Papers

Small-molecule optimization integrates medicinal-chemistry reasoning and computational evidence through iterative, multi-objective decisions. When large language models (LLMs) reason over optimization histories stored primarily in conversational context, they must recover candidate identities, prior evaluations, and task constraints to guide subsequent decisions. We present M3OS, a multi-agent LLM system that decouples molecular-design reasoning from optimization-state management through Monte Carlo graph search. A persistent graph links evaluated candidates, parent-child transformations and evaluation evidence, while rewards and visit statistics guide LLM-assisted parent selection. Two branches combine tool-driven candidate generation with knowledge- and case-guided medicinal-chemistry editing. An execution harness controls graph updates through structured output extraction, molecular validation and task-bound evaluation. Agents receive role-specific contexts, while the graph preserves optimization trajectories beyond their active contexts. Across three molecular optimization benchmarks, M3OS achieves higher success rates than baselines, supporting the integration of persistent search state, specialized agents and controlled execution for multi-constraint optimization.

Background & Objective Accurate segmentation of neurons in microscopy images of neuronal cultures is crucial for research on neurodegenerative diseases and neurotoxicity. Manual annotation of such images is time-consuming, subjective, and inconsistent across experts. Deep learning (DL) models offer an effective alternative, but require high-quality training datasets composed of microscopy images with accurately segmented neurons, typically created by experts. Neuronal cultures can be imaged using either phase-contrast or fluorescence microscopy. While live neurons are easily detected in fluorescence images, this modality requires staining, which affects cell viability. Conversely, phase-contrast imaging is non-invasive but makes neuron identification more challenging. Methods In this work we present a robust computer vision pipeline for the automatic generation of expert-level neuron segmentation masks from fluorescence microscopy images. These masks are used to train DL models for neuron identification in phase-contrast images. Our method relies on paired fluorescence and phase-contrast images captured simultaneously at the same magnification and coordinates, ensuring alignment across modalities. Once trained, the DL models can segment neurons in phase-contrast images alone, eliminating the need for fluorescence staining. Results We validate our approach by comparing the automatically generated masks with expert annotations using multiple agreement metrics, including IoU, Accuracy, and Gwet's AC1. Such metrics are calculated not only for the identification but also for the segmentation of instances. Conclusions This study presents a classical computer vision algorithm for generating neuron segmentation masks, which can be used for downstream applications such as non-invasive cell viability analyses by means of DL.

Modeling resting-state functional magnetic resonance imaging (rs-fMRI) data is crucial for understanding brain-wide neural activity. However, traditional methods struggle to capture complex temporal dynamics over long horizons, to account for the brain's anatomical spatial structure, and to model high-dimensional ambient signals that lie on a low-dimensional intrinsic subspace. We propose FAST-Brain, a unified flow-aligned spatio-temporal surrogate brain model that addresses all three challenges. At its core is a flow-aligned generative framework that directly predicts the clean blood-oxygen-level-dependent (BOLD) signal, paired with a graph convolutional network that captures spatial structural constraints and a Transformer that models long-range temporal dependencies. Theoretically, we show that under a low-dimensional subspace assumption, the approximation error of our model scales with the intrinsic dimension rather than the ambient dimension, which justifies our direct modeling of the BOLD signal. Extensive experiments on synthetic and Human Connectome Project datasets demonstrate that FAST-Brain achieves state-of-the-art performance in recovering functional connectivity, effective connectivity, and the implicit low-dimensional signal subspace.

Biological models based on mathematical simulations (e.g., ordinary differential equations) are hugely beneficial for understanding biological processes and predicting the outcomes of experiments. Such models are built using a variety of sophisticated modeling tools. Unfortunately, the complexity of these tools is often a barrier to use by experimental biologists. To improve the usability and impact of biological models, we have created a desktop platform (DeskIridium) and a web-based simulator (WebIridium, hosted as a GitHub page) that, in combination, provide features that promote ease of use by experimental biologists, including: human-readable editing of models via the Antimony syntax; sliders for adjusting parameter values while simultaneously displaying simulation results in real time; zero-install distribution; AI chat integration; and generation of standalone Python implementations of SBML models to support reproducibility. The desktop version uses the well-established libroadrunner simulation package; the web-based application uses an Emscripten translated version of COPASI. Both simulators are SBML-compatible, allowing users to easily import previously built models or edit existing models using the easy-to-use antimony language. We used modern AI methods for software development and share the lessons we learned. Binaries, source code, and the web interface are available at: https://github.com/sys-bio/IridiumSimulator and https://github.com/sys-bio/WebIridium.

Proteins change shape as they function, yet most inverse folding models predict amino acid sequences from a single, fixed backbone. A central challenge in protein engineering is to design proteins that undergo specific motions, which requires accounting for how their structures change over time. This motivates inverse protein folding conditioned on protein motion. We introduce SPINET, which predicts sequences from molecular dynamics trajectories. It uses cellular sheaves to represent residue interactions within each frame and recurrent units to integrate information across frames, then predicts all amino acids in a single pass. We evaluate SPINET on mdCATH and ATLAS, where it outperforms all evaluated static and ensemble baselines in sequence recovery. On mdCATH, it achieves 56.7% top-1 recovery, compared with 44.5% for the strongest static baseline and 40.7% for the strongest ensemble baseline. We also evaluate whether the predicted sequences are compatible with conformations sampled along the target trajectory. On mdCATH, they achieve a median TM-score of 0.760, and structural recovery favors target conformations over unrelated decoys for 99.5% of test domains.

When people of reproductive age move between regions, replacement-level fertility need not produce spatially balanced population replacement. Migration genealogies connect a woman's birth region, through survival and movement, to her daughters' birth regions across generations. We decompose existing genealogical series for stable births and reproductive value into first-return paths, on which a lineage again produces a descendant in its reference region without intermediate births there. Discounting at the intrinsic growth rate yields a first-return distribution with an Euler–Lotka-type normalization. Its mean recurrence generation, the expected generations until first return, equals the normalized product of stable births and reproductive value and, at replacement, reciprocal net reproduction sensitivity to within-region reproduction. Using Japan's 2010, 2015, and 2020 censuses, vital statistics, and life tables, we compare 47 prefectures under national replacement. Based on 2020 rates, mean recurrence is approximately 10 generations for Tokyo and 500 for Akita; Fukushima varies across observation years. Similar one-generation birth contributions conceal different descendant destinations and subsequent return pathways. These period-based results reveal how reproductive pathways generate regional differences in stationary populations. Population replacement must therefore be analyzed jointly through fertility, migration, and regional conditions, with mean recurrence identifying the strength of closed reproductive pathways.

Large language models (LLMs) have demonstrated strong capabilities in biological reasoning; however, genomic disease inference remains largely dependent on memorized gene-disease associations rather than understanding biological pathways. This shortcut learning undermines robustness and generalization, and breaks down when molecular identifiers are unavailable. We present GenoMorph, a multimodal genomic reasoning framework that shifts disease prediction from associative gene-disease mapping toward pathway-grounded reasoning. GenoMorph couples a frozen DNA foundation model with question-conditioned cross-attention fusion, self-adaptive latent reasoning (LatentSp), a residual reasoning gate for iterative genomic evidence reinjection, and rejection sampling fine-tuning regularized by hierarchical optimal transport (OT). Rather than learning direct gene-disease mappings, GenoMorph aligns genomic sequence representations with latent pathway dynamics, enabling reasoning trajectories that follow molecular interactions before producing disease predictions. LatentSp dynamically allocates computation according to reasoning confidence, reducing unnecessary reasoning steps and improving inference efficiency. We further construct an anonymized benchmark from the Kyoto Encyclopedia of Genes and Genomes (KEGG), replacing every gene and molecular identifier with anonymous symbols while preserving sequences and pathway topology, thereby removing memorization shortcuts. GenoMorph raises the weighted F1 from 0.7863 (BioReason) to 0.9412, and rejection sampling fine-tuning with self-adaptive latent reasoning pushes it to 0.9725 while cutting latency nearly 60%. On the anonymized benchmark it reaches 0.9465 F1, substantially outperforming prior systems and confirming that accurate disease prediction can arise from pathway reasoning rather than memorized gene-disease associations.

Predicting phenotypic and transcriptional responses to perturbations at single-cell resolution provides a powerful tool for probing biological systems. However, existing methods typically rely on fixed mappings learned during training, making it challenging to calibrate distribution shifts or adapt to novel perturbation conditions during inference. Here, we present scEGFlow, an energy-guided flow matching framework that dynamically bridges control and perturbed cellular states. scEGFlow models continuous transitions from control cell populations to perturbed states using conditional flow matching. It then applies condition-specific energy gradients to correct and steer these predictions, enabling flexible adjustments without retraining the flow model. Evaluations across benchmarks spanning imaging phenotypes and transcriptomic profiles show that scEGFlow outperforms existing methods in reconstructing response distributions under both seen and unseen perturbation conditions, faithfully preserving cellular manifold geometry and population heterogeneity. This advantage is notable when adapting to new conditions with only a few measured cells, consistently improving prediction accuracy. Furthermore, scEGFlow accurately recapitulates perturbation-induced up- and down-regulation patterns across consensus gene expression signatures, where energy guidance improves the agreement between predicted and observed regulatory directions. Ultimately, these findings demonstrate that scEGFlow provides a modular, generalizable, and steerable solution for single-cell perturbation modeling. By grounding generative flows in learned biological landscapes, this architecture establishes a new computational paradigm for navigating and manipulating cellular behavior in silico.

Genetic design automation maps Boolean specifications to regulatory networks and DNA sequences, but a successful mapping does not establish the probability that every output remains correct over time. This paper presents Proof-Carrying Synthetic Biology (PCS-Bio), a formal architecture for acyclic genetic logic circuits operated under fixed inputs. An ideal checker connects Boolean equivalence, sequence and model provenance, local stochastic contracts, and any surrogate-to-target discrepancy bounds. Under explicit semantic and checker assumptions, these obligations imply a joint temporal refinement guarantee without assuming independence among molecular events. Assignment-specific sufficient cubes select the branches needed to prove each output value. This can reduce risk and delay accounting provided that the retained local contracts remain uniform over the physically present but logically masked inputs. The reported evaluation exercises three separate interfaces: an archived Cello execution with sequence reconstruction, a restricted exact rational checker for a synthetic finite-state instance, and diagnostic IEEE~754 binary64 replay. Across 60 deterministic Boolean formula graphs, slicing reduced the worst-assignment risk-charge sum in 55 cases and the maximum accounting delay in 54. These results concern proof accounting and selected implementation components. They do not establish an integrated sequence-bound temporal certificate or physical validation.

Genome foundation models are growing into sparse mixture-of-experts (MoE) networks whose expert weights no longer fit on the machines that hold the sequences, yet sending a private genome to rented accelerators exposes it: we show that a single server hosting one expert recovers the input nucleotides with 99.8% top-1 accuracy. We present CipherGenome, a protocol that keeps the embedding, attention and router of a 15.1B-parameter MoE genome model on a trusted thin client and outsources every expert projection, 95.8% of the parameters, to untrusted and possibly colluding GPU servers under module-LWE encryption. The design exploits three structural facts: expert layers are linear between two SwiGLU gates, expert weights are public, and GPU integer tensor cores can evaluate a ciphertext-weight product exactly modulo $2^{48}$ in a single GEMM. The client evaluates the nonlinearity exactly and re-encrypts with fresh secrets, so no polynomial approximation or bootstrapping is ever needed. On 72 windows from 12 bacterial genomes, encryption adds $2.54 \times 10^{-4}$ nats per token of KL divergence (95% CI upper bound $3.95 \times 10^{-4}$), below a pre-registered non-inferiority margin and indistinguishable from bf16 inference, while the same inversion attack falls to chance level. A reusable public hint cuts end-to-end latency by 3.54 times, wire compression reduces traffic 6.8 times, per-layer padding reduces routing leakage from 54.9% to 8.9% accuracy, and HE-compatible int4 experts remain non-inferior to their plaintext counterparts. Per expert and token, the server-side cost is more than six orders of magnitude below a CKKS baseline.

Genome foundation models are most useful where sequences are generated, yet the largest models need datacenter accelerators and a place to send private DNA. We ask whether a 15-billion-parameter genome mixture-of-experts (MoE) model can instead run on volunteers' web browsers, with the experts spread across many untrusted devices, without changing its predictions and without revealing the sequence to any single device. We build a system in which a trusted coordinator runs attention and routing while browser workers run every expert feed-forward network through hand-written WebGPU kernels, and we protect the expert inputs with real-valued Lagrange coded computing: each worker receives only a Gaussian-padded share, computes the expert's linear maps, and the coordinator decodes from any two of three workers. On GenomeOcean-MoE (8 experts, top-2 routing, 24 layers), the browser path matches native llama.cpp at every quantization level, the distributed path stays at the BF16 numerical noise floor (KL 0.0036 nats per token), and an unfitted latency model predicts decode time within 0.74% (median) under emulated wide-area links. We first show that plaintext expert inputs are not private: a probe recovers the token from a single vector at every depth, and one worker can identify the source genome from 300 unordered tokens with 92% accuracy. With coded experts, an adaptive attacker trained on shares falls to the most-frequent-token baseline, one worker's information about each token is bounded below one bit per forward pass, and the fidelity cost stays below the BF16 noise floor; in Chrome, coded decoding runs at 220 to 376 ms per token, depending on how much of the routing is hidden, and continues without replicas when a worker fails.

Can a genome model retain a detectable record of the synthetic sequences used to train it? We study watermark inheritance through distillation with GenoTrace, a codon-aware extension of green-list watermarking. Two token-level factors modulate the teacher's generation bias using codon position and organism-specific codon usage. The resulting sequences train a smaller student, whose outputs are audited without an active watermark processor. In a three-seed GenomeOcean-500M-to-100M experiment, the joint configuration achieves a mean audit score of 17.88 and 94.5% detection at a fixed threshold. It retains 49.0% detection after key-aware token substitution, compared with 0% for the available single-seed plain-watermark comparator, and 47.0% after combined mechanism-targeted nucleotide edits. Additional experiments establish inherited signal across five organism-conditioned datasets and teacher-student size ratios up to 40. Component ablations and computational sequence-quality assays reveal distinct operating points for detection strength and coding coverage. GenoTrace provides a practical token-level construction and an empirical account of how genomic structure shapes inherited watermark signals. The findings concern shared-tokenizer distillation and the tested editing procedures, with calibration and biological utility treated as separate evaluation requirements.

Decoding brain states requires models that capture both the evolution of neural activity and interactions among groups of brain regions. Existing EEG methods often treat recordings as multivariate time series or represent functional connectivity with pairwise graphs, leaving dynamic higher-order interactions largely unmodeled. We introduce the Temporal Simplicial Neural Network (T-SNN), which represents EEG recordings as sequences of evolving simplicial complexes. By combining simplicial convolutions with recurrent updates, T-SNN jointly learns higher-order interactions and their temporal evolution. On the seven-class SEED-VII emotion recognition task, T-SNN outperforms convolutional, recurrent, graph-based, and Transformer methods in both trial-wise and cross-subject evaluations. Incorporating eye-movement features further improves performance, demonstrating the framework's potential for multimodal brain-state decoding.

Protein–ligand binding affinity prediction is fundamental to computational drug discovery, yet modern AI-driven models are limited by pervasive heterogeneity in their training data: bioactivity values are aggregated across diverse assay types and experimental conditions without accounting for protocol-level differences, introducing systematic noise. Existing harmonization approaches either discard assay-level metadata or collapse it into coarse categorical distinctions, leaving rich contextual signal unused. We address this gap with two contributions. First, we introduce Assay-Aware BindingDB, augmenting 74,425 BindingDB protein–ligand pairs across four assay types (ITC, SPR, RBA, and FPA) with structured metadata extracted from primary literature using a two-stage agentic framework that separates evidence extraction from ontology-conditioned JSON synthesis. Against domain-expert references, the framework achieves presence F1 $\geq 0.947$ and semantic content accuracy $\geq 0.913$ across all assay types. Second, we develop a context-conditioned affinity model that injects an assay-context embedding into the Boltz-2 affinity module. On a paper-level held-out split, the model reduces combined-regime MSE from $1.27$ to $1.19$ and increases Pearson correlation from $0.64$ to $0.67$, with significant gains for SPR and FPA. ITC, the only label- and immobilization-free assay considered, shows no improvement, consistent with its design removing the protocol artifacts the metadata captures. These results support the hypothesis that systematically curated assay metadata provides informative signal for affinity prediction.

Traditional models of collective behavior rely on prescribed interaction rules, leaving unresolved the question of how behavior arises from neural representations of space. Here, we develop a first-principles theory in which movement, decision-making, and collective organization emerge by coarse-graining fast neural dynamics on a topological representation of directional space. For a ring manifold encoding heading, this reduction yields a macroscopic theory of behavior: a decision landscape over directions that admits a harmonic decomposition. In this framework, behavior is governed by a spectral organization of directional information rather than ad hoc rules. We demonstrate that target-seeking, avoidance, choice, spatial decision-making, and diverse forms of collective motion arise as distinct organizations of the underlying harmonic landscape. The theory unifies neural representations, behavioral decisions, and collective dynamics in a single mathematical description.

Proteins populate conformational ensembles, yet structure-based biomolecular design typically optimizes candidates against a single target conformation. Consequently, a candidate that fits one state can lose favorable interactions or develop steric clashes when the target adopts another. We introduce FlexEvo, a model-agnostic evolutionary framework that adapts candidates once at inference time from a single target conformation to improve compatibility with alternative natural conformations unseen during adaptation, without retraining the source model or requiring a conformational ensemble. FlexEvo casts cross-state adaptation as geometry-constrained bi-objective optimization, balancing preservation of input-state interactions against robustness to plausible conformational perturbations. To limit the search space and reduce invalid structural edits, geometry-derived FlexBoxes define protected anchor regions, adaptable regions for local exploration, and forbidden regions for clash avoidance. A unified all-atom representation supports topology-preserving adaptation across diverse binder categories, while Pareto selection preserves nondominated candidates across the two objectives. We evaluate FlexEvo across multiple generation baselines and nine representative binder categories spanning diverse molecular sizes and structural topologies. FlexEvo reduces the category-balanced mean relative performance degradation from 47.8% to 4.4%, while adding only 1.4–3.1 minutes of adaptation per sample. These results establish single-state inference-time adaptation as a practical route toward robust biomolecular complex design across protein conformational landscapes.

Infectious disease models that allow for reinfection, such as the SIS or SIRS frameworks, typically treat all infections as exchangeable and independent, erasing the temporal structure of individual reinfection histories. Here, we introduce a minimal "chain SIR" model that resolves this limitation by indexing compartments by reinfection count and allowing transmission, recovery, and waning rates to depend on that count. The dynamics generate an advective flux along the reinfection ladder, producing traveling waves in reinfection space and a coherent structure in the population's lifetime infection histories. We derive an analytical expression for the wave speed and identify the general conditions under which such cohort waves exist and persist, offering a new lens to interpret long-term prevalence patterns and the emergence of age- or immunity-structured endemicity. Finally, comparing the speed formula with longitudinal cohort data, we quantify the reduction in reinfection rate attributable to immunological responses for several seasonal viruses, including influenza A/H3N2 and respiratory syncytial virus (RSV).

Mapping resting-state brain organization to individual differences in cognitive ability remains a major challenge in population neuroinformatics. Although deep learning enables flexible modeling of brain connectivity, limited interpretability restricts its scientific and clinical utility. To address this objective, we developed an explainable deep learning framework based on sparse projected residual networks to predict fluid, crystallized, and total intelligence from resting-state functional magnetic resonance imaging in 5,285 participants from the Adolescent Brain Cognitive Development study. We incorporated three complementary explainability methods (Integrated Gradients, Gradient Shapley Additive Explanations, and Occlusion) to interpret model behavior. The framework outperformed existing approaches, achieving Pearson correlations of 0.44, 0.58, and 0.56 for fluid, crystallized, and total intelligence, respectively, corresponding to predictive improvements of 6 to 9 percent. All three explainability methods produced near-identical feature rankings (pairwise rank correlations greater than 0.99). Consensus maps revealed a dual-layered functional architecture where primary predictive hubs localized within canonical systems, while the strongest global predictive pathways frequently bypassed these hubs through distributed, long-range relay connections. These findings suggest that intelligence emerges from the interaction between localized computational hubs and distributed communication pathways. Ultimately, these normative network architectures provide clinical reference maps to detect individual deviations, supporting earlier diagnosis, cognitive subtype stratification, and treatment monitoring in atypical neurodevelopment.

If consciousness is functional, a basic question is what awareness of a content actually changes in how a system operates on it. We ask, for a particular content X and mental or bodily process Y, whether awareness of X changes whether, or how well, X can be used in process Y. Crucially, X-aware and X-unaware conditions must be compared in ways that rule out poorer information about X as a sufficient explanation. Our current literature sweep yields a small but informative functional profile. The clearest current evidence concerns goal-sensitive control, especially regulation of attentional influence, with additional evidence linking awareness to metacognitive evaluation. Meanwhile, one feature-binding paradigm suggests that short-lived feature-location binding and retrieval can remain possible without awareness. This preliminary profile suggests a selective rather than universal immediate functional role for awareness. But such a functional profile is not yet a theory of consciousness. A full-stack functionalist theory must also account for the broader phenomena associated with consciousness - the explanatory profile: the structure and manner of presentation of perceptual and affective experience, subject-world organisation, awareness judgments, and problem reports. Finally, the functional and explanatory profiles constrain theory construction from different directions, but neither determines the process architecture that could connect them. Bridging this gap requires abductive construction: proposing candidate architectures, implementing and intervening on them, and progressively revising them as further constraints accumulate. In sum, we propose a framework for constructing full-stack functionalist theories of consciousness, and take the first step towards detailing the functional profile.

Learning population dynamics from temporally sparse, unpaired distribution snapshots is a fundamental challenge in developmental biology. Recent approaches based on neural differential equations and flow matching can interpolate between observed population snapshots, but may struggle to extrapolate beyond the training horizon and often lack an explicit mechanism for modeling developmental branching. We propose KoopCell, a unified generative framework based on Koopman-Mori-Zwanzig theory that jointly learns representations and predictive linear latent dynamics. Theoretically, using the weak continuity equation, we derive a closed-form least-squares estimator for the Koopman generator from distribution snapshots and establish convergence guarantees under suitable assumptions. To model branching dynamics, we further develop KoopCell-M, which incorporates non-Markovian memory into the latent Koopman dynamics through a Markovian embedding. Experiments on synthetic systems and three scRNA-seq datasets demonstrate the ability of our framework to recover Koopman spectra, model branching through memory, and scale to predicting high-dimensional gene expression distributions, achieving state-of-the-art performance among the evaluated methods.

The allometry of cancer risk in mammals is scale-specific, as the inter-specific, intra-specific, and inter-organ patterns in cancer risk scaling are distinct from each other. While cancer risk barely changes with increasing body sizes across species, larger conspecifics are known to be at a higher risk of cancer. Cancer risk trends with age and lifespan have likewise been documented in humans and other species. Nevertheless, mammals broadly share developmental features, and the twin processes of cell division and differentiation are central to developmental dynamics. In this study, we suppose that a better understanding of these processes across biological scales could lead to a clearer understanding of cancer risk allometries. We develop an agent-based model in which a cell compartment grows from one cell to a target size. We assess how developmental dynamics scale with compartment size and influence mutation accumulation. Our data identify specific regions of the parameter space where the accumulation of neutral mutations increases with cell number, while providing a mechanistic explanation for such behavior. The accumulation of non-neutral mutations reveals an interesting antagonism in cell fitness between mutation and differentiation, which could change the viability of a given developmental strategy. Our model is able to produce a wide range of trends in cancer risk allometries in different parts of its parameter space, reflecting the observed heterogeneity across biological scales. Our results provide a theoretical framework that allows us to elucidate the conditions of mutation-differentiation balance under which having more cells does lead to higher cancer risk, and importantly, the conditions under which it does not.

Persistent homology and persistent Laplacians have become effective descriptors of large molecular binding interactions, the latter encoding multiscale geometry and spectral information beyond the harmonic subspace. Both, however, are built on undirected graphs and pairwise contracts, while the interactions that determine binding are often directional and involve more than two atoms at once. We introduce persistent hyperdigraph learning (PHL), which represents these directed, many-body interactions directly. Because hyperdigraph Laplacian spectra become costly to compute at higher topological orders, we further use stochastic trace estimation to develop a matrix-free formulation(MFPHL) that estimates Laplacian trace statistics from probe-based quadratic forms evaluated through sparse boundary operators, without assembling or diagonalizing. The number of probes required for a target relative accuracy of the trace estimate is independent of matrix dimension, and per-probe cost scales with operator sparsity. On protein-protein binding affinity benchmarks, MFPHL reduces feature-generation time by roughly two orders of magnitude relative to the eigenvalue-based pipeline. Its predictive accuracy matches that of spectral PHL on the P2P wild-type set within training-seed variability but is lower on the two larger datasets. This dataset-dependent trade-off brings higher-order hyperdigraph features within practical reach.

We report a pre-registered test of five hypotheses about the synapse-flow random walk on the connectome of the male Drosophila central nervous system (166,700 neurons, 124 million synapses), in which a walker moves to a postsynaptic partner in proportion to synapse number. The hypotheses concern the spectral gap and its dependence on the neck connective, the localisation of the leading modes of an input-normalised signed map, the certified mixing depth measured by the Dobrushin coefficient, its robustness to per-synapse detection confidence, and the dependence of the signed spectrum on the neurotransmitter sign convention. After public registration and a code freeze, each was tested once. Two held: the two-neuron photoreceptor modes that lead the signed spectrum are an artefact of normalising by very small inputs, removed by an input floor at the median, and they do not depend on the sign convention. Three failed: at a threshold of five synapses per connection the spectral gap is an order of magnitude smaller than predicted ($|\lambda_2| = 0.9965$) and the chain is certifiably far from mixed after 128 steps, and at no confidence level tested was the mixing depth certifiably robust. Exploratory analyses trace the slow mode to eleven neurons of the cord, seven of them mesothoracic efferent neurons, that become nearly closed once weak connections are dropped, find a similar boundary set in the lamina of the FlyWire female brain, show that null models preserving cell-type wiring reproduce the slow modes, and show that exact chains built from the confidence data change the depth profile after 32 steps by at most 0.017 at the pre-registered confidence level, far less than the worst-case certificate allows. Random-walk summaries of connectomes are dominated by nearly closed sets at the edges of the reconstruction unless these are treated explicitly.

Therapeutic sutures can localize bioactive payloads to wounds, but burst release and insufficient coating durability can compromise regeneration and increase infection risk. In this work, we introduce a data-driven discovery strategy for bioresorbable polymer suture coatings that improve therapeutic retention and release kinetics. We develop GenPoly, an end-to-end multimodal generative framework that learns a shared polymer representation over paired polymer string sequences and molecular graphs via contrastive alignment, and couples this representation to property prediction, synthetic accessibility filtering, and motif-based candidate clustering to discover coating families beyond commonly used linear aliphatic polyesters. Starting from a clinically prevalent baseline, GenPoly identifies candidate coatings and selects representative polymers for experimental evaluation on nanoparticle-loaded sutures with recombinant human EGF to an in vitro human keratinocyte wound model. A discovered polymer coating of the LA-TMC family shows improved payload retention and sustained release, exhibiting a $3.3\times$ increase in rhEGF concentration, accompanied by more localized Ki-67-positive keratinocyte proliferation at the wound bed, in comparison with the current state-of-the-art candidates. These findings suggest new opportunities in AI-driven polymer discovery, and highlight the viability of GenPoly in engineering bioresorbable coatings for suture-based therapeutic delivery in targeted tissue regeneration.

Many DNA foundation models are pretrained by masking parts of a sequence and asking the model to reconstruct them. Standard masked pretraining exposes the encoder to special [MASK] tokens that are absent at inference, creating a mismatch between training and downstream use. The role of an explicit global sequence representation such as a [CLS] token and how it should be trained also remain poorly understood for DNA barcodes. We introduce BarcodeMAE+ and study model architecture, global [CLS] representation, and auxiliary pretraining objectives across arthropod COI (BIOSCAN-5M) and fungal ITS (UNITE+INSD) barcodes. Across both barcode regions, the encoder-decoder MAE-LM architecture outperforms its matched encoder-only counterpart in nearly all evaluated configurations, supporting MAE-LM as an effective architectural design for DNA barcode foundation models. A trained global [CLS] representation provides substantial additional gains: on BIOSCAN-5M, [CLS] accuracy increases from 47.53% without an auxiliary objective to 80.65% with cross-entropy genus classification. The best auxiliary objective is region-dependent: cross-entropy performs best on BIOSCAN-5M, whereas pairwise same-genus classification performs best on UNITE+INSD, reaching 73.19% on Yeast and 63.07% on Filamentous Fungi. BarcodeMAE+ outperforms published DNA foundation model baselines on BIOSCAN-5M and achieves the highest Yeast accuracy among the evaluated UNITE+INSD baselines using frozen encoder representations. Similarity-weighted softmax KNN voting further stabilizes accuracy as neighbourhood size increases. Overall, encoder-decoder masked pretraining and an explicitly trained global representation are strong design choices for DNA barcode foundation models, while the optimal objective for learning that representation depends on the biological domain.

Traveling waves of activity in neural tissue can be halted by spatial inhomogeneity in synaptic coupling. We study an integrate-and-fire network in which each neuron fires once and the coupling decays exponentially. For this model the leading-edge firing map reduces exactly to a scalar equation for the wave speed in space, with a slow unstable and a fast stable homogeneous speed, $c_1$ and $c_2$, and a periodic modulation of the coupling enters this equation pointwise. Positive periodic waves terminate in folds. For slowly varying modulation the fold amplitude approaches a plateau set by the trough of the modulation, where the local bottleneck speed is $\sqrt{c_1 c_2}$; the approach to the plateau is set by the local geometry of the trough. For rapidly varying modulation the fold amplitude grows linearly with frequency, with a slope given by a full-amplitude average over the integrated modulation profile; a weak-ripple truncation of that average overestimates the slope about 2.5-fold at the default coupling. A perturbative recursion in the amplitude gives the speed profile explicitly. We distinguish loss of the periodic wave from failure of a particular launch, and the excitatory regime $\epsilon\le 1$ from its sign-changing extension. The results are checked against direct integration of the reduced equation and first-spike firing-map simulations of the network.

Effective-connectivity estimation from brain signals often relies on Gaussian residual modeling, which enables tractable estimation but can discard informative distributional structure and distort inferred directed interactions when empirical residuals are non-Gaussian. We show across multiple modalities, species, and experimental conditions that both brain signals and fitted channel residuals frequently deviate from Gaussianity. We therefore introduce a distribution-aware, information-theoretic measure of effective connectivity based on channel capacity under general residual distributions. To estimate the resulting capacity from empirical, potentially non-Gaussian residuals, we develop a dual-flow min-max estimator based on normalizing flows, in which a generator searches over admissible input distributions under a power constraint while an observer estimates output entropy. We provide a theoretical characterization of the estimator, showing that the observer objective recovers differential entropy up to a KL approximation term, that the formulation reduces to classical Gaussian capacity as a special case, and that residual entropy can alter achievable information rates beyond variance; game-gap and error analyses further characterize optimization and approximation sources. In brain-like simulations with known directed connectivity, Dual-flow achieves the highest AUROC and AUPRC across ten conditions spanning diverse network topologies, hidden drivers, feedback, and heterogeneous hemodynamics, compared with Gaussian capacity, Granger causality, VAR-LiNGAM, and GIMME. Applied to multimodal brain signals, the method reveals time- and condition-resolved directed interactions consistent with known neurobiological circuitry. Together, these results establish a principled distribution-aware framework for effective-connectivity estimation beyond Gaussian residual modeling.

Engram cells in hippocampal CA1 represent contextual information associated with events experienced by animals and constitute a cellular substrate of episodic memory. Recent experiments have shown that a subset of hippocampal place cells is recruited as engram cells for individual contexts. However, the principle governing engram cell allocation across contexts remains unclear. Here, we develop an information-theoretic framework that quantifies the trade-off between spatial and contextual information encoded by CA1 neurons. Our theory shows that limited neural resources inevitably create competition among contexts for the recruitment of place cells as engram cells. Solving this optimization problem determines the fraction of engram cells allocated to each context as a function of its occurrence probability. The theory predicts a non-monotonic relationship between context probability and engram allocation, reflecting competition between spatial and contextual information under resource constraints. Consequently, the recruited fraction emerges through a discontinuous transition at a critical probability, reaches a maximum at intermediate probabilities, and decreases for highly frequent contexts. Furthermore, we analytically derive the phase boundary for the emergence of finite engram cell allocation as a function of contextual input strength and the relative importance of contextual information. These findings identify competition for limited neural resources as a key determinant of engram cell allocation and provide experimentally testable predictions for how memory representations are distributed across contexts under resource constraints.

We prove that, in phenotype-structured populations under uniform competition, the long-term phenotypic distribution does not depend on the proliferation rates: it is the stationary distribution of the switching dynamics alone. The density u(x,t) of cells with phenotype x evolves by advection and diffusion in phenotype space (switching) and by proliferation at a phenotype-dependent rate r(x,t), modulated by a factor g(U) common to all phenotypes, where U is the total population. This extends to continuous phenotypes a recent result for compartmental models. On a bounded interval with no-flux boundary conditions, the total population converges monotonically to the carrying capacity U*, the density converges in L1 to U*psi, where psi is the stationary density of the switching dynamics, and the nonlinear model is asymptotically equivalent to the linear one; by an explicit estimate, the imprint of fitness decays at the spectral gap of the switching dynamics. On the whole real line we prove the same convergence under two natural conditions, confinement and no escape to infinity, covering Ornstein-Uhlenbeck dynamics, multi-well landscapes, and heavy-tailed densities. If g'(U*) < 0 and psi satisfies a Poincare inequality, convergence is exponential in a weighted L2 norm, while no uniform L1 rate holds for Ornstein-Uhlenbeck dynamics. The proof follows the compartmental one: under uniform competition the reaction term has one sign, so its size is the growth rate of the total population, integrable in time, and the switching dynamics contracts the zero-mass perturbations it produces. Since it uses only the Markov semigroup generated by switching, the proof extends to general mechanisms; we apply it to nonlocal switching by jumps and to diffusions with non-gradient drift in bounded domains of R^d, whose stationary density is not of Boltzmann form and carries a circulating flux.

Ovarian follicle development has been modeled either by compartmental models, where developmental stages are represented by discrete compartments, or by physiologically structured population models (PSPMs), formulated as transport PDEs describing follicles along a continuous maturation variable. Compartmental models reproduce full-cycle hormonal and follicular dynamics but cannot describe cellular features. PSPMs capture multiscale behavior, yet lack a direct link to compartmental descriptions, making hormonal feedback difficult to incorporate. Here, we introduce a class of ODE systems derived as finite-dimensional reductions of PSPMs via a perturbative moment closure. These systems provide backbone approximations of the structured dynamics, retaining key nonlinear mechanisms governing recruitment, selection for dominance, and atresia while projecting maturation onto macroscopic variables. Zero- and first-order moments, derived from phenomenological assumptions regarding follicular maturation, allow us to realistically model follicle sizes and blood estradiol concentrations over one follicular wave. This application is supported by bovine data and likely generalizable to other mammalian species.