Papers

Sliding-scale insulin is the default hospital response to high blood glucose. Its correction factor was designed for patients who make no insulin, yet it is routinely ordered for patients whose pancreas still works, including those on high-dose steroids. We treat the sliding scale as what it is, a proportional controller sampled every four hours, acting on a patient who already contains a working glucose controller of her own. We test it in a non-diabetic adolescent on high-dose corticosteroids and parenteral nutrition, and in 4,995 virtual patients. It fails for three structural reasons, and no choice of correction factor fixes any of them. First, the patient's own loop settles in 11.5 minutes while injected insulin takes 64 minutes to peak, so most of each dose simply replaces insulin she would have secreted; in simulation the ordered scale moved her mean glucose by less than 1.5 mg/dL. Second, one unit lowers glucose twice as much at 110 mg/dL as at 190, so any correction factor strong enough to work when glucose is high overshoots when it is low; in 99.5% of virtual patients no constant factor does both. Third, four-hour sampling is far below the Nyquist rate, so successive readings are uncorrelated and each dose responds to a value that does not persist. Even the argument that correction doses rest the beta cells, taken on its own terms, favors continuous delivery. We propose replacing the scale with a continuous insulin infusion co-delivered with the dextrose and adjusted once a day on mean glucose, the one quantity four-hour monitoring can measure.

Depression has no diagnostic blood test. Language models promise tireless, consistent assessment, but can accurate raters disagree about individuals? We pre-registered 880 language-model raters, crossing 11 open models with prompting and scoring choices, and applied them to 189 interviews against the eight-item Patient Health Questionnaire. Model choice explained 30.0% of summed-symptom score variance, stable participant differences 10.5%. Two randomly drawn raters with area under the receiver operating characteristic curve (AUC) >= 0.70 disagreed on screening decisions for 40% of participants, on average. Average over-rating governed how many were flagged, yet equal-capacity raters chose differently for about one participant in five. A locked analysis of 86 new interviews reproduced the main pre-registered findings. Exploratory recalibration with 40 labelled participants raised accuracy from about 60% to 75% and halved disagreement, leaving one participant in five decided differently. Calibration repaired much of the rater dependence without securing agreement about individuals.

Machine learning can accelerate molecular discovery by designing molecules and planning experiments. However, many scientific challenges demand molecules with very rare properties, and in this sparse setting, existing algorithms offer little gain over random guessing. We propose a method to efficiently search large regions of molecular space using algorithmically controlled stochastic synthesis. Rather than design, make and test individual molecules, we design and make complex mixtures, test them as a pool, then deconvolute the molecule-activity map. We optimize synthesis to encode maximal information. Theoretically, this approach can reduce the number of experiments required to find the optimal molecule among $d$ candidates from $\mathcal{O}(d)$ to $\mathcal{O}(\log d)$ or $\mathcal{O}(1)$. In simulation, on estimated protein fitness landscapes, it finds active molecules with an order of magnitude fewer experiments than existing Bayesian optimization methods.

Biological connectomes encode structured solutions to visual computation that may provide reusable inductive biases for artificial vision. We develop ConnectomeX around FlyVision, a trainable architecture that preserves parallel ON/OFF processing, recurrent computation and population-level graph interaction while scaling model capacity across tasks. FlyVision reached 99.34% accuracy on MNIST with 80,608 parameters and 78.03% on CIFAR-10 with 81,408 parameters. On ImageNet-1K, FlyVision Base and Large reached 60.79% and 66.25% top-1 accuracy with 1.8 and 3.7 million parameters, while a Large local-k7 model with a learned low-frequency branch reached 66.53%, compared with 69.25% for ResNet18 with 11.7 million parameters. On a 22-class skin-disease benchmark, FlyVision Large achieved 63.78% accuracy and 95.28% macro-AUROC with 2.99 million parameters. In four-class chest radiography, ImageNet-pretrained FlyVision Base and Large reached 92.60% and 92.76% accuracy with 1.33 and 2.97 million parameters, compared with 91.56% for ImageNet-pretrained ResNet18 with 11.18 million. BrainAGE extends FlyVision to volumetric T1-weighted MRI by applying a shared ImageNet-pretrained FlyVision Large encoder to 24 sagittal, coronal and axial slices per scan and combining slice-level age estimates by confidence-modulated Gaussian voting. On 433 held-out scans, three-axis fusion achieved a mean absolute error of 5.98 years and R^2 = 0.868. Across the 224x224 classification tasks, the best FlyVision configuration remained within three percentage points of ResNet18 on ImageNet-1K and skin-disease classification and exceeded it on chest radiography with substantially fewer parameters. These results show that a conserved connectome-informed computation can scale from compact recognition to large-scale natural and biomedical vision.

Electrophysiological recordings provide powerful tools for characterizing the dynamics of neuronal networks. In vitro neuronal cultures offer a controlled setting for investigating network responses to diverse interventions, including pharmacological and optogenetic stimulation. However, conventional analyses often reduce electrophysiological activity to aggregate measures calculated over fixed temporal windows, providing only a static representation of the network state. Here, we introduce a comprehensive, multiparametric analytical framework designed to characterize both the temporal evolution of network activity and the transitional states induced by external interventions. The framework combines multiple network discriminators with a compositional analysis that resolves electrode-level responses into excited, inhibited, and unchanged states over successive temporal segments. We apply the framework to electrophysiological recordings obtained under pharmacological interventions with 4-aminopyridine (4-AP), optogenetic stimulation, and additional benchmark conditions. The results demonstrate that the proposed analysis can reveal subtle and transient responses that may be difficult to detect using conventional aggregate measures, including responses to low-dose pharmacological interventions. These findings highlight the value of temporally resolved and compositional analyses for characterizing heterogeneous neuronal network responses in vitro.

Motivation: Plant disease resistance genes, particularly those encoding NB-LRR proteins, are important targets for crop improvement. Proteome-based domain or motif searches can only identify NB-LRRs among existing gene models, meaning they cannot recover loci that have been missed or incorrectly predicted by the reference annotation. The full-length, homology-based R-gene prediction (HRP) method circumvents this issue by reconstructing gene models directly on the genome. However, the original implementation of this method requires several separate phases of classification, comparison and filtering operations. Results: HRPv2 is an automated, enhanced version of the original strategy. The labour-intensive, step-by-step curation process used in HRP has been replaced by a reproducible filtering framework. Enhancing two steps of the homology search process has enabled HRPv2 to better account for the specific NB-LRR variability of the genome. Performance validation confirmed that the number of full-length NB-LRRs annotated in both the automatically predicted gene set of the respective genome assembly and the final NB-LRR repertoire has increased in HRPv2 compared to HRP. Availability and implementation: HRPv2 and its associated documentation and reproducible test data are available at https://github.com/AndolfoG/HRPv2. Detailed installation and dependency information is provided in the repository README. A version-pinned Conda package has also been developed and locally validated to provide a reproducible execution environment.

Contextual priors improve neural-to-language decoding by reshaping candidate scores. However, confidence is read from the same reshaped scores, so the errors a prior leaves behind can become more confident with no change in accuracy to reveal it. We study how a prior shapes confidence in speech retrieval on MEG-MASC and MOUS using local decoding scores, a contextual prior combined by additive shallow fusion, and the fused top-two margin as confidence. Among initially incorrect predictions, we find a confidence-ordering reversal: a larger margin makes a repair more likely when the correct candidate starts near the top of the local ranking, but less likely when it starts lower. On MEG-MASC, pooled correctness AUROC is 0.87, yet AUROC separating repairs from residual errors falls from 0.70 at initial ranks 2-3 to 0.39 at ranks 21-50. Errors starting beyond rank 20, inside the reversed region, make up 46.6% of all post-fusion errors. We propose a score-level account: a repair must first close the correct candidate's initial deficit, limiting its final margin, whereas a residual error can build a large margin between two incorrect candidates. A causal intervention that changes only the fusion weight moves the reversal to deeper ranks as predicted. Under a word-level LM prior, it keeps moving after accuracy gain peaks, so a weight chosen for accuracy does not settle confidence. Reading local and prior scores separately improves selective decoding: the decoder answers on 74.5% of windows instead of 56.7%, while 92% of output sets still contain the correct candidate. Confidence after contextual fusion should retain the local and contextual evidence behind each prediction, not just the fused scores. Project website: https://confidencereversal.github.io/; Code: https://github.com/AmadeusFake/NeuDecodingConfReversal

Nonlinear neural networks develop structured internal representations, yet how their geometry is determined by the tasks being learned remains poorly understood. Here, we develop an analytical framework for piecewise-linear feedforward and recurrent networks that links learning, activation-region structure, and neural selectivity. We show that, at any stationary point of gradient-aligned learning, a nonlinear network decomposes into local linear regressions over its activation regions. Deviations from the corresponding least-squares solutions are jointly constrained by network weights shared across regions and vanish in the low-error regime, yielding an approximate piecewise least-squares decomposition of the task. This structure admits a decision-tree interpretation, which we recover numerically by fitting trees to predict network activation patterns from the input. We further derive how the regions in which neurons are active determine the task statistics they capture, thereby organizing neural selectivity into distinct subpopulations. The resulting predictions closely match the selectivity geometry observed in simulated networks and two empirical neural datasets. Finally, we show that neural baseline regulates activation pattern diversity, placing networks along a continuum between coarse, generalizing representations and fine-grained, expressive representations. Together, these results establish activation regions as a unifying framework for describing how nonlinear networks decompose task structure into local computations and how those computations can be revealed through neural activity.

Migration and selection jointly shape evolutionary outcomes in spatially structured populations. Migration can vary over time as ecological shifts, such as changes in sea level, alter habitat connectivity. Here, we study the impact of periodic migration on selection within a geographically subdivided population. Using a two-deme Moran model with spatially heterogeneous selection, we analyze a scenario in which a mutant genotype is advantageous in one habitat and disadvantageous in the other. Keeping the time-averaged migration rate fixed, we vary the period, relative phase, and directional asymmetry of migration and examine the resulting steady-state mutant frequency. We find that migration periodicity generally drives the population toward neutrality: relative to constant migration, it decreases the mutant frequency when mutants are advantageous on average and increases it when they are deleterious, without reversing the direction of selection in the parameter regimes examined. This effect is strongest for out-of-phase migration, which models seasonal migration, and is further enhanced by directional asymmetry. The response to the migration period is generally non-monotonic, with an intermediate characteristic period producing the largest deviation from constant-migration behavior under in-phase migration. These results arise from the coupling between migration and local selection in Moran process: temporal modulation of migration changes not only the exchange of individuals between habitats but also the local population composition on which selection acts. Our results show that populations with identical mean migration rates can show different evolutionary outcomes depending on the temporal organization of gene flow.

Where generalization capacity–the ability to extract context-invariant relational structures–first emerges remains a central question in AI and neuroscience. The foundation for this capacity lies upstream of the hippocampus, within the entorhinal cortex, where parallel pathways dissociate relational structure in the medial entorhinal cortex (MEC) from sensory content in the lateral entorhinal cortex. However, as Eichenbaum argued, such factorization likely originates earlier, driven by the segregation of the dorsal ('where') and ventral ('what') visual streams. Supporting this, grid-like firing patterns–a signature of MEC (context-invariant codes)–also appear in preceding neocortical regions along the dorsal pathway. Yet, how such representations are computationally formed along upstream pathways remains unknown. To investigate this in silico, we developed ReGraph, a recurrent dual-stream graph model with biological inductive biases, including retina-driven stream-specialized encoding, dorsal-to-ventral modulation, and dynamic lateral connectivity. Trained on the action benchmark Something-Something V2, ReGraph revealed a pathway-specific emergence of relational mapping: context-invariant codes and grid-like spatial bases uniquely co-emerged along the extended dorsal stream. In contrast, their absence in single-stream, unmodulated variants, and standard baselines implies that these inductive biases are prerequisites for relational structures. Crucially, our post-hoc analyses demonstrated that these grid-like bases serve as reusable routing templates for information processing via lateral connectivity. Together, our findings provide a computational account that generalization may not be a faculty that emerges abruptly within a dedicated region, but a property that already takes shape as sensory information is parsed into factorized streams of hierarchical visual processing.

Phylogenetic networks generalize phylogenetic trees as models of evolutionary history, allowing lineages to merge as well as to diverge. For many types of genetic data the root position of such a network cannot be recovered, so that only a semi-directed network can be inferred: a mixed graph in which only the edges entering a reticulation vertex are directed. A common strategy for inferring such a network is to first infer the subnetwork it induces on each set of $k\geq 3$ of its leaves, called a $k$-net, and then to assemble these pieces. This can only succeed if the $k$-nets determine the network, in which case that network is said to be encoded by its $k$-nets. Semi-directed networks of level-1 and 2, those whose biconnected components contain at most one, respectively two, reticulations, are known to be encoded by their $4$-nets, or quarnets, whereas level-3 networks are not. Even so, in this paper we show that level-3 semi-directed networks are encoded by their $5$-nets, or quinnets, and we characterize the limitation of quarnets exactly: we show that a single previously reported counterexample captures the only obstruction, every other level-3 network being encoded by its quarnets. Our proofs rest on a collection of encoding results for individual structural features of a network, which we establish for networks of arbitrary level and which are of independent interest.

Electrophysiological source imaging (ESI) aims to estimate cortical source activity from noninvasive electrophysiological measurements such as electroencephalogram (EEG). However, ESI is fundamentally ill-posed because source activity is substantially higher-dimensional than sensor observations, resulting in non-unique solutions. Recent learning-based approaches address this ambiguity by learning data-driven source priors, yet they often struggle to generalize across subject-specific cortical geometries. To address this, we propose CANDLE, a learning-based ESI model that estimates source activity on subject-specific cortical geometries. CANDLE learns a prior over the null space induced by the source-to-sensor mapping derived from T1-weighted MRI, restricting learning to unobservable source components while preserving geometric constraints. To train CANDLE, we develop a whole-brain simulator spanning over 1,100 subject-specific cortical geometries with source configurations derived from over 26,000 statistical brain maps. Trained exclusively on simulated data, CANDLE outperformed prior ESI methods on simulated source activity estimation and generalized to two empirical tasks: (i) intracranial stimulation localization from simultaneously recorded scalp EEG and (ii) epileptogenic zone estimation from presurgical interictal EEG. Our project page is available at https://candle-esi.pages.dev}{https://candle-esi.pages.dev.

Existing molecular and materials learning approaches often rely on a limited set of structural representations, which may capture only selected aspects of complex three-dimensional structure. Here, we introduce mathematical invariant-enabled topological neural networks (MITNNs), a framework that represents complex structures through multiple complementary mathematical views and integrates them with topological neural architectures. MITNNs combine multiscale invariants from topology, spectral theory, commutative algebra, differential geometry, and discrete curvature, capturing complementary structural information from the same system. Systematic invariant-subset, architecture-subset, and ensemble analyses show that predictive performance depends on how mathematical representations and neural architectures are paired, with selected combinations outperforming individual models and the aggregation of all available components. Across protein-ligand binding, metal-organic framework properties, mutation-induced protein solubility, and molecular toxicity prediction, MITNN consistently outperforms existing methods. These results establish MITNN as a mathematically multimodal framework for scientific machine learning.

Model-guided directed evolution seeks to identify high-fitness protein variants under limited oracle budgets. Protein language models (PLMs) provide rich representations for this task, but task-agnostic zero-shot scores can be misaligned with a target assay, while supervised search in high-dimensional embedding spaces can make surrogate modeling and uncertainty estimation sample-inefficient. We propose the Linear Fitness Subspace (LFS) hypothesis: within mutation-induced residue-level representation changes, a compact, assay-specific set of directions makes fitness variation linearly accessible from few labeled variants. This is a local, supervision-recoverable statement rather than a claim that protein fitness landscapes or global PLM geometry are universally linear. Building on this observation, we introduce Subspace-Guided Evolutionary Search (SGES), which estimates an LFS from a small initial sample and performs surrogate modeling, uncertainty estimation, and acquisition in the learned subspace. Across 10 core ProteinGym assays, 87 extended static-validation assays, and an 18-assay budgeted-search evaluation, SGES improves fitness prediction and search efficiency over zero-shot PLMs and recent ML-guided protein optimization baselines. Controlled comparisons with PCA, random projections, label-shuffled PLS, classical mutation features, and acquisition ablations further isolate the benefit of a fitness-aligned site-delta coordinate.

This paper addresses the challenge that, under China's current mosquito-control policy for chikungunya—clearing stagnant water, killing adult mosquitoes, and preventing bites—epidemics can still recur and continue to rise. By constructing a vector–host dynamical model that incorporates asymptomatic infections and a screening rate, we derive approximate analytical expressions for the epidemic peak value and peak time, and reveal the intrinsic link between short-term transients and long-term outcomes. Simulations across three scenarios—human-seeded, mosquito-seeded, and joint human–mosquito-seeded—show that (i) even when the vector population is effectively suppressed, asymptomatic carriers can still sustain transmission; (ii) the effect of the screening rate on the peak time is non-monotonic, and there exists a critical threshold that maximizes the delay of the epidemic; and (iii) moderate screening can both suppress the first wave and avoid leaving an excessively large susceptible pool that would amplify subsequent waves. Accordingly, we upgrade the original policy to a Twelve-character strategy for prevention, mitigation, and control—clearing stagnant water, killing adult mosquitoes, preventing bites, and screening cases early—providing theoretical support for chikungunya and other mosquito-borne diseases.

Ayurvedic formulations represent a rich source of traditional knowledge, encompassing distinct therapeutic approaches, medicinal ingredients, and underlying principles of drug action. However, systematic integration of this knowledge with standardized modern biomedical terminology and resources remains limited. Here, we present IMPPAT 3.0, an updated version of the Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT: https://cb.imsc.res.in/imppat/) database that extends its scope by incorporating curated and harmonized information on Ayurvedic formulations from authoritative sources, while expanding its coverage of medicinal plants, phytochemicals, and therapeutic use terms. IMPPAT 3.0 further enriches plant and phytochemical information with annotations on clinical trials, patents, bioactivity, protein targets, spectral data, plant image links, and AyuCaRe reports. The compiled data is also organized as IMPPAT-KG, a knowledge graph that enables exploration of relationships among IMPPAT entities. We demonstrate the utility of the resource through a network medicine analysis of single herbal drugs (SHDs) reported for rheumatoid arthritis (RA), revealing significant proximity of their protein targets to RA-associated genes, and pinpointing of phytochemical pairs with potentially complementary effects on RA pathogenesis. In conclusion, by integrating traditional medicinal knowledge, IMPPAT provides a FAIR-compliant ethnopharmacological platform for systematic investigation of Indian medicinal plants and Ayurvedic formulations for drug discovery applications.

A single spatial snapshot of a system with multiple interacting populations captures positions but not the underlying dynamics that have led to the observation. This work asks what the stationary second-order spatial statistics of a snapshot can reveal about the structure of the linear reaction-diffusion dynamical model, and in particular about the pairwise directed entries of its interaction operator. The observation is the matrix-valued structure factor $S(k)$ as a one-parameter family in the diffusion-inherited dependence on the wavenumber $\kappa=|k|^2$. The main result is that the directed interaction operator $A$ and the diffusivity matrix $D$ are generically identifiable for any number of interacting populations from $\{S(\kappa)\}$ up to a single global time rescaling. The findings do not contradict known bounds and the recent result that spatial observational data only determine the Markov equivalence class of the underlying graph. In this work, we identify physical assumptions that lift this barrier. The absolute time scale is not identifiable from a single snapshot of any sample size and requires an external clock. For tumor-immune tissue, the results imply that directed cell-cell interactions are in principle recoverable from one section, that the direction cannot be inferred from the mean densities or a covariance matrix, but from the wavenumber dependence of the cross and autospectra, and that a baseline section determines the interaction structure but not the absolute rates.

A spiking neuron is a dynamical system exhibiting a limit cycle (a spike) when subject to sufficiently excitatory input. Famous neuroscience experiments by Bryant and Segundo as well as Mainen and Sejnowski revealed that the spike times of some biological neurons are more reliable when subject to time-varying stimuli compared to constant ones. Provided with an industrial physics-based transient noise SPICE simulation framework compatible with foundry transistor compact models, we have demonstrated similar behaviours for a CMOS analog spiking neuron designed for neuromorphic computing hardware platforms. Under constant excitation current, the neuron operates in oscillatory regime and the empirical periods (interspike intervals) suffer from accumulated phase noise (jitter) during successive cycles, mainly due to the thermal noise of transistors. A time-varying input is reported to be capable of triggering output spikes according to a controlled statetransition mechanism, thereby significantly reducing the spike time jitter in the excitability regime. The physical limitation of the oscillatory or rate-coding regime in terms of reliabilitydissipation tradeoff is further evidenced by a stochastic thermodynamic uncertainty relation, a theorem that applies to general overdamped dissipative stochastic dynamical systems.

Language models can score psychiatric questionnaires from speech, but agreement with self-report may reflect the questionnaire rather than the person. We introduce psychometric representational similarity analysis, a framework for comparing the structure of speech-derived scores, self-report, item wording and theory, and implement it alongside person-level construct scoring in COMPASS 2.0. We show how similarly worded items induce covariance without psychological signal. In pre-registered discovery and confirmation analyses of clinical interviews from 275 participants, language-derived symptom geometry resembled wording more than self-report, with no structure beyond wording detected by the registered tests. Geometric agreement with self-report survived assigning participants someone else's answers, whereas person-paired scores captured distress more than specific symptoms. Complementary analyses examined counselling quality and wording structure across 34 instruments and the Research Domain Criteria (RDoC) framework. These findings distinguish agreement about psychological structure from evidence that language-derived assessments track individual people.

Content-based image retrieval (CBIR) in neuroimaging enables the identification of structurally similar brain scans, supporting diagnosis, prognosis, and treatment planning; however, existing methods are often limited to small datasets, single brain regions, or coarse class labels, thereby restricting their clinical utility and generalizability. Here, we present NeuroCBIR, a framework for fast and flexible retrieval of both whole-brain and region-specific 3D T1w MRI scans. A total of 103 cortical and subcortical regions are extracted to enable both whole-brain and region-level queries. NeuroCBIR leverages latent representations learned by a variational autoencoder (VAE) combined with contrastive learning, producing scan-specific embeddings that capture anatomical patterns. These embeddings were evaluated for subject re-identification, zero-shot age prediction, and zero-shot multi-class pathology stratification. Re-identification performance was high across both whole-brain and brain-region levels (mean average precision across the top-5 retrieved images (mAP@5) >= 98.4%), with robust generalization across datasets and acquisition conditions. While NeuroCBIR is not trained for age prediction or pathology stratification, zero-shot evaluations for these two tasks demonstrate that the embeddings encode meaningful information for downstream tasks. Embedding extraction on a 4-core CPU required approximately 18.7 s per scan, whereas similarity search was effectively instantaneous (less than 0.01 s). NeuroCBIR is publicly available for brain MRI with more than 26,000 precomputed T1w MRI embeddings. It supports reproducible research, region-specific flexibility, and clinically meaningful personalized diagnostic support. The software is available at https://github.com/minnelab/NeuroCBIR.

Topological entanglements are central to understanding and predicting the properties of polymer melts. Yet, they make equilibrium sampling computationally challenging, as decorrelation times grow rapidly with chain length. Here, we introduce a Monte Carlo scheme that bypasses typical computational bottlenecks by working in a self-assembly ensemble rather than at fixed composition. Strictly local moves efficiently propagate backbone reconnections across scales while conserving the number of linear chains, achieving near-linear scaling of decorrelation time with system size, $\tau_{\rm eq}\sim V^{1.0}$. With this method, formulated for a fully-packed lattice, we equilibrate periodic systems totalling up to $\simeq 1.1\times 10^9$ monomers, accessing a universal melt regime insensitive to lattice details. We analyze intra- and inter-chain entanglements for chains of up to $N\simeq 5 \times 10^5$ monomers, revealing that they manifest as localized knots and links rather than as global tangles. Finally, we show that the magnitude of the Gauss linking integral between neighbouring chains grows only as $N^{1/4}$.

We're often in a situation where we have models of measles transmission that are stuck at a coarse population scale. This paper is about increasing their resolution or, said differently, creating consistent models for the population's subcommunities. We pay special attention to the fact that even if the full population is isolated, subcommunities are open to measles importations and related consequences of population movement. It turns out that the resolution issue can be productively framed as a constrained optimization problem, where the constraint is aggregation to the coarse model. That mathematical scaffolding allows us to make epidemiologically motivated approximations concentrated at the large population scale, where they're more valid, which leaves the estimates at the fine subcommunity scale atypically unstructured. We develop the idea in the context of the pre-vaccination-era 60 city UK dataset, building transmission models for all 60 cities. We find that they have intuitive seasonality, volatility, and importation elements, but that they depend on nontrivial dynamics in their case reporting probabilities. Potential interpretations of those surveillance processes are discussed in some detail, and we also describe how they influence inference on the balance between competing cryptic transmission and transient elimination dynamics.

Establishing ordinary differential equations (ODEs) describing population data is a fundamental part of mathematical modeling in pharmacology, crucial to developing digital twins. However, doing so from sparse, noisy data is a slow, expert-driven task. Existing automated methods either search a restricted model space or ignore population inter-individual variability. Here we introduce APOD (Agentic Population ODE Discovery), a language-model agent that iteratively reasons over biological knowledge and fit diagnostics in an open-ended search space to discover a population digital twin (PDT), i.e., a shared ODE system with between-subject variability. On synthetic pharmacokinetic and tumor-dynamics benchmarks, APOD recovered ground-truth structures in 94-100% of runs, 12-fold faster in median than an established library-based search. On real cohorts it converged to valid structures, and proposed a PDT of radioligand-therapy-induced platelet dynamics that predicts thrombocytopenia from first-cycle data and simulates alternative dosing schedules that lower the predicted risk of toxicity.

The dynamics of chemical reaction systems with two chemical species can be described (under mass-action kinetics) by planar autonomous systems of ordinary differential equations (ODEs) with right-hand sides containing polynomials. While their behaviour close to hyperbolic critical points is well understood, their dynamics has not been fully characterized for strongly non-hyperbolic critical points, where the linearization close to the equilibrium is given by the zero matrix. In this paper, the behaviour of such chemical reaction systems is investigated. Considering second-order chemical reaction networks with a positive equilibrium point, we show that only nine geometric equivalence classes are possible out of the sixteen classes for general ODE systems. Examples of chemical reaction networks in each class are presented. All sixteen geometric equivalence classes can be realized by chemical systems if the non-hyperbolic equilibrium point is located at the origin.

Personality is associated with economic outcomes, but whether these relationships are causal remains unclear. We exploit within-family variation in genetic propensity toward the Big Five generated by random genetic transmission from parents to offspring. Combining polygenic indexes from the Lifelines cohort study with 19 years of administrative tax records in the Netherlands, we find that greater genetic propensity toward emotional stability increases earnings and household wealth, while genetic propensity toward conscientiousness increases household wealth. The other three traits show no consistent pattern across outcomes and specifications. The effect of genetic propensity toward emotional stability on earnings remains positive as we progressively account for genetic propensity toward educational attainment, cognitive performance, and depression. These findings strengthen the evidence that personality causally affects earnings and wealth.

Living neuronal networks transform inputs through recurrent cellular and population dynamics, yet it is unknown which network architecture supports which computation. Neurons-on-a-chip turn this question into a design problem because microchannels guide axonal growth and set the network architecture. We introduce IC$^3$, an Integrated Characterisation of Communication-Driven Computation, which characterizes network state through neuronal dynamics, functional communication, and structural support. We implemented nine architectures in silico as conductance-based spiking networks and tested each on frequency decoding, temporal-order discrimination, and fading memory. Predominantly feedforward circuits decoded best. Sequential Chain and Microchannel Diode had the lowest IC$^3$ and recruited a third of reachable neurons, yet achieved the two highest scores on both classification tasks. Across architectures, higher IC$^3$ went with lower classification scores. We term this new direction neurotopomorphic computing, in which the physical organisation of neuronal connectivity is engineered as part of the computing substrate.

Behavioral variability reflects differences in internal and external parameters and provides a substrate for natural selection. However, uncovering its structure is challenging because behavior evolves nonlinearly across multiple timescales. Our goal is to reconstruct phenotypic variation from finite behavioral observations without prescribing the scales at which individuals should be compared. To achieve this, we introduce a multiscale dissimilarity that compares dynamics across all statistically resolvable resolutions by constructing reduced transfer operators at progressively finer scales and weighting their differences by finite-sampling uncertainty. This dissimilarity defines a geometry of dynamical phenotypes, which we reconstruct using diffusion maps. We show that the resulting phenotypic coordinates locally follow the parameter directions to which dynamics are most sensitive. We validate our approach in a stochastic model and apply it to bacterial and larval zebrafish behavior. In bacteria, we identify run speed as a major component of inter-individual variability, associated with the chemotaxis protein CheB. In zebrafish, we find that prior prey experience reshapes behavioral dynamics and phenotypic variability, with paramecia experience concentrating fish in a prey-capture-associated region of phenotypic space. Together, these results provide a framework for identifying internal and environmental variables that structure dynamical phenotypes across scales.

Task-fMRI connectomes reveal state-dependent neural reconfigurations, yet conventional methods marginalize these signals by aggregating distinct conditions into static pairwise graphs, thereby obscuring condition-specific multi-ROI organization. We introduce CoHyFuse, a condition-aware ROI-centered hypergraph framework that constructs a task-state-specific incidence matrix from condition-wise functional connectivity (FC)-profile embeddings, allowing the same ROI to form different multi-ROI hyperedges across task phases. Condition-specific neighborhood sizes $K_q$ further adapt the hyperedge scale to each task state, and the resulting condition embeddings are fused with a complementary whole-session FC branch for prediction. In the AABC cohort (N=1,074), CoHyFuse achieved the best mean out-of-fold predictive performance among evaluated baselines on FACENAME Fluid Cognition Composite (FCC) prediction (7.83$\pm$0.10 MAE, 0.439$\pm$0.026 \(R^2\)) and VISMOTOR age prediction (7.52$\pm$0.37 MAE, 0.592$\pm$0.022 \(R^2\)). In an auxiliary CMI-HBN attention-deficit/hyperactivity disorder (ADHD) classification benchmark (N=223), CoHyFuse obtained 72.0$\pm$2.1% macro-AUC and 74.2$\pm$2.9% accuracy. Ablation studies support the contributions of condition-wise incidence construction and dual-view fusion, suggesting that state-resolved ROI-set structure provides complementary predictive information beyond whole-session FC alone. Occlusion analysis identifies the Distraction condition as the primary driver of model prediction, pointing toward the Salience/Ventral Attention Network (SAN)–FrontoParietal Network (FPN) and within-SAN hyperedge-defined ROI-set motifs as candidate model-relevant patterns. This framework provides an interpretable, state-resolved view of the connectome for downstream cohort analysis.

Extracting patient-specific vascular trees from volumetric medical images is fundamental to computational angiography and non-invasive hemodynamic assessment. Conventional voxel segmentation models often sever delicate bifurcations, while heuristic Euclidean Minimum Spanning Trees introduce non-anatomical shortcuts. Moreover, linear Poiseuille flow neglects quadratic kinetic dissipation across arterial narrowings, underestimating ischemia. We formulate an end-to-end framework decoupling continuous geometric arborescence generation from non-linear hemodynamics. First, an autonomous 3D Ostium Landmark Localization Head with dual-sinus query channels and spherical-gated refinement eliminates centerline seeding dependency, achieving cohort mean localization error of 7.63 mm (7.43 mm LCA, 7.83 mm RCA; 71.4% <= 8.0 mm) from raw contrast context. Second, a Spatially-Grounded Deformable Step Flow Architecture queries continuous 3D feature pyramids via trilinear sampling, sequentially generating trajectories with anchor boundary enforcement (X(0) = P_start). Third, a Top-Down Recursive Arborescence State Machine detects bifurcation peaks via Tree-NMS and parameterizes predecessor parent pointers (p_k < k), guaranteeing single connected acyclic tree topology (beta_0 = 1, beta_1 = 0) with differentiable step termination. Fourth, an iterative Picard non-linear Kirchhoff solver with Young-Tsai / Gould quadratic dissipation enforces machine-precision mass conservation (residual 5.82e-11 mL/s). Across 14 development patients under standardized in-silico stenosis stress testing (Q_0 = 4.0 mL/s), linear Poiseuille flow misclassifies 75% diameter lesions as non-ischemic (FFR > 0.80) in 14/14 cases, whereas our non-linear solver captures functional ischemia (FFR = 0.5864, lesion disparity 32.89 mmHg, p = 6.10e-5) with 3.66x collateral shunting. Test set firewall isolation was maintained.

Stochasticity shapes evolutionary dynamics in finite populations beyond the reach of infinite-population theories. Using a stochastic birth–death framework on random regular networks, we establish evolutionary stability criteria for finite structured populations playing three-strategy games and identify critical degree thresholds governing invasion dynamics. Our framework goes beyond two-strategy evolutionary games to reveal that the initial composition of multi-type mutants, together with population structure and stochasticity, shapes the evolutionary fate of the resident population.