.", "The conditions under which stereotype correction interventions generalise from laboratory to field are not established." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-stereotype-formation-persistence.yaml" }, { "id": "u-strategic-voting-frequency-real-elections-empirical-magnitude", "title": "What fraction of voters in real elections with plurality or ranked-choice voting vote strategically (not according to their true first preference), what is the net electoral effect of strategic voting on outcomes, and does the Gibbard-Satterthwaite theorem's prediction of universal manipulability manifest at empirically relevant rates?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No dataset combines true preference rankings (from conjoint surveys) with actual ballot choices at scale, preventing direct measurement of strategic voting frequency.", "The effect of ballot information (whether voters know aggregate preference distribution) on strategic voting rate has not been studied with real electoral stakes.", "Comparison of strategic voting rates across voting systems (plurality, RCV, approval, score) using pre-election preference surveys and post-election ballot analysis has not been done in a controlled way.", "Whether strategic voting is individually rational at the individual level (low probability of being pivotal) is resolved theoretically (often not worth it) but contradicts observed behaviour." ], "suggested_hypotheses": [ "h-approval-voting-reduces-strategic-manipulation-vs-plurality" ], "file": "unknowns-catalog/social-science/u-strategic-voting-frequency-real-elections-empirical-magnitude.yaml" }, { "id": "u-traffic-jam-phantom-formation-threshold", "title": "What is the exact critical density threshold rho_c at which phantom traffic jams spontaneously form from uniform flow, and how does this threshold depend on driver behavioral parameters (reaction time, following distance preferences)?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "No first-principles derivation of the fundamental diagram from microscopic driver behavior.", "The transition between free-flow and synchronized flow (Kerner three-phase theory) lacks microscopic explanation.", "Phantom jam nucleation probability (below rho_c) from rare large fluctuations is not quantified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-traffic-jam-phantom-formation-threshold.yaml" }, { "id": "u-trust-network-scale", "title": "How does interpersonal trust scale from dyadic to community to institutional levels, and when does network structure facilitate or undermine trust formation?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The mapping from interpersonal network structure to generalised social trust (trusting strangers) has no agreed theoretical mechanism.", "Cross-cultural trust measurement using experimental games (trust game, public goods) versus surveys gives divergent results.", "The threshold at which network structure shifts from trust-enabling to trust-fragile is not identified." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-trust-network-scale.yaml" }, { "id": "u-urban-segregation-self-reinforcement", "title": "To what degree does residential racial and economic segregation self-reinforce through school quality, social networks, and political power?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The relative contribution of taste-based discrimination, economic sorting, and political mechanisms to sustained segregation is not causally identified.", "The conditions under which desegregation policies succeed versus fail are not predictable from current theory.", "Segregation dynamics in cities with different housing market structures have not been compared in a unified framework." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-urban-segregation-self-reinforcement.yaml" }, { "id": "u-voter-model-zealots-persistent-minorities", "title": "In voter models with zealots (committed agents who never change opinion), what fraction of committed minority advocates is sufficient to shift consensus in heterogeneous social networks, and how does network community structure modulate this tipping threshold?\n", "status": "open", "domain": "social-science", "systematic_gaps": [ "Analytical solution of voter model with zealots on arbitrary random graphs", "Empirical measurement of zealot fraction in real social movements", "Optimal seeding strategies for committed minorities in modular networks", "Connection to social influence experiments and online platform dynamics" ], "suggested_hypotheses": [ "h-network-community-structure-drives-polarization" ], "file": "unknowns-catalog/social-science/u-voter-model-zealots-persistent-minorities.yaml" }, { "id": "u-war-onset-prediction", "title": "What variables most reliably predict the onset of interstate and civil wars, and do existing models generalise across historical periods and regions?", "status": "open", "domain": "social-science", "systematic_gaps": [ "Conflict prediction models trained on pre-2000 data perform poorly on post-2000 conflicts; the conflict landscape has changed in ways not captured by traditional variables.", "The distinction between variables that are genuine causes versus indicators (epiphenomena) of conflict is not established.", "Civil war and interstate war are modelled separately but their interaction (spillover, proxy conflicts) is poorly theorised." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-war-onset-prediction.yaml" }, { "id": "u-wisdom-of-crowds-condorcet", "title": "Under what conditions does social influence in online crowds irreversibly destroy collective accuracy, and is there a critical correlation threshold above which crowd wisdom collapses?", "status": "open", "domain": "social-science", "systematic_gaps": [ "The critical correlation threshold ρ* above which crowd accuracy falls below single-expert accuracy has not been analytically derived for fat-tailed individual estimate distributions.", "Whether sequential exposure to others' estimates increases ρ proportionally to the average displayed rating or only to the first few ratings seen (primacy effect) is unknown from behavioral experiments.", "Platform design interventions (anonymized ratings, delayed display, diverse ordering) have not been tested in controlled experiments for their effect on ρ." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science/u-wisdom-of-crowds-condorcet.yaml" }, { "id": "u-homophily-echo-chamber-causality", "title": "Does social network homophily causally produce echo chambers and political polarization, or do pre-existing attitude differences drive both homophily and polarization simultaneously?", "status": "open", "domain": "social-science-network-science", "systematic_gaps": [ "Large-scale field experiments randomly assigning network structure (homophilous vs heterophilous recommendations) and measuring downstream belief change are lacking.", "The mechanism of echo chamber effects (selective exposure, social proof, algorithmic amplification) has not been disentangled.", "Cross-platform comparisons of assortativity coefficients and their correlations with offline polarization across countries are limited." ], "suggested_hypotheses": [], "file": "unknowns-catalog/social-science-network-science/u-homophily-echo-chamber-causality.yaml" }, { "id": "u-social-capital-causal-vs-correlational", "title": "Whether network centrality measures (betweenness, eigenvector) causally determine socioeconomic outcomes or merely correlate with them, and whether targeted network interventions can increase social mobility by changing individuals' centrality positions\n", "status": "open", "domain": "social-science-network-science", "systematic_gaps": [ "Most social capital research is observational; causal identification requires network experiments (randomised introductions, natural experiments in network formation) that are rare and ethically constrained.", "Selection effects -- high-centrality individuals may achieve high-centrality positions because they have underlying traits (social skills, resources) that independently drive outcomes; the network position may be a proxy, not a cause.", "Chetty et al. (2022) used Facebook friendship data to show that cross-class friendships (friending bias) predict upward income mobility causally — the largest network science study of social capital — but mechanisms are debated.", "Interventions designed to increase betweenness centrality (community bridge-building programmes) have limited evidence for effectiveness at scale." ], "suggested_hypotheses": [ "h-structural-holes-income-mobility-mediation" ], "file": "unknowns-catalog/social-science-network-science/u-social-capital-causal-vs-correlational.yaml" }, { "id": "u-colloidal-glass-transition-mode-coupling-breakdown", "title": "Why does mode-coupling theory (MCT) predict the colloidal glass transition at phi_MCT ~ 0.516 while experiments show phi_glass ~ 0.58-0.64, and what physical mechanism — activated hopping, cooperative rearrangements, or structural heterogeneity — controls the glass transition above phi_MCT?\n", "status": "open", "domain": "soft-matter", "systematic_gaps": [ "Direct measurement of the dynamic lengthscale (point-to-set correlations, multi-point susceptibility chi_4) as a function of phi has not been done with sufficient statistics to distinguish RFOT from facilitation theory.", "The crossover from MCT-like power-law relaxation to activated (stretched-exponential) dynamics at phi ~ phi_MCT has not been characterised with particle-resolved tracking at sufficient temporal resolution.", "The effect of polydispersity (prevents crystallisation in experiments but absent from MCT theory) on the glass transition phi_glass has not been systematically isolated from the dynamic arrest mechanism." ], "suggested_hypotheses": [ "The dynamic heterogeneity lengthscale xi_4 in hard-sphere colloids grows as xi_4 ~ (phi_glass - phi)^{-nu} with nu ~ 0.5-1.0 above phi_MCT, distinguishable between RFOT (nu ~ 0.5) and facilitation theory (nu ~ 1.0) predictions by confocal microscopy 4-point correlation function measurements.\n" ], "file": "unknowns-catalog/soft-matter/u-colloidal-glass-transition-mode-coupling-breakdown.yaml" }, { "id": "u-jamming-transition-universality-class", "title": "Does the jamming transition in frictionless sphere packings belong to the same universality class as mean-field percolation, and how do friction, asphericity, and polydispersity alter the critical exponents and diverging length scale near phi_J?", "status": "open", "domain": "soft-matter", "systematic_gaps": [ "Experimental measurement of the diverging length scale xi in 3D granular packings near phi_J is technically challenging due to boundary effects", "Simulation studies are mostly 2D or use frictionless spheres; realistic 3D frictional polydisperse packings require larger computational effort", "The connection between jamming and the glass transition in thermally activated systems is not resolved by current field-theoretic approaches" ], "suggested_hypotheses": [], "file": "unknowns-catalog/soft-matter/u-jamming-transition-universality-class.yaml" }, { "id": "u-spatial-autocorrelation-economic-convergence-causality", "title": "Does high Moran's I spatial autocorrelation in regional income cause income divergence (reinforcing inequality via agglomeration), or does divergence cause high autocorrelation (sorting of high-productivity workers into high-income regions) — and can the Krugman bifurcation point be identified empirically from the trajectory of spatial autocorrelation statistics?\n", "status": "open", "domain": "spatial-economics", "systematic_gaps": [ "Causal identification of spatial autocorrelation → divergence vs. sorting → autocorrelation using exogenous transport cost shocks has not been done with sufficient power.", "Pre-bifurcation early-warning signals (critical slowing down in Moran's I autocorrelation time series, analogous to ecological tipping point detection) have not been applied to regional income data.", "The relationship between Moran's I and the spatial lag parameter rho in econometric models has not been systematically empirically mapped across different spatial scales and governance regimes." ], "suggested_hypotheses": [ "The trajectory of Moran's I for regional GDP in EU NUTS-3 regions (1990-2020) shows critical slowing down (increasing lag-1 autocorrelation of the Moran's I time series) prior to the post-2008 divergence episode — testable as an early-warning indicator of the Krugman bifurcation.\n" ], "file": "unknowns-catalog/spatial-economics/u-spatial-autocorrelation-economic-convergence-causality.yaml" }, { "id": "u-bayesian-dropout-trial-decision-calibration-gap", "title": "Can dropout-based uncertainty be calibrated sufficiently for adaptive trial stopping decisions?", "status": "open", "domain": "statistics", "systematic_gaps": [ "Few head-to-head comparisons with validated Bayesian monitoring designs.", "Limited analysis of operating characteristics under delayed outcomes.", "Regulatory-ready calibration procedures are not standardized." ], "suggested_hypotheses": [ "h-bayesian-dropout-uncertainty-improves-adaptive-trial-decisions" ], "file": "unknowns-catalog/statistics/u-bayesian-dropout-trial-decision-calibration-gap.yaml" }, { "id": "u-bayesian-phase-transition-learning", "title": "Do real machine learning models undergo sharp phase transitions in generalization analogous to the thermodynamic underfitting-overfitting transition?", "status": "open", "domain": "statistics", "systematic_gaps": [ "Whether double descent corresponds to a thermodynamic phase transition in the posterior (Bayesian) or only in the minimum-norm interpolant (frequentist) has not been resolved.", "The replica calculation applies to random feature models; its validity for structured feature distributions (real language or image data) is untested." ], "suggested_hypotheses": [], "file": "unknowns-catalog/statistics/u-bayesian-phase-transition-learning.yaml" }, { "id": "u-cryoem-bayesian-map-calibration-across-platforms", "title": "How comparable are Bayesian posterior widths reported by different cryo-EM software stacks when processing identical particle stacks — especially prior choices affecting MAP versus sampled volumes?", "status": "open", "domain": "statistics", "systematic_gaps": [ "Round-robin uncertainty challenges akin to ML benchmarking competitions but with frozen electron-microscopy datasets", "Ground-truth phantom volumes at noise levels representative of experimental acquisitions for calibration auditing" ], "suggested_hypotheses": [ "h-cryoem-bayesian-x-single-particle-reconstruction" ], "file": "unknowns-catalog/statistics/u-cryoem-bayesian-map-calibration-across-platforms.yaml" }, { "id": "u-elastic-net-prior-calibration-under-correlated-designs", "title": "How should elastic-net mixing parameters be calibrated as composite Laplace-Gaussian prior scales when predictors are strongly correlated and scientific interpretation depends on selected groups?\n", "status": "open", "domain": "statistics", "systematic_gaps": [ "Benchmarks comparing predictive error, selection stability, and prior-scale interpretability.", "Domain-specific guidance for correlated biological, imaging, and economic features." ], "suggested_hypotheses": [ "h-mixing-parameter-matches-posterior-sparsity-stability-curves" ], "file": "unknowns-catalog/statistics/u-elastic-net-prior-calibration-under-correlated-designs.yaml" }, { "id": "u-posterior-landscape-multimodality", "title": "How does multimodality in the posterior distribution arise in Bayesian inference for high-dimensional models, and what sampling methods reliably explore it?", "status": "open", "domain": "statistics", "systematic_gaps": [ "No diagnostic reliably detects failure of MCMC to explore all posterior modes without knowing the true posterior.", "Theoretical conditions on likelihood/prior structure that guarantee posterior unimodality are available only for restricted model classes (log-concave).", "The connection between posterior landscape geometry (energy barriers) and the capacity of parallel tempering to mix between modes is not quantitatively understood." ], "suggested_hypotheses": [ "h-variational-bayes-mean-field-equivalence" ], "file": "unknowns-catalog/statistics/u-posterior-landscape-multimodality.yaml" }, { "id": "u-ridge-as-gaussian-map-prior-identifiability", "title": "When does cross-validated ridge λ carry a coherent Bayesian interpretation under model mismatch and heavy-tailed true coefficients?", "status": "open", "domain": "statistics", "systematic_gaps": [ "Empirical comparison of ridge CI coverage versus full Bayes under scientific small-n settings.", "Sparsity vs L2 tradeoffs in ill-posed inverse problems are often chosen ad hoc." ], "suggested_hypotheses": [ "h-ridge-penalty-matches-bayesian-width-in-neural-decoding" ], "file": "unknowns-catalog/statistics/u-ridge-as-gaussian-map-prior-identifiability.yaml" }, { "id": "u-catalytic-converter-cold-start-mitigation-strategies", "title": "What are the most cost-effective strategies to eliminate the cold-start emission spike (responsible for ~80% of vehicle emissions per trip) for both conventional and hybrid powertrains as electrification penetrates the fleet?\n", "status": "open", "domain": "surface-chemistry", "systematic_gaps": [ "PNA and HC trap performance under real-world driving conditions (variable temperature, humidity, aging) has not been fully characterized over 150,000 mile lifetimes.", "The economic break-even point between EHC electricity cost and avoided emission penalties has not been systematically analyzed across markets and regulatory regimes.", "Cold-start strategies for hybrid vehicles with prolonged engine-off periods are not standardized or optimized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/surface-chemistry/u-catalytic-converter-cold-start-mitigation-strategies.yaml" }, { "id": "u-crispr-hdr-efficiency-post-mitotic-cells", "title": "Why is homology-directed repair (HDR) efficiency <1% in post-mitotic neurons, cardiomyocytes, and skeletal muscle cells following CRISPR-Cas9 DSBs, and can prime editing or base editing fully bypass this constraint to enable therapeutic gene correction in non-dividing tissues?\n", "status": "open", "domain": "synthetic-biology", "systematic_gaps": [ "The cell-cycle dependence of prime editing vs. ABE/CBE base editing in the same isogenic cell lines (dividing vs. arrested at G0 vs. differentiated post-mitotic) has not been systematically compared.", "The role of mismatch repair (MLH1 suppression in PE5max) in post-mitotic cells is unknown — MMR activity may differ in terminally differentiated cells.", "In vivo AAV-delivered prime editing efficiency for cardiomyocytes and neurons has not been directly compared to ex vivo data with matched pegRNA designs." ], "suggested_hypotheses": [ "Prime editing efficiency in post-mitotic cardiomyocytes is limited by competition from the MMR pathway recognizing the 3′ flap as a mismatch substrate; co-delivery of dominant-negative MLH1 (as in PE6 system) will increase prime editing efficiency ≥5-fold in post-mitotic CMs to >20%, enabling therapeutic correction of LMNA point mutations.\n" ], "file": "unknowns-catalog/synthetic-biology/u-crispr-hdr-efficiency-post-mitotic-cells.yaml" }, { "id": "u-genetic-circuit-crosstalk-noise", "title": "How does molecular crosstalk and stochastic gene expression noise limit the complexity and reliability of engineered genetic circuits in living cells?", "status": "open", "domain": "synthetic-biology", "systematic_gaps": [ "No comprehensive crosstalk matrix for common synthetic biology transcription factor libraries has been measured experimentally.", "The scaling of circuit noise with circuit complexity (number of interacting parts) has not been systematically characterized in bacteria or mammalian cells.", "Methods to quantify metabolic burden of circuit expression in real time, to enable adaptive feedback control of resource allocation, are not available." ], "suggested_hypotheses": [ "h-biological-computing-turing-completeness" ], "file": "unknowns-catalog/synthetic-biology/u-genetic-circuit-crosstalk-noise.yaml" }, { "id": "u-retroactivity-insulation-genetic-circuits", "title": "Can retroactivity (impedance-mismatch loading effects between genetic circuit modules) be sufficiently attenuated by biological insulator modules to enable reliable large-scale genetic circuit composition?", "status": "open", "domain": "synthetic-biology", "systematic_gaps": [ "Quantitative measurement of retroactivity in vivo across different circuit types and organism chassis is sparse.", "The metabolic cost of insulator modules and its effect on host cell fitness has not been systematically characterized.", "No large-scale synthetic genetic circuit (>20 modules) has been demonstrated to function as designed, making it unknown whether retroactivity is the limiting factor." ], "suggested_hypotheses": [], "file": "unknowns-catalog/synthetic-biology/u-retroactivity-insulation-genetic-circuits.yaml" }, { "id": "u-rna-folding-planar-pseudoknot-limits", "title": "Which biological RNAs require pseudoknot representations beyond planar DP, and how often do planar approximations distort functional predictions?", "status": "open", "domain": "synthetic-biology", "systematic_gaps": [ "Benchmarks disproportionately sample short sequences; long-range contacts challenge planar models.", "Co-transcriptional folding kinetics are not captured by static energy minimization." ], "suggested_hypotheses": [ "h-nussinov-energy-approximates-planar-graph-parsimony" ], "file": "unknowns-catalog/synthetic-biology/u-rna-folding-planar-pseudoknot-limits.yaml" }, { "id": "u-synthetic-biology-chassis-orthogonality", "title": "Can a fully orthogonal genetic chassis be engineered that runs synthetic gene circuits without crosstalk with host transcription/translation machinery?", "status": "open", "domain": "synthetic-biology", "systematic_gaps": [ "The minimum set of host resources that must remain shared (e.g., metabolism, membrane maintenance) vs. those that can be made orthogonal has not been determined.", "Fitness costs of running parallel orthogonal and endogenous machinery are not characterized over evolutionary timescales." ], "suggested_hypotheses": [], "file": "unknowns-catalog/synthetic-biology/u-synthetic-biology-chassis-orthogonality.yaml" }, { "id": "u-boolean-grn-criticality-empirical-tests", "title": "Do empirical mammalian gene regulatory networks operate near Kauffman-style critical points once asynchronous stochastic dynamics replace synchronous Booleans?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Perturbation datasets resolving cascades at minute-scale temporal resolution across hundreds of genes jointly", "Mapping discrete Boolean abstraction errors onto quantitative drift-diffusion limits for transcription" ], "suggested_hypotheses": [ "h-kauffman-boolean-x-gene-network-attractor-stability" ], "file": "unknowns-catalog/systems-biology/u-boolean-grn-criticality-empirical-tests.yaml" }, { "id": "u-cost-matrix-misspecification-in-optimal-transport-lineage-maps", "title": "When does cost-function misspecification make `b-optimal-transport-x-single-cell-developmental-lineage-mapping` biologically misleading?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Few studies report sensitivity analyses over biologically plausible transport costs.", "Cross-dataset reproducibility of inferred couplings is inconsistently audited." ], "suggested_hypotheses": [ "h-optimal-transport-lineage-couplings-improve-fate-prediction-calibration" ], "file": "unknowns-catalog/systems-biology/u-cost-matrix-misspecification-in-optimal-transport-lineage-maps.yaml" }, { "id": "u-coupling-topology-thresholds-for-beta-cell-synchrony-collapse", "title": "What validation boundary conditions determine when `b-kuramoto-synchrony-x-beta-cell-islet-oscillations` remains decision-useful?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-grid-inspired-phase-coherence-metrics-predict-beta-cell-dysfunction-earlier" ], "file": "unknowns-catalog/systems-biology/u-coupling-topology-thresholds-for-beta-cell-synchrony-collapse.yaml" }, { "id": "u-latent-space-collapse-risks-in-single-cell-vae-models", "title": "Under which noise regimes does `b-variational-autoencoders-x-single-cell-latent-state-denoising` suffer latent collapse?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Collapse diagnostics are not standardized across single-cell model toolchains.", "Few benchmarks link latent collapse to downstream biological decision errors." ], "suggested_hypotheses": [ "h-beta-vae-regularization-improves-single-cell-state-separability" ], "file": "unknowns-catalog/systems-biology/u-latent-space-collapse-risks-in-single-cell-vae-models.yaml" }, { "id": "u-mca-global-sensitivity-beyond-log-linear", "title": "When metabolic steady states leave log-linear neighborhoods of MCA elasticity definitions, which global sensitivity methods (Sobol, DGSM) recover comparable biological insights without elasticity breakdown artifacts?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Benchmark suites coupling genome-scale kinetic models with global sensitivity estimates across clinically relevant inhibition strengths", "Translation guides connecting MCA outputs to pharmacologist-friendly dose-response summaries without double-counting correlations" ], "suggested_hypotheses": [ "h-metabolic-control-analysis-x-local-sensitivity" ], "file": "unknowns-catalog/systems-biology/u-mca-global-sensitivity-beyond-log-linear.yaml" }, { "id": "u-simclr-multiomics-batch-effect-collapse-risk", "title": "Under what conditions does contrastive multi-omics alignment collapse biological signal into batch-driven structure?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Insufficient perturbation-ground-truth datasets for causally meaningful validation.", "Current metrics underweight rare-cell and low-abundance signal retention.", "Few comparisons against mechanistic latent-variable baselines on deployment-like shifts." ], "suggested_hypotheses": [ "h-contrastive-pretraining-improves-multiomics-transfer-stability" ], "file": "unknowns-catalog/systems-biology/u-simclr-multiomics-batch-effect-collapse-risk.yaml" }, { "id": "u-spectral-cluster-stability-metabolomics-batch-effects", "title": "How stable are spectral-clustered metabolite modules to batch-effect perturbations of empirical similarity graphs across cohorts and instrument drift?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "Few studies report eigen-gap bootstrap distributions alongside biological interpretation claims.", "Limited integration of compositional data transforms before spectral embedding choices.", "Sparse cross-site replication of module assignments with identical preprocessing contracts." ], "suggested_hypotheses": [ "h-graph-laplacian-regularization-improves-module-replicability" ], "file": "unknowns-catalog/systems-biology/u-spectral-cluster-stability-metabolomics-batch-effects.yaml" }, { "id": "u-transport-cost-selection-in-cross-platform-multiomic-alignment", "title": "What failure boundaries determine when `b-optimal-transport-barycenters-x-multiomic-patient-alignment` remains decision-useful?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "No shared benchmark isolates transfer gains from domain-specific confounders.", "Calibration drift under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-ot-barycenter-alignment-improves-cross-cohort-multiomic-risk-stratification" ], "file": "unknowns-catalog/systems-biology/u-transport-cost-selection-in-cross-platform-multiomic-alignment.yaml" }, { "id": "u-validity-limits-of-adiabatic-elimination-in-noisy-gene-circuits", "title": "What validation boundary conditions determine when `b-adiabatic-elimination-x-gene-circuit-model-reduction` remains decision-useful?", "status": "open", "domain": "systems-biology", "systematic_gaps": [ "No shared benchmark dataset cleanly isolates transfer gains and failure modes.", "Uncertainty calibration under distribution shift is inconsistently reported." ], "suggested_hypotheses": [ "h-adiabatic-elimination-preserves-switching-time-statistics-in-gene-circuit-surrogates" ], "file": "unknowns-catalog/systems-biology/u-validity-limits-of-adiabatic-elimination-in-noisy-gene-circuits.yaml" }, { "id": "u-persistent-homology-noise-thresholds", "title": "What statistical criteria distinguish topologically significant features from noise in persistent homology, and how do these criteria scale with dataset size?", "status": "open", "domain": "topology", "systematic_gaps": [ "No systematic study of statistical power for persistent homology as a function of (sample size, embedding dimension, noise level) has been published.", "The appropriate null hypothesis for persistent homology in neural data is not established; the most common null (random rotation of data) does not preserve trial structure." ], "suggested_hypotheses": [], "file": "unknowns-catalog/topology/u-persistent-homology-noise-thresholds.yaml" }, { "id": "u-topological-order-non-abelian-anyons-fault-tolerant", "title": "Can non-Abelian anyons (e.g. Majorana zero modes in topological superconductors or ν=5/2 FQH states) be reliably braided to perform fault-tolerant quantum gates, and does the topological protection survive realistic disorder, finite-temperature effects, and leakage out of the anyon subspace?\n", "status": "open", "domain": "topology", "systematic_gaps": [ "No experiment has demonstrated non-Abelian braiding statistics; all current evidence for Majorana modes is indirect (zero-bias conductance peaks).", "The minimum topological gap needed for fault-tolerant operation at a given temperature has not been calculated including realistic disorder effects.", "Leakage error rates for braiding protocols have not been measured experimentally." ], "suggested_hypotheses": [], "file": "unknowns-catalog/topology/u-topological-order-non-abelian-anyons-fault-tolerant.yaml" }, { "id": "u-hott-univalence-axiom-computational-interpretation", "title": "What is the computational interpretation of the Univalence Axiom in Homotopy Type Theory — does it have a constructive proof term, and can HoTT be given a complete computational semantics that makes the axiom provable rather than assumed?\n", "status": "open", "domain": "type-theory", "systematic_gaps": [ "The computational content of the Univalence Axiom (what does running a program of type UA look like?) is not defined in standard HoTT.", "The relationship between Cubical Type Theory and the simplicial set model (canonicity, initiality) is not fully proved.", "Whether univalence can be added to proof assistants without breaking definitional equality (which is required for efficient type checking) is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/type-theory/u-hott-univalence-axiom-computational-interpretation.yaml" }, { "id": "u-urban-biodiversity-governance-regime-causality", "title": "Does polycentric urban governance causally increase urban biodiversity and ecosystem service delivery relative to centralised or fragmented governance, and what governance design features (scale-matching, monitoring, sanctions, polycentrism) drive differences in urban green infrastructure outcomes?\n", "status": "open", "domain": "urban-ecology", "systematic_gaps": [ "Quasi-experimental evaluation of urban governance regime changes (municipal boundary reorganisation, new community stewardship programmes) on biodiversity and ecosystem service delivery has not been conducted with adequate controls.", "The interaction between income inequality (luxury effect) and governance quality on urban biodiversity has not been disentangled — whether governance quality mediates the income-biodiversity relationship is unknown.", "Long-term monitoring of polycentric governance experiments (e.g., NYC Stewardship Network, London Urban Forest Partnerships) with before-after control-impact design is lacking." ], "suggested_hypotheses": [ "Cities with >3 active neighbourhood-level green infrastructure stewardship programmes per km² show 25% higher urban tree canopy persistence over 10 years compared to matched cities with centralised parks management only, controlling for total green infrastructure investment — testable using remote sensing time series and governance database matched-pair analysis.\n" ], "file": "unknowns-catalog/urban-ecology/u-urban-biodiversity-governance-regime-causality.yaml" }, { "id": "u-smart-city-equity-algorithmic-routing", "title": "How can smart city traffic and resource optimization algorithms be designed to satisfy both system efficiency objectives and distributional equity constraints across neighborhoods?", "status": "open", "domain": "urban-science", "systematic_gaps": [ "No published smart city deployment has prospectively measured demographic distributional impacts of algorithmic traffic routing at fine spatial resolution.", "The tradeoff between system efficiency and equity (Pareto frontier) has not been empirically characterized for any real urban network.", "Participatory mechanisms for residents to express preferences and constraints within city optimization frameworks do not exist at production scale." ], "suggested_hypotheses": [], "file": "unknowns-catalog/urban-science/u-smart-city-equity-algorithmic-routing.yaml" }, { "id": "u-urban-heat-islands", "title": "What is the relative contribution of albedo, green infrastructure, anthropogenic heat, and sky view factor to urban heat island intensity across different city morphologies and climate zones?", "status": "open", "domain": "urban-science", "systematic_gaps": [ "No study has directly measured all four SEB components (QH, QE, QG, QA) for the same city using eddy covariance, isotopic tracing, and remote sensing simultaneously.", "The marginal effectiveness of green infrastructure for UHI reduction is well-established in humid climates but poorly quantified in dryland cities where irrigation effects may exceed or negate cooling benefits.", "Future UHI projections under climate change require coupled urban canopy models in regional climate models, but Urban Canopy Model parametrizations are not validated across diverse cities." ], "suggested_hypotheses": [], "file": "unknowns-catalog/urban-science/u-urban-heat-islands.yaml" }, { "id": "u-urban-scaling-law-exponent-inequality-cultural-variation", "title": "Does the urban superlinear scaling exponent β ≈ 1.15 vary systematically with national inequality (Gini coefficient), urban planning regime, or transportation technology, and can deviations from β = 1.15 be used to identify cities that are underperforming or overperforming their interaction-based potential?", "status": "open", "domain": "urban-science", "systematic_gaps": [ "Cross-national comparison of β controlling for measurement heterogeneity (GDP definition, city boundary definitions, data quality) has not been conducted with sufficient rigour to establish whether β variation is real or methodological.", "The post-COVID change in β for patent and innovation outputs (due to remote work shifting knowledge spillovers out of physical proximity) has not been measured; this is a natural experiment for the interaction-network theory of scaling.", "Prediction of β from measured road network fractal dimension d_f has not been validated across cities with sufficiently varied d_f (gridded US cities vs. organic European cities vs. high-density Asian cities)." ], "suggested_hypotheses": [ "Urban superlinear scaling exponent β is inversely related to city Gini coefficient — β decreases by ~0.03 per 0.1 increase in Gini, because high inequality concentrates innovation in a small elite subnetwork that scales sub-linearly (the inequality-corrected scaling theory predicts β_effective = 1 + 2/d_f × (1 - Gini)).\n" ], "file": "unknowns-catalog/urban-science/u-urban-scaling-law-exponent-inequality-cultural-variation.yaml" }, { "id": "u-urban-segregation-phase-diagram", "title": "What is the full phase diagram of the Schelling segregation model as a function of tolerance threshold, density, and neighborhood size?", "status": "open", "domain": "urban-science", "systematic_gaps": [ "The Schelling phase diagram has not been mapped in the full (tolerance, density, neighborhood-size) parameter space.", "The role of network topology (lattice vs. small-world vs. scale-free) on the segregation phase transition has not been systematically characterized." ], "suggested_hypotheses": [], "file": "unknowns-catalog/urban-science/u-urban-segregation-phase-diagram.yaml" }, { "id": "u-protein-language-model-viral-escape-epistasis-misspecification", "title": "Do protein language-model priors mis-specify epistatic interactions in viral escape forecasting?", "status": "open", "domain": "virology", "systematic_gaps": [ "Limited standardized calibration benchmarks under realistic distribution shift.", "Sparse prospective evaluations against established domain baselines.", "Under-specified uncertainty reporting for high-impact operational decisions." ], "suggested_hypotheses": [ "h-protein-language-model-priors-improve-viral-escape-forecasting" ], "file": "unknowns-catalog/virology/u-protein-language-model-viral-escape-epistasis-misspecification.yaml" }, { "id": "u-quasispecies-fitness-landscape-mapping", "title": "What is the structure of the fitness landscape for RNA viruses, and how does landscape ruggedness determine the error threshold and the evolutionary accessibility of drug resistance?", "status": "open", "domain": "virology", "systematic_gaps": [ "Complete fitness landscapes are only available for small proteins (< 200 aa); viral replicases are too large for full DMS", "Epistasis (interaction between mutations) is poorly characterized for RNA virus polymerases", "The mapping from in vitro fitness to in vivo replication fitness is uncertain" ], "suggested_hypotheses": [], "file": "unknowns-catalog/virology/u-quasispecies-fitness-landscape-mapping.yaml" }, { "id": "u-quasispecies-nk-parameter-identifiability", "title": "Can coarse NK ruggedness parameters be identified uniquely from deep mutational scanning fitness tensors when epistatic entries are sparse and measurement noise anisotropic — mirroring quasispecies mutation-selection inference challenges?", "status": "open", "domain": "virology", "systematic_gaps": [ "Joint inference benchmarks coupling simulated quasispecies trajectories with NK-ground-truth landscapes under controlled sequencing depth limits", "Uncertainty quantification pipelines exporting posterior widths on ruggedness descriptors into vaccine recommendation dashboards without overconfidence" ], "suggested_hypotheses": [ "h-viral-quasispecies-x-nk-rugged-landscape" ], "file": "unknowns-catalog/virology/u-quasispecies-nk-parameter-identifiability.yaml" }, { "id": "u-pyroconvection-prediction-coupled-fire-atmosphere-models", "title": "Under what meteorological and fuel conditions does pyroconvection (fire-driven convection) become self-organizing into pyrocumulonimbus storms, and can operational coupled fire-atmosphere models predict this transition with sufficient lead time for evacuation decisions?\n", "status": "open", "domain": "wildfire", "systematic_gaps": [ "Observational datasets of pyroCb events with collocated fire behavior, atmospheric soundings, and radar data are sparse and poorly coordinated.", "The critical fire intensity threshold for pyroCb initiation has not been empirically estimated from observational data.", "WRF-SFIRE and similar coupled models have not been systematically validated against pyroCb events; their skill for pyroCb initiation is unknown." ], "suggested_hypotheses": [], "file": "unknowns-catalog/wildfire/u-pyroconvection-prediction-coupled-fire-atmosphere-models.yaml" } ] }