Seeds are fundamental to agricultural productivity but also act as potential vectors for pathogens, leading to substantial losses at seedling emergence. This study focuses on one major arable crop (i.e., Wheat) which is subject to significant biotic stress. The objective is to evaluate the efficacy of biocontrol agents as sustainable alternatives to conventional seed treatments, with the goal of enhancing seed protection and increasing tolerance to biotic threats. Multi-season trials were conducted, integrating physiological, molecular, and metabolic analyses to elucidate the responses of treated seeds across key developmental stages (development, maturation, and germination). The findings indicate that the effectiveness of biocontrol agents is influenced by both the genotype and physiological stage of the seeds. Biocontrol treatments were shown to induce specific defence mechanisms and reduce pathogen pressure. This research study will pave the way to develop robust assessment tools for evaluating the performance of biocontrol strategies and to optimise their deployment in seed protection frameworks.

Visual brand language is the set of visual properties that convey brand identity for a product. What is the impact of visual brand language on a person's ability to recognize and understand the functional identity of an object? Using an empirically supported modeling framework based on the JIM model of object recognition and the LISA model of analogical inference, we simulated the impact of visual brand language on object recognition, the allocation of attention, and retrieval of functional information about objects. Our simulations predict that brand information captures attention and can slow recognition of an object's functional category, with greater degrees of branding causing larger effects. These results have potential implications for the usability and experience of designed objects.

Cells represent one of the most fundamental units of life. Underlying their robust performance against environmental variability, such as temporal fluctuations of chemical signals, between different cell types, is a dynamical interrelation between the two components of an intracellular pathway: a gene-regulatory network and its upstream signal transducers. To understand how a single cell utilizes this feedback to self-regulate its gene-expressions, we develop a multiscale model of the pathway's components, in which the adaptive variables responsible for signal interpretation follow a feedback-induced learning process. We then derive a macroscopic theory capturing the covariations between these components - so-called collective modes. Our theory shows how cells can achieve robust output against signal fluctuations via self-regulation rather than simple noise suppression. Such robustness corresponds to a transition from random- to structured collective modes beyond a critical adaptation rate.

Biological neurons assign credit across branching dendrites, where synaptic drive, dendritic conductance, local voltage, and somatic teaching signals interact to shape synaptic plasticity. We study conductance-based dendritic networks with E/I synapse banks, shunting inhibition, and tree-structured branch-to-soma coupling, and examine when restricted somatic feedback can approximate compartment-specific backpropagated errors. Exact gradients factor into local eligibility x compartment error terms: the eligibility uses presynaptic activity, driving force, and input resistance, whereas the fast non-local term is a path-specific error obtained by transporting a soma error through dendritic gains. This factorization turns local learning into a credit-signal compression problem. We test the hypothesis that shunting inhibition benefits learning under these constraints when it reshapes the compartment-error field to better match global scalar, per-soma, low-rank, or path-structured feedback. Exact-gradient reconstruction verifies the factorization; path-gain, rank, broadcast-fidelity, inhibition-intervention, and transported-error-oracle diagnostics support the proposed mechanism. Under nonnegative conductances and per-soma 5-factor (5F) feedback, shunting LocalCA remains 5--6 percentage points below matched backpropagation on MNIST, Fashion-MNIST, and figure-ground MNIST, indicating that feedback-field fidelity remains a major bottleneck. These results show how E/I conductance, shunting inhibition, and dendritic branching can reshape credit-signal geometry in restricted local learning.

Models of complex systems often have many parameters, yet are constrained by far fewer experimentally accessible observables: similar activity can emerge from coordinated parameter changes. We formalize these compatible parameter sets as \emph{viable parameter manifolds}: the inverse images of a system's target dynamical behaviors under a parameter-to-feature map. The relevant codimension is not the number of reported features, but the effective rank of that map at the target scale. Co-varying features lower the codimension, while poor conditioning, high curvature, or regime mixing degrade learnability. We train conditional score-based diffusion models on simulated parameter--feature pairs and use them as amortized samplers of prior-weighted viable sets. In the Lorenz system, scalar trajectory statistics generate thin viable sheets, and two-feature conditioning localizes a transition-adjacent corridor. In the Izhikevich neuron model, four firing descriptors lie close to a nearly two-dimensional family of features, and the learned inverse images reveal distinct regular and irregular compensation geometries. In a recent ODE reduction of finite spiking networks, the same framework reveals excitatory--inhibitory compensation, timescale--coupling tradeoffs, and input-dependent viable manifolds across 4--12 parameter dimensions. In this view, robustness, compensation, and hidden parameter dependencies are organized as inverse geometry, with diffusion models providing practical tools for sampling, visualizing, and interrogating that geometry.

Microbial keratitis requires rapid pathogen identification to guide treatment, but culture- and PCR-based diagnostics are slow and resource-intensive. We developed a triple-phase multimodal framework for bacterial-versus-fungal keratitis classification using slit-lamp photographs acquired under blue-light, sclerotic-scatter, and white-light illumination, together with clinical metadata. The model combines cross-modality contrastive learning, modality-specific fine-tuning, and feature-level multimodal ensemble learning for patient-level prediction. We evaluated the framework on a multicenter dataset of 1,645 patients and 17,158 images from India and the United States. The model achieved 85.84% accuracy, 84.46% average F1-score, and 0.885 AUC. Site-specific evaluation showed that pooled results were overly optimistic, whereas resampling- and balance-based re-evaluation provided a more realistic assessment of cross-site generalization. Under all settings, our framework remained the top-performing approach. Upon acceptance, the code will be released and dataset access will be provided subject to University of Michigan data-sharing clearance.

Codon harmonization aims to adapt the coding sequences for heterologous expression while preserving the native-like patterns of frequent and rare codons that may influence local translation dynamics and co-translational protein folding. However, widely used harmonization metrics, such as $\%$MinMax, are defined on discrete codon sequences and are, therefore, not readily compatible with gradient-based neural codon design. Here, we introduce Smooth $\%$MinMax, denoted as $\%{\rm MinMax}_{(s)}$, a differentiable relaxation of the conventional hard $\%$MinMax metric, denoted as $\%{\rm MinMax}_{(h)}$. $\%{\rm MinMax}_{(s)}$ replaces the discrete codon-usage values with probability-weighted synonymous-codon usage values and replaces the hard $\%$Max/$\%$Min branch with a sigmoid-gated interpolation. This formulation preserves the signed interpretation of $\%{\rm MinMax}_{(h)}$, while enabling optimization with respect to the synonymous-codon probabilities and learnable parameters. In human-to-Escherichia coli codon harmonization experiments, $\%{\rm MinMax}_{(s)}$ closely approximates $\%{\rm MinMax}_{(h)}$ and supports gradient-based profile matching in synonymous-codon probability space. These results suggest $\%{\rm MinMax}_{(s)}$ as a practical bridge between profile-based codon harmonization and neural synonymous-sequence design.

Precise sound localization relies on microsecond sensitivity to interaural time differences (ITDs), yet binaural perception exhibits sluggish tracking of dynamic acoustic cues. How these properties coexist remains unresolved. Here, ITD is represented as a stable equilibrium of neural population dynamics rather than by the classical place-coding framework originally proposed by Jeffress in 1948. In this framework, excitatory and inhibitory interactions across frequency channels generate a population signal that drives a dynamical system toward an equilibrium corresponding to the estimated ITD. Despite relying on relatively slow temporal dynamics, the model achieves microsecond-level precision and reproduces key physiological observations, including frequency-dependent best-delay distributions, without requiring explicit delay lines or precisely timed inhibition. These findings provide a potential explanation for how precise ITD sensitivity can arise from slow neural dynamics.

Multi-compartment Hodgkin-Huxley (HH) models provide a principled framework for predicting neural dynamics and responses to electrical stimulation. However, fitting HH biophysical parameters typically requires intracellular recordings, which are invasive and low-throughput, limiting the ability to capture the geometry and cell-specific properties of many neurons in a given neural circuit. Multi-electrode arrays (MEAs) offer a scalable alternative - high-density extracellular measurements from full neural populations, but HH model complexity has so far precluded reliable biophysical inference from extracellular data alone. Here, we introduce a framework to rapidly infer HH parameters from designed features of extracellular MEA measurements by leveraging differentiable biophysical simulation and simulation-based inference, unlocking a wide range of downstream applications. In this work, we focus on a central goal of translational neuroengineering: predicting neural spiking responses to candidate neurostimulation patterns that would take hours to measure clinically. To validate our approach, we collected hundreds of hours of stimulation and recording data from isolated macaque retina with a 30 um-pitch 512-electrode array. Our framework predicted previously unseen multi-electrode stimulation responses with 90.6% accuracy using HH models fit from only a few minutes of recording, replacing hours of stimulus testing.

Arthur Guyton's classic pressure-natriuresis model posits that dietary sodium challenges induce a transient expansion of blood volume that the kidneys rapidly rectify to restore a strict homeostatic baseline, reducing cardiac output to baseline values despite continued higher sodium diet. While this model remains a cornerstone of medical education, it was established in animal models that included surgical reductions in renal mass. Decades of direct human evidence, including long-term balance and spaceflight simulation studies, show that healthy individuals exhibit substantial, persistent plasma volume expansion and sustained cardiac output elevation during prolonged high-sodium intake with little effect on the mean arterial blood pressure. To reconcile these empirical inconsistencies, we propose "sodium allostasis" as an alternative regulatory framework. We argue that sodium regulation operates via two distinct mechanisms: a strict concentration homeostasis that maintains plasma sodium levels (~140 mEq/L) via dilution, and an allostatic accommodation that can sustain a persistently expanded blood volume and higher total body sodium mass. This paradigm fundamentally reframes salt sensitivity. Rather than a primary defect in renal sodium excretion, salt sensitivity reflects a failure of the vasculature to accommodate expanded plasma volume. Furthermore, human and animal data reveal that this chronic allostatic state carries a hidden, profound metabolic cost, forcing energy-intensive sodium reabsorption into poorly oxygenated renal medullary segments and inducing tissue hypoxia independent of blood pressure. Shifting focus from rigid homeostatic volume regulation to vascular accommodation and sodium allostasis provides an accurate physiological foundation for cardiovascular medicine and opens novel, vascular-targeted therapeutic pathways for hypertension and volume disorders.

Generative models present a promising alternative to expensive molecular dynamics for computationally querying protein dynamics, yet many existing approaches treat ensembles as unordered snapshots rather than temporally coherent trajectories, or scale poorly with protein size. We present a new physics-informed representation using Fourier transforms as an inductive bias for the multiscale temporal nature of protein dynamics. Diffusion in the spectral domain allows for disentangling of dynamics into slow conformational modes and fast atomic jitter, enabling rapid and improved prediction of dynamics across a range of temperatures. This is facilitated by denoising of structure and temperature conditioned spectral volumes where the low frequencies directly encode per-residue flexibility. Trained on the mdCATH dataset, we evaluate our model, DynaMode, on a held-out test set achieving strong performance across a set of ensemble-based metrics including a Root Mean Squared Fluctuation (RMSF) pearson $r$ of $0.844$. Code is available at this https URL.

This work presents a stochastic exploration framework for large, implicitly defined chemical reaction spaces that are too large to be generated and stored as explicit molecular networks. The exploration strategy mimics stochastic chemical kinetics by combining collision-based pair selection with reaction-template instantiation on demand. In each step, the algorithm first samples molecules to collide, then samples a reaction template, and finally samples a concrete reaction instance among the matches of that template. This collision-first factorization avoids exhaustive enumeration of all currently possible reactions and enables exploration of large atomistic reaction spaces under open- or closed-system conditions. We demonstrate the framework on formose chemistry as a case study and analyse both the chemical behaviour reached by the exploration and the computational effects of caching. The implementation is intended as a general tool for exploratory analysis of generative reaction systems.

How can a species persist in an environment where it is always outcompeted? Using a minimal predator-prey model with environment-dependent parameters, we show that a predator driven to extinction in each of two static environments can survive indefinitely once the environment alternates between them fast enough. We derive the critical switching rate above which persistence occurs, and show that random (Poisson) switching needs to be faster than periodic switching in order to offset prolonged spells in the unfavorable environment. We then generalize the mechanism to any two-species system, and can predict persistence solely based on the sign of a single ``switching rescue function" assembled from the two boundary vector fields. This general result has broad reaching consequences: for instance, when applied to a standard model of viral dynamics, it predicts that two drugs which each clear a pathogen on their own can fail when alternated, giving a non-resistance-based explanation for the failure of drug-cycling strategies. Our results demonstrate that the tempo of environment change, as opposed to the environments themselves, can lead to species survival.

We mathematically model the dynamics of the number of migratory fish observed at a fixed location along a river in a random environment. Particularly, as a new approach, we construct a stochastic differential equation that incorporates the influence of environmental factors on the fluctuations in the start and end of migration. The model is a diffusion bridge with a non-Lipschitz diffusion coefficient, called the Cox-Ingersoll-Ross bridge, and has random initial and terminal times arising from time-change, so that the influences of environmental factors can be efficiently incorporated. The well-posedness of the model is first established, which is considered novel and significant in applied mathematics. Second, we estimate the parameters of the model based on the latest multiyear daily data set for the upstream migration of Plecoglossus altivelis altivelis (Ayu) by relying on the hypothesis that water temperature affects the migration of the fish, which has been suggested in existing studies. We also explore the application of the proposed model to the challenging task of analyzing environmental DNA data. This study advances the development of a theory of fish migration that is simple yet can take environmental factors into account.

We propose and analyse a mathematical model of evolutionary adaptation for non-degenerate (permanent) replicator systems, in which the fitness landscape matrix evolves on a slow timescale -- the evolutionary time -- while the species dynamics unfold on a fast timescale. Under a two-timescale separation justified by Tikhonov's theorem, the adaptation problem reduces to maximising the mean fitness at steady state over a convex admissible set of fitness landscape matrices. We derive a fitness variation formula and establish necessary and sufficient conditions for a fitness maximum, showing that the optimisation reduces at each step to a linear programming problem. The algorithm is applied to four canonical replicator systems: the hypercycle, the bi-hypercycle, the anthill system, and the RNA molecule network. In all cases the evolutionary process follows a universal three-phase pattern: an initial phase of fitness growth without equilibrium shift, during which purely altruistic replication gives way to mixed altruistic-selfish behaviour; a second phase of dominant species emergence; and a stabilisation phase analogous to the error catastrophe threshold in quasispecies models. A key consequence is that all evolved systems acquire resistance to parasitic species. We further prove that without non-degeneracy constraints the process leads to sequential species annihilation, with a provable spectral lower bound on fitness increase by dimension reduction.

Comparing whether two dynamical systems implement the same computation despite differences in coordinates or measurements is a central problem in neuroscience and machine learning. Dynamical Similarity Analysis [DSA; Ostrow et al., 2023] addresses this problem by aligning finite-dimensional Koopman approximations through an orthogonal similarity transformation. Here we show that orthogonal alignment is neither necessary nor sufficient for topological conjugacy: conjugate systems may require a non-orthogonal basis-transfer matrix that DSA cannot capture, while non-conjugate systems may have orthogonally equivalent Koopman operators that DSA fails to distinguish. We use this observation to formulate Conjugacy-based Similarity Analysis (CSA), which restricts alignments to those induced by candidate state-space bijections rather than arbitrary orthogonal matrices. We prove that CSA's fitted alignment is the finite-data projection of the composition operator associated with the candidate bijection, and use controlled examples to show why this distinction matters when observable dictionaries are chosen explicitly or implicitly from data. These results clarify what Koopman-based similarity measures must ensure to support claims of identifying conjugacies between computational systems.

Understanding the differences between individual instances of the same complex system remains a central challenge, particularly in biological contexts. Parenclitic networks constitute a suitable means to detect deviations in correlations with respect to reference populations. Here, we introduce parenclitic hypergraphs, a general framework for identifying anomalies in higher-order correlations across arbitrary interaction orders. After validating the method on synthetic datasets and benchmark ones, we apply it to patient-derived cancer organoids, capturing temporal changes in gene expression between healthy and cancerous tissues as the disease progresses. Our approach not only reproduces known oncogenic signatures, but also reveals a previously unrecognized candidate therapeutic target. Since organoids are generated from individual patients, our method provides, for the first time, a viable protocol for personalized cancer therapy based on higher-order correlation patterns. These findings offer a novel, systems-level strategy for precision oncology grounded in complex systems theory.

Artificial Intelligence has had a profound impact on the biological sciences, and in particular has accelerated research on protein form and function. Enzymes are no exception: a surge of predictive models have been recently developed to address a range of enzyme tasks. Models addressing enzyme-substrate (ES) or enzyme-reaction (ER) compatibility could be especially valuable for enzyme annotation, biosynthetic pathway elucidation, and biocatalyst retrieval, the central challenge of which is the identification of a true catalyst (or truly compatible reaction) among many similar candidates. While existing models report strong performance on alternative benchmarks, less is known about their capabilities in this regime. Herein, we benchmark four recently released ES and ER prediction models, using tasks and datasets tailored to this setting. We first show that two representative ES prediction models perform near random baselines across two enzyme families when considering enzymes and substrates not encountered during training. To evaluate additional models across a consistent dataset, we next assemble the largest cytochrome P450 (CYP) reaction dataset to date, 2,922 reactions across 768 enzymes, and construct a CYP ranking benchmark requiring the correct enzyme to be prioritized among all CYPs in its native organism. We again find that most models do not outperform sequence-based (BLAST) baselines even after fine-tuning. We finally adapt the bimolecular structure prediction model Boltz to ES prediction by training supervised classifiers on residue-ligand pair embeddings, and show that this approach consistently surpasses the BLAST baselines on our CYP ranking benchmark. Together, our results argue for more discovery-relevant benchmarking and suggest that interaction-aware representations from full biomolecular complexes may provide a promising basis for enzyme prioritization.

Due to the challenges of analyzing and storing massive volumes of genomic and metagenomic sequence data, significant efforts have been made to accelerate (meta)genomic analyses and store sequence data compressed. Despite the benefits of these techniques, we identify two major outstanding problems in accessing stored sequence data and supplying it to the analysis units: (i) the data movement bottleneck due to moving large amounts of low-reuse data from storage and the unnecessary burden on the rest of the system, and (ii) the data preparation bottleneck, where compressed sequence data needs to be first decompressed and formatted before analysis. We present customized storage-centric systems, which efficiently (i) analyze (meta)genomic data inside storage, and (ii) enable highly-compressed storage and high-performance access of large-scale sequence data, thereby alleviating the overheads of data movement, computation, and data preparation. First, we introduce GenStore, an in-storage processing system that filters genomic data not requiring expensive computation directly inside storage. Second, we propose MegIS, an in-storage processing system that significantly reduces the data movement overhead of metagenomic analysis. Third, we introduce GRAINS, a storage-centric system for analysis on large-scale (meta)genomic graphs in storage. Fourth, we propose SAGe, an algorithm-architecture co-design for highly-compressed storage and high-performance access of sequence data. We demonstrate that the proposed systems significantly (e.g., by one to two orders of magnitude) improve performance, energy efficiency, and cost-efficiency, all at the same time. We hope these systems facilitate broader adoption of (meta)genomics and inspire research on other data-intensive domains in health and life sciences.

Introduction: Objective neuroimaging biomarkers may improve Parkinson's disease motor assessment by capturing brain variation not directly observable from clinical examination. We used interpretable machine learning to predict current motor severity, measured by MDS-UPDRS Part III, from QSM and multiband multi-echo resting-state fMRI-derived ReHo features. Methods: Regional QSM and ReHo features were extracted from 28 participants, including 24 individuals with Parkinson's disease and 4 controls. Thirteen feature-set experiments evaluated imaging-only, clinical-only, imaging-plus-clinical, full, reduced, and multimodal inputs. Support vector regression, Elastic Net, Random Forest, and XGBoost models were trained using nested cross-validation. Performance was assessed using pooled held-out R^2, RMSE, MAE, Pearson correlation, permutation testing, and the proportion of participants predicted within +/-5 MDS-UPDRS Part III points. Results: Imaging-only models carried meaningful predictive signal, whereas the clinical-only model performed weakly. Full fMRI, full QSM, and clinical variables provided the strongest global fit, explaining 45.4% of variance in motor severity. Selected QSM plus clinical variables produced the most clinically close predictions, with 75.0% of participants predicted within +/-5 points and the lowest MAE among top-performing models. SHAP highlighted cerebellar, thalamic, striatal, insular, and motor cortical features. Conclusion: QSM and multiband multi-echo fMRI-derived ReHo capture distinct, interpretable dimensions of Parkinson's disease motor severity. These findings show that structural and functional imaging contribute differently depending on the clinical prediction goal.

Computational models of the human heart are widely used to study electromechanical and fluid-dynamical cardiac function and to support applications such as in silico clinical trials. However, most studies remain limited to single or patient-specific anatomies, restricting the inclusion of population-level variability required for uncertainty quantification. A key challenge is translating medical-image segmentations, which may contain artifacts, mesh defects or disjoint domains, into topologically coherent geometries suitable for multiphysics simulations. In this work, we present a semi-automatic pipeline that converts CT-based segmentations into simulation-ready cardiac meshes within a few minutes while preserving anatomical and topological consistency. Building on modern deep learning segmentation methods, the framework incorporates a template-based registration stage to regularize artifacts and enforce mesh-quality constraints. A Chamfer-distance morphing strategy deforms a high-quality template toward each segmented heart, matching individual chambers while preserving topology. The resulting meshes are watertight, isotopological, and endowed with consistent point-to-point correspondence. The pipeline is validated on 58 healthy cardiac CT scans, including all cardiac chambers and proximal vessel segments. The resulting meshes can be represented in a unified shape space, enabling the construction of a statistical shape model of the heart and major vessels. Principal Component Analysis shows that a low-dimensional latent space efficiently captures population variability, while Gaussian Mixture Modeling enables synthetic anatomy generation. Overall, the proposed framework (released open-source) provides a pathway from raw segmentations to simulation-ready cardiac geometries, enabling anatomically consistent virtual cohorts for large-scale in silico studies.

Neuroimaging research requires manipulating heterogeneous data structures, including raw MRI volumes, volumetric parcellations, cortical surface meshes, tractograms, and connectivity matrices, across tools with incompatible interfaces and file formats, forcing researchers to repeatedly re-implement routine but technically demanding operations. We present CLABTOOLKIT, an open-source Python package that consolidates these operations into a single, coherent framework by representing volumetric, surface, and streamline data as interoperable Python objects. Five core data structures (Parcellation, Surface, AnnotParcellation, Tractogram, and Connectome) encapsulate common neuroanatomical entities and provide consistent methods for loading, processing, and exporting data across standard neuroimaging formats (e.g., NIfTI, GIFTI, FreeSurfer annotations, TCK/TRK), including connectome generation from a parcellation and scalar-map projection onto tractogram streamlines. Complementary modules support BIDS dataset management, FreeSurfer integration, diffusion MRI processing, morphometric analysis, graph-theoretical network analysis, and GPU-accelerated multi-panel visualization via PyVista. The toolkit comprises 19 modules organised into six layers, exposing 13 object-oriented classes with 234 methods and 207 standalone functions, and a JSON-based configuration system enables workflow customization without code changes. Unlike existing neuroimaging libraries, which typically address these tasks separately, CLABTOOLKIT combines color and lookup-table management, parcellation manipulation, multi-surface visualization, and tractography utilities within a single framework. CLABTOOLKIT is compatible with Python 3.9-3.12 and released under the Apache 2.0 license. Source code, documentation, and example workflows are available at this https URL.

Pathologic complete response and tumor shrinkage measure whether breast cancer responds to neoadjuvant therapy, but not whether that response was structurally favorable, persistent, or hidden beneath volume loss. We built an outcome-blind longitudinal DCE-MRI manifold from I-SPY2 trajectories to test whether pretreatment imaging carries a structural response phenotype missed by conventional descriptors. The dominant axis of response geometry was not recoverable from the full clinical and genomic stack -- age, receptor subtype, MammaPrint, PAM50, treatment arm, and tumor burden -- but became strongly recoverable once baseline structural entropy was added. A constrained representation mapping recovered the same axes as unconstrained decomposition, establishing the structure as intrinsic rather than a post-hoc interpretation. The phenotype persisted through therapy, and as treatment proceeded the volumetric signal faded while entropy stayed separated -- a crossover from burden to structural persistence. Among complete responders, structurally disordered tumors could shrink more early yet remain structurally disordered, a volumetric deception invisible to endpoint labels. External analyses in UCSF, I-SPY1, and Duke established recurrence relevance under representation-dependent boundaries, and a representation-family commensurability assessment showed why feature-name matching is insufficient: the same label can fail, transport, or entangle with extraction geometry. Pretreatment MRI therefore exposes a structural response phenotype that endpoint-based language leaves invisible -- including, among complete responders, a pretreatment imaging signal of structurally distinct response states that awaits prospective validation.

Recent advances in molecular large language models have led to strong performance on molecular understanding and generation tasks, yet these gains often come without reliable structural grounding. In particular, existing approaches conflict with the chemistry principle that structure determines function: despite their downstream success, current molecular LLMs perform poorly on basic structure recognition, suggesting that they fail to capture molecular graphs from canonical SMILES. To remedy this, we propose MolBasic, a structure-first framework that strengthens structural comprehension via SMILES-Graph translation. MolBasic is built around a multi-level structure perception benchmark, where bidirectional SMILES-Graph conversion serves as the core task to align sequential and topological representations. On top of this foundation, we employ a progressive learning scheme with a standardized Chain-of-Thought (CoT) to steer models from structure acquisition toward higher-level molecular reasoning. Experiments show that MolBasic substantially improves structural understanding and yields robust gains on downstream tasks, including property prediction and objective optimization, supporting our structure-first paradigm.

Functional laws of large numbers (FLLNs) describe the mean-field trajectory of epidemics on networks, but say nothing about the fluctuations around it. These fluctuations are governed by moments of the degree distribution not relevant at the level of the mean. A rigorous functional central limit theorem (FCLT) exists for the susceptible--infected ($SI$) process on configuration-model graphs, but no analogue exists for $SIS$, where recovery reintroduces vertices into the susceptible pool with partially known neighborhoods, breaking the clean neighborhood distribution the $SI$ derivation relies on. We develop a tractable variance approximation for Markovian $SIS$ on configuration-model graphs, combining Gleeson's approximate master equation (AME) framework with a van Kampen system-size expansion in the spirit of the $SI$ FCLT. We derive a closed drift and diffusion matrix for a reduced susceptible/$SI$-edge/$SS$-edge count vector and obtain the time-dependent covariance via the associated Langevin/Lyapunov equation. Validation against Gillespie simulation across Poisson, regular, and power-law networks shows close agreement, with deviations near the epidemic threshold and in strongly heterogeneous networks.

Reliable analysis of bird vocalisations in passive acoustic monitoring requires models handling multiple, imbalanced annotation targets. We extend BirdCallNet for joint species and call-type classification on the long-tailed WiWa dataset and investigate how task-loss balancing interacts with pretrained representations and adaptation depth. We evaluate four bird-domain encoders, ConvNeXtBS, EAT, BirdMAE, and ProtoCLR, with separate species and call-type heads under linear probing, attentive probing, and full fine-tuning. A manually tuned fixed objective is compared with homoscedastic uncertainty weighting and Dynamic Weight Averaging across all three adaptation regimes, while GradNorm is evaluated only under full fine-tuning. Results indicate that the factorised multi-task formulation yields the most consistent improvements over the combined single-task baseline for call-type recognition, while its effect on species recognition depends on the adaptation regime. Full fine-tuning is not consistently optimal: ConvNeXtBS achieves the highest mean species performance under linear probing, whereas BirdMAE provides the strongest call-type performance under attentive probing. Adaptive weighting benefits species recognition more consistently than call-type recognition. Uncertainty weighting is particularly effective for species recognition under attentive probing, whereas Dynamic Weight Averaging is generally stronger for the same task under full fine-tuning. GradNorm achieves competitive call-type performance for selected backbones but consistently underperforms other weighting strategies for species recognition and incurs higher computational and memory costs. Overall, the preferred loss-balancing strategy depends on the backbone, adaptation regime, and target task, while frozen-backbone adaptation can provide a more favourable performance-efficiency trade-off than end-to-end fine-tuning.

Accurately modeling biomolecular interactions is a central bottleneck in biology and therapeutic discovery. Here, we introduce Open Drug Discovery Engine (OpenDDE), an open-source, all-atom biomolecular foundation model that uses co-folding as the entry point to a scalable AI-driven drug discovery engine. Rather than treating structure prediction as an isolated endpoint, OpenDDE is designed as a shared structural reasoning layer for modeling sequence-structure-function relationships across biomolecular complexes, enabling complex structure prediction today while providing a foundation for de novo design, affinity estimation, structure-conditioned optimization, and more. OpenDDE integrates advances in all-atom architecture, atomic latent reasoning, inference optimization, and large-scale data processing to achieve IsoDDE-level co-folding accuracy within a reproducible and openly accessible framework. We also identify two scaling-law directions for co-folding models, revealing practical routes for continued improvement through data, model, inference, and training scaling. By releasing training code, inference pipelines, checkpoints, and benchmarks, OpenDDE aims to democratize access to frontier biomolecular intelligence, accelerate global collaboration, and lay an open foundation for next-generation drug discovery systems that can move from predicting molecular structures toward designing, scoring, and optimizing therapeutic candidates for human health.

The basic reproduction number is the spectral radius of a matrix, $R_0=\rho(K)$. Taking that definition literally, we ask what $K\mapsto\rho(K)$ discards. A matrix carries three kinds of information: its dominant eigenvalue, its dominant eigenvectors, and its departure from normality. $R_0$ keeps only the first; the other two are where the epidemic's social structure lives. The right eigenvector is the burden distribution, the left the source distribution; they coincide when the system is normal and diverge under heterogeneity. Across the $177$ national contact matrices of Prem et al., the operator is \emph{never} normal, and once age-specific susceptibility is included, its source and burden eigenvectors are misaligned by a median of $26^{\circ}$, exceeding $40^{\circ}$ in some countries: the groups that drive transmission are systematically not those that bear it. We prove that under reciprocal contact this misalignment obeys a Kantorovich bound set by the susceptibility contrast $q_{\max}/q_{\min}$ alone, and zero when susceptibility is uniform, with the excess in real, non-reciprocal matrices contributed by contact asymmetry. Transient amplification, by contrast, stays small, so the operative social content is the misalignment, not transient blow-up. The omission also has teeth: because minimizing $R_0$ protects those who \emph{spread} infection, while minimizing deaths protects those who \emph{die} from it, the two target different age groups; the former sometimes raises average infection fatality even as it lowers the scalar. When contact is strongly structured and susceptibility is heterogeneous, we suggest reporting $R_0$ along with its eigenvectors rather than reporting it alone.

The transition of Large Language Models (LLMs) from passive generators to autonomous agents has introduced significant challenges in reliability, security, and state management. Current agentic architectures are often constructed ad-hoc, prone to hallucination cascades, infinite loops, and prompt injection attacks. This paper argues that many of these failure modes can be analyzed using control motifs long studied in systems biology, provided the comparison is made at the level of typed interfaces and coordination structure rather than literal biological mechanism. We develop a typed interface correspondence between Gene Regulatory Networks and agentic software systems using polynomial functors and wiring diagrams. Five biological motifs are mapped to composable software design patterns: Coherent Feed-Forward Loops for noise suppression, Adaptive Immunity for layered security, Mitochondrial Signaling for resource governance, Endosymbiosis for neuro-symbolic integration, and Morphogen Diffusion for spatially varying coordination. An epistemic topology layer derives Kripke-style knowledge operators from the wiring diagram's observation structure and proves four predictive theorems for multi-agent scaling. The core contributions are: (1) the Agentic Operad, a typed syntax for agent composition with provable error suppression bounds for feed-forward topologies; (2) an epistemic topology with four theorems (error amplification, sequential penalty, parallel acceleration, and tool density scaling) whose qualitative predictions are consistent with published multi-agent benchmarks; and (3) a six-layer progression from structure through development, grounded in autonomous learning frameworks and convergence proxies from the empirical literature. A reference implementation with 1,813 tests and 116 examples illustrates practical feasibility.

Biological systems exhibit a hierarchical structure, characterised by directed flow from upstream regulators to downstream effects. Although this ordering provides a natural scaffold for causal inference, most causal discovery and GRN methods either ignore the tiered organisation or condition on all upstream variables, which becomes infeasible for high-dimensional omics data. We present ASCEND (Ancestral Scalable Causal discovEry via iNherited Descent), a constraint-based framework that leverages known two-tiered structure to enable genome-scale causal discovery. ASCEND introduces a divide-and-conquer strategy that maintains dynamically updated ancestral conditioning sets for each downstream variable, dramatically reducing the number of conditional independence tests required, and achieves polynomial-time complexity where traditional approaches face exponential blow-up. Through extensive simulations and real biological data, we demonstrate that ASCEND accurately recovers ancestral relationships, scales properly and much faster, and outperforms existing gene regulatory network inference methods in both causal precision and computational efficiency. The algorithm's ability to resolve directionality makes it particularly suited for integrating multi-omic data where upstream regulators (e.g., SNPs, methylation sites) and downstream responses (e.g., gene expression) are measured jointly.

Accurate prediction of patient-specific therapeutic response from pre-treatment transcriptomes is hindered by the scarcity of matched clinical response labels and post-treatment molecular profiles. Preclinical transfer-learning models can simulate drug-induced expression changes but are often hard to interpret and unstable, whereas knowledge-graph methods provide mechanistic context yet remain static and fail to capture drug-induced transcriptomic perturbation dynamics. We propose PREDIKTOR, a patient-centered multi-view framework that aligns a personalized network view with a transferable transcriptomic perturbation view to predict clinical drug response. For each patient, we construct an individualized gene regulatory network from tumor expression using DysRegNet and augment it with drug-target links from DrugBank; a graph neural encoder yields a drug-centric, mechanistically grounded embedding. In parallel, a frozen condition-specific gene-gene attention model pretrained on LINCS L1000 generates a simulated post-perturbation transcriptomic profile for the same patient-drug pair. We align the two views in a shared latent space via a CLIP-style contrastive objective with drug-context hard negatives, then concatenate the representations for end-to-end response classification. On TCGA, PREDIKTOR consistently outperforms state-of-the-art baselines under patient-, drug-, and tissue-split evaluations, and transfers zero-shot to the I-SPY2 trial, improving AUROC by 5.6% over competing methods. The aligned embeddings yield stable gene and pathway attributions that recover known mechanisms, supporting actionable and interpretable precision oncology.

Most classification problems assume the classes are roughly separable, so that an individual sample can usually be assigned to one class. Single-cell perturbation data violates this assumption: two perturbations can produce different populations of cells while overlapping so much that an individual cell could belong to either. Per-cell accuracy then measures this overlap rather than model quality. We see this on Tahoe-100M and the Virtual Cell Challenge, where a linear classifier, an MLP, and a Transformer all plateau near macro-F1 0.2-0.3 even though almost every pair of perturbations is statistically distinguishable. The fix is to score perturbations across the whole population rather than cell by cell. We average a classifier's per-cell probability vectors over all cells of a perturbation to form a population profile, then rank candidate perturbations by this profile; we call the resulting score the Classifier Discrimination Score (CDS). Taking the top-ranked class recovers the winning perturbation. It needs no retraining, costs linear time in the number of cells, and recovers near-perfect identification from the same weak models. CDS differs from the pseudobulk-based Perturbation Discrimination Score (PDS) used in recent benchmarks only in where the average is taken, raw gene expression for PDS versus a learned discriminative space for CDS, and identifies the true perturbation more reliably on both datasets, with the gap widening as cells grow scarce. Because a metric that misranks the ground truth will misrank the models scored against it, per-cell accuracy and raw-pseudobulk scores should be used with caution when comparing perturbation models.

We study dynamical systems arising from reaction networks under mass-action kinetics. For certain choices of the rate constants (parameters), such systems are complex-balanced (vertex-balanced), which guarantees the existence of a unique positive equilibrium. Moreover, this equilibrium is asymptotically stable (admitting a global Lyapunov function) and linearly stable. In a series of recent papers, Craciun and collaborators introduced and studied disguised complex-balanced systems, that is, mass-action systems that are dynamically equal to auxiliary complex-balanced systems and therefore inherit their strong stability properties. Determining the parameter values for which a given system is disguised complex-balanced is a nontrivial algebraic problem. In this work, we show that the defining conditions for disguised complex-balanced equilibria naturally give rise to parametrized systems of polynomial inequalities. Using the framework for positive algebraic geometry developed by Müller and Regensburger, we reformulate these systems as binomial equations (on the disguised complex-balanced flux cone). Computing the disguised complex-balanced parameter locus can be viewed as a quantifier-elimination problem, and our approach eliminates the concentrations (state variables) from the problem. We illustrate our results using the running example of a recent paper by Boros et al.

Cell-type deconvolution, the task of estimating the proportions of constituent cell types in a heterogeneous biological sample, is a core problem in computational biology. Methods that rely on epigenetic marks such as DNA methylation typically operate on aggregated methylation estimates, discarding the pattern-level information carried by individual DNA reads. Existing read-level approaches that exploit this information are scarce, and all remain restricted to few-class settings; scaling them further is an open problem because, at scale, non-discriminative reads dominate and hard labels conflict with the many-to-many mapping between methylation patterns and cell types, preventing classifier convergence. To overcome this, we propose data-driven soft labels that estimate the conditional cell-type distribution for each read, and integrate this scheme into Syto, a new modular framework for read-level classification-based deconvolution. On a whole-body atlas of 39 human cell types, Syto reduces MSE by 2.56$\times$ over SoTA, with gains transferring to an out-of-distribution dataset spanning 16 tissues. Syto lays the foundation for modeling increasingly large cell-type panels, with improved applications in biology and healthcare. The proposed soft-labeling scheme is further translatable to any setting with a many-to-many signal-to-label mapping.

Scientists often seek to draw causal inferences from structured data that is not independently and identically distributed, such as spatial data, network data, or molecular data. We develop geometric causal models (GCMs), a framework for causal inference from dependent data that exploits underlying symmetries of the data generating process. For example, in spatial data, we consider processes that are symmetric under translations, or in graph data, symmetric under permutations of the nodes. We show how symmetries, formalized with group theory, can enable causal identification and estimation. We deploy ergodic theory for amenable groups to establish identification, and combine geometric deep learning with scalable Bayesian inference for estimation. We recover i.i.d. causal models and do-calculus when the data is a sequence and the symmetry is permutation equivariance, and find novel types of causal models when we use alternate structures and symmetries. As an example, we construct a causal model that satisfies the symmetries of DNA. This GCM enables new estimators for the effects of genetic variation, combining deep functional genomics models to describe outcomes and DNA language models to describe propensities. We illustrate on semisynthetic data.

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests, and genetic tests over a prolonged period of time, a process commonly described as the diagnostic odyssey. Addressing this odyssey has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features that artificial intelligence algorithms can use to facilitate clinical diagnosis, to prioritize candidate diseases for further laboratory or genetic testing, and to support the phenotype-driven reinterpretation of genome or exome sequencing data. Existing methods that use frontal facial photographs were built on conventional convolutional neural networks, rely exclusively on facial images, and cannot capture non-facial phenotypic traits or demographic information that are essential for accurate diagnosis. Here we introduce GestaltMML, a multimodal machine learning approach based solely on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally a list of Human Phenotype Ontology terms) to improve prediction accuracy. We evaluate GestaltMML on 528 diseases from the GestaltMatcher Database and on several in-house and published cohorts, including Beckwith-Wiedemann syndrome, Sotos syndrome, NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome, and KBG syndrome. GestaltMML improves on the state-of-the-art image-only ensembled model, narrows the diagnostic accuracy gap for patients from under-represented ancestries, and clarifies when multimodal fusion is beneficial and when image-only inference is preferable. The results suggest that GestaltMML can greatly narrow the candidate diagnoses of rare diseases and may facilitate the reinterpretation of sequencing data.

Federated learning (FL) enables collaborative analysis of biomedical data without exchanging sensitive patient-level information, but its performance in multi-center studies may be compromised by batch effects which can obscure biological signals. Here, we systematically assess the impact of uncorrected batch effects on FL outcomes using four multi-center omics datasets, including transcriptomic, proteomic, and metabolomic data, and two representative algorithms: federated k-means clustering and federated random forest classification. Our results demonstrate that uncorrected batch effects undermine unsupervised FL and can substantially degrade supervised FL performance, indicating that privacy-aware batch-effect correction is essential for reliable FL. To enable privacy-preserving BEC in distributed bulk omics data, we introduce fedRBE ( this https URL ), a federated implementation of limma's removeBatchEffect() method enhanced by secure multi-party computation, suitable for datasets with missing values and non-identical feature sets across clients, including proteomics and metabolomics data.

Rational design of lipid nanoparticles (LNPs) for tissue-specific delivery critically depends on predicting the composition of the protein corona that forms on the lipid surface after intravenous administration. However, conventional characterization of the protein corona relies on costly and time-consuming mass spectrometry experiments, which require physically prepared liposome samples and therefore cannot serve as a pre-synthesis screening strategy for large candidate lipid spaces. The adsorption of plasma proteins onto liposomal surfaces is shaped by lipid chemical structures, protein properties and the biological environment, making this process difficult to simulate directly. In this work, we propose that scoring lipid-plasma protein pairs and ranking the resulting scores can provide a practical signal for revealing the relative composition of the liposomal surface protein this http URL we introduce GenShin, a geometry-enhanced pose-free graph neural network designed to score lipid-plasma protein pairs. GenShin is pretrained on compound-protein affinity data to initialize a generalizable scoring function and is then fine-tuned on a rank fine-tuning dataset constructed from liposomal protein-corona abundance measurements to adapt the model to lipid-plasma protein pair scoring. Before fine-tuning, GenShin achieves competitive pose-free affinity prediction on the PDBbind v2016 benchmark compared with representative pose-dependent models. CASF-2016 perturbation experiments using the pretrained GenShin model further show that pose-dependent inference substantially degrades when intermolecular poses are unreliable, whereas GenShin remains stable without requiring such poses. This supports the practical advantage of GenShin for large-scale lipid-protein scoring.

Terracettes, striking, step-like landforms that stripe steep, vegetated hillslopes, have puzzled scientists for more than a century. Competing hypotheses invoke either slow mass-wasting or the relentless trampling of grazing animals, yet no mechanistic model has linked hoof-scale behavior to landscape-scale form. Here we bridge that gap with an active-walker model in which ungulates are represented as stochastic foragers moving on an erodible slope. Each agent weighs the energetic cost of climbing against the benefit of fresh forage; every hoof-fall compacts soil and lowers local biomass, subtly reshaping the energy landscape that guides subsequent steps. Over time, these stigmergic feedbacks concentrate traffic along cross-slope paths that coalesce into periodic tread-and-riser bands, morphologically analogous to natural terracettes. Our model illustrates how local foraging rules governing movement and substrate feedback can self-organize into large-scale topographic patterns, highlighting the wider role of decentralized biological processes in sculpting terrestrial landscapes.

Identifying the network of species interactions is a fundamental step toward understanding ecosystem stability and biodiversity. However, the interpretability of empirical interaction measures remains a major challenge. Experimental estimates frequently exhibit puzzling temporal fluctuations, including sign shifts typically interpreted as transitions between competition and facilitation. Here, we analyze the temporal behavior of pairwise interaction measures to demonstrate that these fluctuations - and apparent shifts in ecological roles - can emerge intrinsically from standard population dynamics, without any underlying change in the actual ecological relationships. We show that inferred interactions are heavily distorted by experimental protocol choices, particularly the duration of observation and microbial growth constraints. By systematically evaluating interactions across timescales, we uncover a principled mechanism to mitigate these biases: short-term measurements reliably isolate direct, pairwise species couplings, whereas longer-term observations inevitably absorb indirect community feedbacks and systemic experimental constraints. By disentangling direct couplings from indirect network effects, our framework provides a robust, timescale-aware approach to interpreting empirical interaction matrices, offering critical quantitative guidance for experimental design and predictive ecosystem modeling.

Effective analysis in neuroscience benefits significantly from robust conceptual frameworks. Traditional metrics of interbrain synchrony in social neuroscience typically depend on fixed, correlation-based approaches, restricting their explanatory capacity to descriptive observations. Inspired by the successful integration of geometric insights in network science, we propose leveraging discrete geometry to examine the dynamic reconfigurations in neural interactions during social exchanges. Unlike conventional synchrony approaches, our method interprets inter-brain connectivity changes through the evolving geometric structures of neural networks. This geometric framework is realized through a pipeline that identifies critical transitions in network connectivity using entropy metrics derived from curvature distributions. By doing so, we significantly enhance the capacity of hyperscanning methodologies to uncover underlying neural mechanisms in interactive social behavior.

Encoding the distance between locations in space is essential for accurate navigation. Grid cells, a functional class of neurons in medial entorhinal cortex, are believed to support this computation. Inspired by recent work finding populations of grid cells to have small, but robust heterogeneity in their grid properties, we hypothesize that distance coding can be achieved by a simple de-correlation of population activity. We develop a mathematical theory for describing this de-correlation in one-dimension, showing that its predictions are consistent with simulations of noisy grid cells. Our simulations highlight a non-intuitive prediction of such a distance by de-correlation framework. Namely, some further distances are better encoded than some nearer distances. We find preliminary evidence of this ``sweet spot'' in previously published rodent behavioral experiments and demonstrate that a decoder which estimates distance from the de-correlation of populations of simulated noisy grid cells leads to a similar pattern of errors. Finally, we extend our theory to two-dimensions and, by simulating noisy grid cells in two-dimensions, find that there exists a trade-off between the range of distances that can be encoded by de-correlation of population activity and the distinguishability between different distances, which is controlled by the amount of variability in grid properties. We show that the previously measured average amount of grid property variability strikes a balance, enabling the encoding of distances up to several meters. Our work provides new insight on how grid cells can underlie the encoding of distance and why grid cells may have small amounts of heterogeneity in their grid properties.

Codon usage bias has a crucial impact on the translation efficiency and co-translational folding of proteins, necessitating the algorithmic development of codon optimization/harmonization methods, particularly for heterologous recombinant protein expression. Codon harmonization is especially valuable for proteins sensitive to translation rates, because it can potentially replicate native translation speeds, preserving proper folding and maintaining protein activity. This work proposes a Monte Carlo-based codon harmonization algorithm, MOSAIC (Monte Carlo-based Simulated Annealing for Linked Codons), for the harmonization of a set of linked codons, which differs from conventional codon harmonization, by focusing on the codon sets rather than individual ones. Our MOSAIC demonstrates robust computational performance on ribosomal proteins (S18, S15, S10, and L11) as model systems. Among them, the harmonized gene of RP S18 was expressed and compared with the expression of the wild-type gene. The harmonized gene clearly yielded a larger quantity of the protein, from which the amount of the soluble protein was also significant. These results underscored the potential of the linked codon harmonization approach to enhance the expression and functionality of sensitive proteins, setting the stage for more efficient production of recombinant proteins in various biotechnological and pharmaceutical applications.

OBJECTIVES: The grandmother hypothesis proposes that ancestral women ceased reproduction midlife to instead provision their grandchildren. An alternative two-sex account proposes that the high energetic burden of caring for slow-developing offspring was met with biparental investment. Menopause evolved because the physiological costs of reproduction increased with age, yet productivity also increased with age, and the benefits of resource transfers by parents and grandparents of both sexes to adult children and their offspring eventually outweighed the diminishing benefits of continued reproduction (Kaplan et al., 2010). The father absent hypothesis proposes that the higher mortality rate of husbands would often have left wives without the resources to raise young children, selecting for early reproductive cessation (Kuhle, 2007). Juvenile production plays little role in the three hypotheses, yet subsequent studies have found it to be surprisingly high. MATERIALS AND METHODS: Simulations were conducted of hunter-gatherer energy consumption and production across the lifespan, taking account of age- and sex-specific survivorship, interbirth intervals, and varying rates of foraging skill acquisition typical of contemporary foragers. RESULTS: There is a pronounced midlife energy deficit that could be averted with the increasing production of maturing juveniles; midlife cessation of reproduction, which limited the number of mouths to feed; and energy transfers from older parents, and sometimes younger couples (e.g., brideservice). DISCUSSION: Menopause emerges as an integral and necessary component of the unique human pattern of relatively short interbirth intervals, a long period of juvenile dependency, and extensive food sharing, supporting and extending the two-sex and grandmother hypotheses.

The loss of biodiversity due to the likely widespread extinction of species in the near future is a focus of current concern in conservation biology. One approach to measure the impact of this extinction is based on the predicted loss of phylogenetic diversity. These predictions have become a focus of the Zoological Society of London's `EDGE2' program for quantifying biodiversity loss and involves considering the HED (heightened evolutionary distinctiveness) and HEDGE (heightened evolutionary distinctiveness and globally endangered) indices. Here, we show how to generalise the HED(GE) indices by expanding their application to more general settings (to phylogenetic networks, to feature diversity on discrete traits, and to arbitrary biodiversity measures). We provide a simple and explicit description of the mean and variance of such measures, and illustrate our results by an application to the phylogeny of all 27 extant Crocodilians. We also provide an example to illustrate how the approach extends to feature diversity.

Generalizable protein function prediction is increasingly constrained by the growing mismatch between exponentially expanding sequences of environmental proteins and the comparatively slow accumulation of experimentally verified functional data. Active learning offers a promising path forward for accelerating biological function prediction, by selecting the most informative proteins to experimentally annotate for data-efficient training, yet its potential remains largely unexplored. We introduce HATTER (Human-in-the-loop Adaptive Toolkit for Transferable Enzyme Representations), a modular framework that integrates multiple active learning strategies with human-in-the-loop experimental annotation to efficiently fine tune function prediction models. We compare active learning training to standard supervised training for biological enzyme function prediction, demonstrating that active learning achieves performance comparable to standard training across diverse protein sequence evaluation datasets while requiring fewer model updates, processing less data, and substantially reducing computational cost.

Confounding pathology with normal anatomical variation remains a significant challenge in unsupervised medical-image anomaly detection, resulting in numerous false positives. To enhance integration of healthy variation, we augment the latent representation of a CNN autoencoder with contextual similarities within a normal cohort through batch-wise hypergraph estimation and a shared-weights graph convolution layer, producing a population-aware embedding. On a heterogeneous brain-tumor dataset of 2D MRI scans, the method improves separability between healthy and pathological samples, achieving an AUC-ROC of 0.90 (95% CI 0.84-0.95, 5.7% absolute gain), and a 16% absolute improvement in average precision (0.78 AP, 95% CI 0.66-0.89), thereby lowering false-positive rates. Moreover, both anomaly detection and downstream tumor versus no-tumor classification performance improve with the size of the mini-batch context captured in the augmented representation, suggesting a tunable lever for integrating healthy variation.

Absolute concentration robustness (ACR) characterizes systems where the steady-state concentration of a specific species remains invariant across all positive steady states. While ACR is a desirable property in biochemical network design, its structural compatibility with conservation laws remains a critical open question. This paper investigates the interplay between conservation laws and non-vacuous ACR in reaction networks, specifically analyzing whether ACR can be preserved or suppressed by augmenting the system with dependent species. We establish two main theoretical results regarding the structural obstructions to ACR. First, for networks governed by conservation laws, we derive a generic criterion demonstrating that augmenting a nondegenerate network with a single dependent species inevitably eliminates non-vacuous ACR for that species under generic rate constants. Second, we provide a complete characterization of non-redundant zero-one networks with dimension at most two. Despite their low dimensionality, these networks capture rich dynamical mechanisms and are sufficient to exhibit non-vacuous ACR, which we classify based on the structural properties of their stoichiometric matrices. A key finding is that all ACR networks contain no more than three different stoichiometric rows. This result rigorously establishes that an abundance of distinct conservation laws acts as a fundamental obstruction to ACR in non-redundant networks.

Existing aging theories describe what changes with age but do not prescribe how to intervene. We propose a control-theoretic framework that is not merely descriptive but prescriptive: it specifies which intervention, at which dose and sequence, under which safety constraints, will restore a measured biological state to a functional region. Aging is defined as progressive loss of safe controllability; biological age is the minimum safe control cost of functional restoration. Drugs are modeled as vector fields on biological state space whose non-commutativity, quantified by Lie brackets, predicts that intervention order determines outcome. The core differentiation from prior theories is operational: the framework outputs ranked targets, optimal sequences, safety-constrained protocols, and falsifiable predictions directly usable in drug discovery, rather than mechanistic ontologies or correlative biomarkers. We present a five-dimensional ODE model with analytic Lie-bracket derivation, a modality-aware control layer, three translational case studies, an implementation architecture with power analysis, and empirical scoring of aging interventions across five biological epochs. Twenty falsifiable predictions are enumerated. The central claim is that control-value reduction predicts translational success better than Hallmark annotation or biomarker reversal alone. If validated, this provides the missing interventional layer connecting aging biology to rational gerotherapeutic discovery.

Mapping the directed flow of information between brain regions -- their effective connectivity -- is central to understanding brain function, yet large-scale recordings sample only a fraction of the brain at a time: sessions, animals, and laboratories cover different, partially overlapping regions, usually without a shared temporal reference. Established directed-connectivity methods (Granger causality, dynamic causal modeling, partial directed coherence, PDC) require all regions to be recorded simultaneously and with a common clock. We introduce SPIDER, a non-parametric, frequency-domain framework that recovers directed information flow from such incomplete, asynchronous recordings: it stitches local power-spectral estimates from overlapping channel subsets into a global spectral matrix and obtains frequency-resolved directed interactions by canonical spectral factorization and PDC, without temporal alignment, while nuclear-norm completion fills in never-co-observed region pairs. With consistency guarantees, we validate SPIDER on simulations, two-photon calcium imaging, and the International Brain Laboratory Neuropixels dataset, recovering directed flow among 50 areas from 43 sessions in 12 laboratories never recorded together. Beyond validation, SPIDER reveals what no single recording can: brain-wide spontaneous flow is largely recurrent, but in the theta band it forms a significant feedforward hierarchy with the hippocampal formation at its source. Applied to resting human intracranial EEG (43 patients, non-overlapping coverage), it recovers the same theta-band hierarchy across species and modality. SPIDER makes whole-brain effective-connectivity analysis tractable for multi-session, multi-animal datasets previously incompatible with directed-flow inference.

Personalized generative brain models require individual neuroimaging data that privacy constraints and re-identification risk make difficult to share, while per-subject fitting procedures cost hours of compute -- limiting clinical translation and multi-site collaboration. We introduce cohort-amortized personalization (CAP), which replaces data sharing with model sharing: a neural density estimator is trained on simulations from a mechanistic whole-brain model under a low-rank cohort prior, and only the compact estimator is distributed, so new subjects are personalized in seconds on their own data alone. To make this prior both compact and atlas-independent, a cross-atlas autoencoder (CrossCoder) maps connectomes from 20 anatomical atlases into a shared latent space, enabling deployment across sites with heterogeneous atlases. We validate CAP on two cohorts: 21 patients with drug-resistant epilepsy (epileptogenic-zone localization F1=0.56) and 832 subjects from the 1000BRAINS aging cohort (predicted age r=0.44); in both, CAP matches or exceeds per-subject inference with hours-to-seconds speed-up. Because the shared artifact couples a cohort prior to a mechanistic simulator, it can serve as a mechanistic surrogate supporting in-silico experimentation and synthetic-cohort generation without raw-data access -- a governance-audited alternative we term synthetic access, allowing for wider adoption of personalized modeling in more diverse settings.

Single-cell drug perturbation models should capture transcriptional response magnitude and whether a treatment changes the proliferative state of the cell. This is difficult because cell-cycle variation is often treated as a nuisance factor, and benchmark processing rarely makes drug-induced phase changes a primary prediction target. We introduce scCycleMol, a cell-cycle-aware perturbation prediction framework built on a curated 24-hour SciPlex3 benchmark with standardized molecule identities, dose and cell-line metadata, modeled genes, and expression-derived cell-cycle supervision. scCycleMol derives cell-cycle supervision from the treated state and applies it to predicted treated expression without using phase as an input covariate. The model includes a learnable full-expression cell-cycle head with circular G1/S/G2M targets, and we evaluate readout-only supervision (with stop-gradient) versus closed-loop supervision (backpropagating through decoder, dose-response module, and drug representation). We also compare molecular representations and pretraining sources to isolate the effect of the cell-cycle objective. On a processed 24-hour SciPlex3 benchmark (635,541 cells, 186 perturbations, 188 compound embeddings, 3 cell lines, 4 doses plus DMSO, 5,080 genes), the best LINCS-pretrained circular variant reaches 0.9093 mean all-gene R-squared and 0.6843 mean DE-gene R-squared. Under matched preprocessing, closed-loop cell-cycle supervision improves phase accuracy by 0.54-0.62 points while keeping mean all-gene R-squared within 0.003 of matched chemCPA no-cell-cycle models; Tahoe-pretrained readout-only circular supervision achieves the strongest phase accuracy at 0.9609.

Workflows in drug-target interaction (DTI) assessment require integrating heterogeneous data from predictive models, curated resources, and observations from experimental literature. This evidence can be incomplete or conflicting. DrugAgent is a large language model (LLM)-based multi-agent system focused on DTI evidence integration that integrates outputs from machine learning, knowledge graph, and retrieval-augmented generation (RAG) agents. DrugAgent converts agent outputs into interpretable representations, then summarizes conflict across the evidence. We evaluated DrugAgent on kinase screening data of 900 pairs spanning 178 kinases and 42 inhibitors, and an androgen receptor antagonist screening benchmark. On the kinase dataset, LLM-as-a-Judge evaluation indicated outputs were faithful to input evidence in 98.8% of cases. Biological plausibility of returned summarization was high (scores 3-4 out of 5) across ground-truth classes: 79% of Weak activity labels cases (81% for Moderate/77% Strong); Strong cases received higher scores than Weak/Moderate. Label stability showed 98% agreement across runs. Results on the antagonist benchmark were consistent with the kinase dataset. Retrieved literature provided the greatest benefit when direct drug-target evidence was available, highlighting the importance of evidence availability for RAG-based integration. DrugAgent provides heterogeneous evidence-grounded DTI assessment, complementing standalone DTI prediction. We provide strategies to model agreement, conflict, and uncertainty in biomedical evidence integration. Code: this https URL.

Bioacoustic data from Passive Acoustic Monitoring (PAM) generates large datasets where obtaining detailed auditing and labelling is often impractical, resulting in weak annotations (e.g., presence/absence of species over several minutes of recording). In order to effectively capture the complex temporal patterns and key features of long audio segments, we propose a framework comprising dataset standardisation, feature extraction, and classification via Temporal Convolutional Networks (TCN). This approach eliminates the necessity for setting heuristic decision rules or creating time-consuming strong labels. To demonstrate the effectiveness of our approach, we use sperm whale (\textit{Physeter macrocephalus}) click trains in 4-minute recordings as a case study, from a dataset comprising diverse sources and deployment conditions to maximise generalisability. Our TCN classifiers achieve recall rates exceeding 0.83 at a 0.13 false positive rate, comparable to agreement rates between expert annotators. We compare two methods of feature extraction, Variational AutoEncoders (VAEs) and traditional handpicking of features, and found them to yield similar performance results, with the VAE-based classifiers seeing a more stable performance across datasets and recording conditions. These results offer a way forward in leveraging numerous existing annotated bioacoustic datasets to train automatic classification models, effectively overcoming previous limitations associated with weak labels.

Conventional multi-stage cell tracking approaches rely heavily on detection or segmentation in each frame as a prerequisite, requiring substantial resources for high-quality segmentation masks and increasing the overall prediction time. To address these limitations, we propose CAP, a novel end-to-end one-stage framework that reimagines cell tracking by treating Cell as Point. Unlike traditional methods, CAP eliminates the need for explicit detection or segmentation, instead jointly tracking cells for sequences in one stage by leveraging the inherent correlations among their trajectories. This simplification reduces both labeling requirements and pipeline complexity. However, directly processing the entire sequence in one stage poses challenges related to data imbalance in capturing cell division events and long sequence inference. To solve these challenges, CAP introduces two key innovations: (1) adaptive event-guided (AEG) sampling, which prioritizes cell division events to mitigate the occurrence imbalance of cell events, and (2) the rolling-as-window (RAW) inference strategy, which ensures continuous and stable tracking of newly emerging cells over extended sequences. By removing the dependency on segmentation-based preprocessing while addressing the challenges of imbalanced occurrence of cell events and long-sequence tracking, CAP demonstrates promising cell tracking performance and is 8 to 32 times more efficient than existing methods. The code and model checkpoints are available at this https URL.

Function-guided protein design is a crucial task with significant applications in drug discovery and enzyme engineering. However, the field lacks a unified and comprehensive evaluation framework. Current models are assessed using inconsistent and limited subsets of metrics, which prevents fair comparison and a clear understanding of the relationships between different evaluation criteria. To address this gap, we introduce PDFBench, the first comprehensive benchmark for function-guided denovo protein design. Our benchmark systematically evaluates eight state-of-the-art models on 16 metrics across two key settings: description-guided design, for which we repurpose the Mol-Instructions dataset, originally lacking quantitative benchmarking, and keyword-guided design, for which we introduce a new test set, SwissTest, created with a strict datetime cutoff to ensure data integrity. By benchmarking across a wide array of metrics and analyzing their correlations, PDFBench enables more reliable model comparisons and provides key insights to guide future research.

Natural Language Processing (NLP) has transformed various fields beyond linguistics by applying techniques originally developed for human language to the analysis of biological sequences. This review explores the application of NLP methods to biological sequence data, focusing on genomics, transcriptomics, and proteomics. We examine how various NLP methods, from classic approaches like word2vec to advanced models employing transformers and hyena operators, are being adapted to analyze DNA, RNA, protein sequences, and entire genomes. The review also examines tokenization strategies and model architectures, evaluating their strengths, limitations, and suitability for different biological tasks. We further cover recent advances in NLP applications for biological data, such as structure prediction, gene expression, and evolutionary analysis, highlighting the potential of these methods for extracting meaningful insights from large-scale genomic data. As language models continue to advance, their integration into bioinformatics holds immense promise for advancing our understanding of biological processes in all domains of life.

By generalizing a class of models recently introduced to account for protracted transients in biological systems, we identify a novel mechanism for hyperuniformity. In this model, competition of individuals over a shared resource serves as feedback that can asymptotically guide the population towards a critical steady state with divergent individual life time. We show that, in its spatially extended form, this many-body model exhibits hyperuniform density fluctuations. Through explicit coarse-graining, we develop a hydrodynamic theory that conforms closely with the results of stochastic simulations. Unlike previous models for non-equilibrium hyperuniform states, our model does not exhibit conservation laws, even in the asymptotic regime. Instead, hyperuniformity arises from the divergence of the range of the resource-mediated interactions. These findings may find applications in engineering, cellular population dynamics, and ecology.

Predictive machine learning models generally excel on in-distribution data, but their performance degrades on out-of-distribution (OOD) inputs. Reliable deployment therefore requires robust OOD detection, yet this is particularly challenging for irregular 3D graphs that combine continuous geometry with categorical identities and are unordered by construction. Here, we present a probabilistic OOD detection framework for complex 3D graph data built on a diffusion model that learns a density of the training distribution in a fully unsupervised manner. A key ingredient we introduce is a unified continuous diffusion over both 3D coordinates and discrete features: categorical identities are embedded in a continuous space and trained with cross-entropy, while the corresponding diffusion score is obtained analytically via posterior-mean interpolation from predicted class probabilities. This yields a single self-consistent probability-flow ODE (PF-ODE) that produces per-sample log-likelihoods, providing a principled typicality score for distribution shift. We validate the approach on protein-ligand complexes and construct strict OOD datasets by withholding entire protein families from training. PF-ODE likelihoods identify held-out families as OOD and correlate strongly with prediction errors of an independent binding-affinity model (GEMS), enabling a priori reliability estimates on new complexes. Beyond scalar likelihoods, we show that multi-scale PF-ODE trajectory statistics - including path tortuosity, flow stiffness, and vector-field instability - provide complementary OOD information. Modeling the joint distribution of these trajectory features yields a practical, high-sensitivity detector that improves separation over likelihood-only baselines, offering a label-free OOD quantification workflow for geometric deep learning.

Accumulation of amyloid beta proteins is a defining feature of Alzheimer's disease, and is usually accompanied by cerebrovascular pathology. Evidence suggests that amyloid beta and cerebrovascular pathology are mutually reinforcing; in particular, amyloid beta suppresses perfusion by constricting capillaries, and hypoperfusion promotes the production of amyloid beta. Here, we propose a whole-brain model coupling amyloid beta and blood vessel through a hybrid model consisting of a reaction-diffusion system for the protein dynamics and porous-medium model of blood flow within and between vascular networks: arterial, capillary and venous. We discretize the resulting parabolic--elliptic system of PDEs by means of a high-order discontinuous Galerkin method in space and an implicit Euler scheme in time. Simulations in realistic brain geometries demonstrate the emergence of multistability, implying that a sufficiently large pathogenic protein seeds is necessary to trigger disease outbreak. Motivated by the "two-hit vascular hypothesis" of Alzheimer's disease that hypoperfusive vascular damage triggers amyloid beta pathology, we also demonstrate that localized hypoperfusion, in response to injury, can destabilize the healthy steady state and trigger brain-wide disease outbreak.

Vision foundation models trained with self-supervised objectives achieve strong performance across diverse tasks and exhibit emergent object segmentation properties. However, their alignment with human object perception remains poorly understood. Here, we introduce a behavioral benchmark in which participants make same/different object judgments for dot pairs on naturalistic scenes, scaling up a classical psychophysics paradigm to over 1000 trials. We test a diverse set of vision models using a simple readout from their representations to predict subjects' reaction times. We observe a steady improvement across model generations, with both architecture and training objective contributing to alignment, and transformer-based models trained with the DINO self-supervised objective showing the strongest performance. To investigate the source of this improvement, we propose a novel metric to quantify the object-centric component of representations by measuring patch similarity within and between objects. Across models, stronger object-centric structure predicts human segmentation behavior more accurately. We further show that matching the Gram matrix of supervised transformer models, capturing similarity structure across image patches, with that of a self-supervised model through distillation improves their alignment with human behavior, converging with the prior finding that Gram anchoring improves DINOv3's feature quality. Together, these results demonstrate that self-supervised vision models capture object structure in a behaviorally human-like manner, and that Gram matrix structure plays a role in driving perceptual alignment.

We present Clin-JEPA, a multi-phase co-training framework for joint-embedding predictive (JEPA) pretraining on EHR patient trajectories. JEPA architectures have enabled latent-space planning in robotics and high-quality representation learning in vision, but extending the paradigm to EHR data -- to obtain a single backbone that simultaneously forecasts patient trajectories and serves diverse downstream risk-prediction tasks without per-task fine-tuning -- remains an open challenge. Existing JEPA frameworks either discard the predictor after pretraining (I-JEPA, V-JEPA) or train it on a frozen pretrained encoder (V-JEPA 2-AC), leaving the encoder unaware of the rollout signal that the retained predictor must use at inference; co-training the encoder and predictor under a shared JEPA prediction objective would supply this grounding, but naïve co-training is unstable, with representation collapse and online/target drift causing autoregressive rollout to diverge. Clin-JEPA's five-phase pretraining curriculum -- predictor warmup, joint refinement, EMA target alignment, hard sync, and predictor finalization -- addresses each failure mode by phase, stably co-training a Qwen3-8B-based encoder and a 92M-parameter latent trajectory predictor. On MIMIC-IV ICU data, three independent evaluations support the framework: (1) latent $\ell_1$ rollout drift uniquely converges ($-$15.7%) over 48-hour horizons while baselines and ablations diverge (+3% to +4951%); (2) the encoder learns a clinically discriminative latent geometry (deteriorating-patient cohorts displace 4.83$\times$ further than stable patients in latent space, vs $\leq$2.62$\times$ for baseline encoders); (3) a single backbone outperforms strong tabular and sequence baselines on multi-task downstream evaluation. Clin-JEPA achieves mean AUROC 0.851 on ICareFM EEP and 0.883 on 8 binary risk tasks (+0.038 and +0.041 vs baseline average).

Most work in audio enhancement targets human speech, while bioacoustics is less studied due to noisy recordings and the distinct traits of animal sounds. To fill this gap, we adapt speech enhancement methods and build BioSEN, a model made for bioacoustic signals. BioSEN has three modules: a multi-scale dual-axis attention unit for time-frequency feature extraction, a bio-harmonic multi-scale enhancement unit for capturing harmonic structures, and an energy-adaptive gating connection unit that uses frequency weights to keep vocalizations from being removed as noise. Tests on three bioacoustic datasets show that BioSEN matches or exceeds state-of-the-art speech enhancement models while using far less computation. These results show BioSEN's strength for bioacoustic audio enhancement and its promise for biodiversity monitoring and conservation.

Collective oscillations in neuronal systems often arise from interactions between excitatory and inhibitory populations rather than from recurrent coupling within a single ensemble. Motivated by the coexistence of strongly and partially synchronized regimes in such systems, we study the Kuramoto Sakaguchi model on a bipartite network. Despite its minimal structure, the model exhibits rich collective dynamics, including both continuous and discontinuous transitions from full synchrony to partial synchrony (PS). In the PS regime, global oscillations fail to entrain one of the two populations, whose oscillators display quasiperiodic dynamics with an average frequency that can significantly deviate from that of the global field, as observed in neuronal networks. We show that this PS state constitutes an example of self-organized quasiperiodicity, arising here in the canonical Kuramoto Sakaguchi model despite its purely linear global coupling.

We investigate linear lumping for parameter-dependent mass action reaction networks, distinguishing between generic and critical parameter regimes. For generic parameters -- those ranging in some non-empty open subset of parameter space -- we prove that exact linear lumping yields only "obvious" reductions: elimination of non-reactant species or projections along stoichiometric first integrals. This characterization extends to reaction networks with product-form kinetics, including Michaelis-Menten and Hill-type rate laws. For mass action systems we proceed to develop an algorithmic approach to identify critical parameter sets -- algebraic subvarieties in parameter space where non-trivial lumpings become available. This procedure reduces the determination of lumping maps to a system of finitely many polynomial equations. It also applies to constrained lumping scenarios (which are frequently motivated by chemical considerations). We then review and extend results about proper lumpings. Finally, we discuss lumpings of a self-replicator system, and of a two-pathway enzyme mechanism, to document the viability of our methods in relevant scenarios. Our results clarify the relationship between structural (parameter-independent) and fine-tuned (parameter-dependent) reductions, with implications for approximate lumping when system parameters lie near critical values