RNA design consists of discovering a nucleotide sequence that optimizes predefined criteria, such as secondary structure. It is useful for synthetic biology, medicine, and nanotechnology. We propose Montparnasse, a Monte Carlo search framework based on Generalized Nested Rollout Policy Adaptation, augmented with a problem-specific prior, slow and long adaptation at level 1, and a lexicographic multicriteria evaluation. Montparnasse solves all 100 puzzles of the Eterna100 V1 benchmark consistently faster than DesiRNA, the previous state of the art, across all time limits, reaching full coverage more than three times faster overall. On messenger RNA secondary structure optimization for hemoglobin alpha, it identifies sequences with more paired bases than the MFE-optimal solution of LinearDesign.

Protein function is largely determined by molecular surface geometry and physicochemical complementarity, yet most protein design methods condition only on backbone structure. We introduce SurfDesign, a surface-conditioned protein design framework that models molecular surfaces as continuous geometric manifolds and integrates them with pretrained protein language models. SurfDesign employs surface-based equivariant message passing to capture surface normals, curvature, and directional geometry, together with a parameter-efficient fine-tuning strategy. Focusing on functional protein design, we show that SurfDesign consistently outperforms prior surface-conditioned and backbone-only methods on de novo binder and enzyme design benchmarks. We also report strong performance on inverse-folding benchmarks as a diagnostic of structural compatibility. Our results highlight manifold-aware surface representations as a principled foundation for functional protein and enzyme design. Code is available at this https URL.

Spatial transcriptomics (ST) is a powerful tool for exploring biological properties dependent on structure, proximity, and interaction in tissue. The methods underpinning ST are developing rapidly but are limited in their ability to profile many thousands of genes at a subcellular scale. Although dissociated from tissue, it is known that the whole-transcriptome readouts of cells in single-cell RNA sequencing (scRNA-seq) retain information about their former in situ neighbourhoods, motivating computational methods to recover it. While paired ST and scRNA-seq datasets are scarce, each modality in its own right is abundantly available. We therefore propose to perform cross-modal translation between unpaired ST and scRNA-seq data. In this work we show that a single-cell foundation model can perform this translation via adversarial fine-tuning. We demonstrate that our method performs favourably against methods built for multi-omics translation.

This study analyses the Ako tidal flat in the Seto Inland Sea, Japan, where nearly all Zostera marina disappeared within a single year in 2025. Using aerial photographs from the 1940s onward, high-resolution satellite imagery, GRUS images (2.5-5 m), and monthly Sentinel-2 composites (10 m), we reconstructed approximately 80 years of seagrass distribution. YOLO-based segmentation using deep learning achieved high accuracy (overall accuracy >= 0.9) across these datasets; although species could not be discriminated, the models captured the major temporal dynamics in vegetation area. The long-term mean seagrass area was 6.8 ha, but values fluctuated widely, from 3.5 ha in 1974 to 41.3 ha in 1989 except 0.2 ha in 2025. Sentinel-2 composites from 2019 to 2026 revealed clear seasonality, with vegetation increasing in early summer and declining from autumn. In 2025, however, the area decreased sharply after summer and remained anomalously low throughout the winter of 2025-2026. Our results, indicating that the 2025 event was not a normal fluctuation but a rapid ecosystem shift involving the loss of the dominant canopy-forming species, most plausibly driven by regionally elevated summer water temperatures. The findings also have implications for seagrass Essential Ocean Variables (EOVs) and the State of Nature (SoN) metrics used in TNFD-aligned nature-related disclosures. Unlike forests, seagrass meadows require finer temporal resolution because both pronounced seasonality and abrupt collapse strongly influence area-based indicators. Therefore, in addition to previously noted issues such as species-level classification accuracy, we recommend that (1) baselines be defined over the longest available record and justified ecologically, (2) seasonal standardization be applied before inter-annual comparisons, and (3) years with extreme area anomalies be flagged rather than used as reference points.

DNA cis-regulatory elements (CREs) such as enhancers control gene expression levels. Accurately predicting regulatory activity from DNA sequences is valuable but challenging, as it requires understanding complex biological regulatory processes. Existing methods typically regress activity scores from sequences in a black-box manner, limiting both interpretability and regression performance. Meanwhile, large language models (LLMs) benefit from explicit reasoning processes, yet directly applying LLMs to raw DNA sequences performs poorly. In this paper, we bridge this gap by introducing R3LM, a framework that teaches LLMs reasoning-informed regression on regulatory DNA through structured biological knowledge. Specifically, we design a biologically grounded data format that structures DNA's regulatory information for improved LLM understanding, and construct CRE-ReasonBench, the first dataset that associates DNA sequences and activity scores with mechanistic reasoning traces. Through two-stage training that first teaches LLMs reasoning over structured biological information then performs regression, R3LM achieves state-of-the-art performance on enhancer prediction across three cell types, outperforming both LLMs with raw sequence input and specialized DNA models while providing interpretable mechanistic explanations. We expect R3LM as an interpretable reward model that can effectively assist biologists in CRE design. Code is available at this https URL.

The Mader model is the most widely used mathematical framework for muscular energy metabolism in German-language sport science, underpinning lactate diagnostics, maximal lactate steady state (MLSS) estimation and training prescription. Despite decades of use, neither its dynamic ODE formulation nor its steady-state equations have been available as open code, leaving results based on the model impossible to reproduce independently. We close this gap with MetaboliSim, an open-source Python implementation of both formulations: a dynamic model that integrates the five-variable ODE system (phosphate potential, $\dot{V}\mathrm{O}_2$, muscle and blood lactate, and glycogen) with a fourth-order Runge-Kutta scheme, and a steady-state model that computes MLSS power and the lactate-power relationship in one- and two-compartment variants. We verified implementation correctness against published reference values and assessed physiological plausibility across constant-load, step-test, sprint and running protocols. The implementation reproduces the published reference output within stated tolerances and remains numerically stable throughout (halving the time step changes blood lactate by less than 0.01 mmol/L), with both formulations yielding congruent MLSS estimates. Key physiological behaviour ($\dot{V}\mathrm{O}_2$ on-kinetics, lactate accumulation, PCr dynamics and the sub/supra-MLSS separation) emerges directly from the model equations without protocol-specific tuning, and a sensitivity analysis shows MLSS power varying approximately linearly with $\dot{V}\mathrm{O}_{2\max}$ and nonlinearly with $\dot{V}\mathrm{La}_{\max}$. As the first openly available implementation of the complete Mader model (AGPL-3.0), MetaboliSim lets independent groups reproduce, verify and build on published model-based results. Source code: this https URL Platform: this https URL

In April 2026, the MV Hondius expedition cruise ship became the site of the first documented cruise ship-associated Andes hantavirus (ANDV) cluster, with 13 confirmed and probable cases and 3 deaths among 149 passengers and crew. We applied a stochastic epidemic model to evaluate four embarkation scenarios under reproductive numbers anchored to published ANDV estimates. Scenario D, involving two latent infected persons at embarkation, was most consistent with the observed outbreak, yielding P(final size >= 13) = 11.6% and P(takeoff) = 58.5% at R0 = 2.12. Approximate Bayesian computation provided complementary support for multiple latent infections at embarkation, especially E1(0)=1 and E3(0)=2, but R0 remained weakly identifiable. A day-35 transmission reduction changed takeoff probability little in this counterfactual model. Findings support exposure-history assessment, early onboard surveillance, rapid isolation of symptomatic cases, and postdisembarkation monitoring for travelers from ANDV-endemic regions.

Ordinary differential equation models are widely used to understand and forecast complex dynamical systems, but their predictive value depends on reliable parameter estimation. Structural identifiability assesses whether parameters can be uniquely recovered from ideal observations, whereas practical identifiability depends on finite, noisy and partially observed data. We introduce the Practical Identifiability Index (PII), a marginal uncertainty-width metric based on the logarithmic span of confidence intervals. Expressed on an order-of-magnitude scale, the PII summarises how tightly individual positive-valued parameters are constrained by available observations, enabling comparison across parameters, models, error structures and observation designs. The PII is intended as a complementary diagnostic, not a standalone identifiability test, and should be interpreted alongside coverage, profile likelihoods, posterior summaries, sensitivity analysis or structural identifiability results. Using parametric bootstrap experiments across growth and compartmental epidemic models, we identify consistent principles: uncertainty decreases as calibration windows become more informative, increases with observation noise and parameter coupling, and remains high for latent or indirectly observed processes. Parameters governing early observable dynamics become constrained sooner, while additional observables can improve constraint for latent progression and recovery parameters. The PII provides a simple, reportable summary of marginal parameter uncertainty for dynamical modelling.

\textit{Tissue graph counterfactuals} ask how a cell's expression would change under altered spatial neighbor contexts. Such queries are central to predicting cell behavior in tissues, but lack a unified definition, with existing methods targeting specific intervention types or treating cells as i.i.d. In this work, we first formalize \textit{tissue graph counterfactuals} as a class of spatial interventions that either rewire connections between cells (\textit{edge perturbation}) or modify the expression of their neighbors (\textit{node perturbation}). We then introduce \textit{Cellina} {\renewcommand{\thefootnote}‡\footnote{this https URL}\addtocounter{footnote}{-1}}, a framework that uses supervised disentanglement to decompose a cell's intrinsic state from its spatial context, using the latter as a conditioning input for counterfactual predictions. Across benchmarks spanning over 2.5 million spatially-resolved cells in colorectal cancer and mouse brain, \textit{Cellina} outperforms spatially-informed and non-spatial competitors in tissue perturbations, disentanglement, and scalability. Additionally, we show that \textit{Cellina} reveals biologically distinct cancer subdomains in an unsupervised manner and enables targeted neighbor perturbation simulations.

The ability to predict protein three-dimensional structures from amino acid sequences is a landmark achievement in molecular biology, where recent deep learning approaches such as AlphaFold are the culmination of decades of work. Yet, the quantitative understanding of how protein sequences give rise to dynamic conformational changes and higher-order assemblies remains unsolved. Folding and conformational states are dynamic, stochastic processes, shaped by sequence, energy, co-translational constraints, chaperone machineries, and the physicochemical conditions of the cellular environment. Recent advances now position the field to move beyond static structural endpoints toward a mechanistic understanding of folding dynamics in living systems. Single-molecule techniques enable time-resolved observation of folding trajectories and intermediate states hitherto hidden by traditional structural biology approaches, while computational innovations and data-driven approaches offer new ways to integrate heterogeneous data across scales. In this Roadmap, we review the current conceptual landscape of protein folding, examine the experimental and theoretical gaps that remain, and discuss emerging strategies that integrate high-resolution measurements with multiscale modeling. We outline a roadmap toward a quantitative and predictive science of protein folding dynamics, conformational kinetics, and macromolecular self-assembly. Realizing this vision would transform our understanding of the dynamics of molecular self-organization, from the folding of individual polypeptides to the emergence of dynamic macromolecular complexes. This will enable rational control of folding and misfolding in health and disease, extend protein engineering principles beyond static structural design, and establish a mechanistic foundation for predictive and personalized interventions in proteostasis-related disorders.

A sufficient account of how the neocortex learns must meet three criteria: 1. Computationally, it must approximate a powerful, general-purpose learning algorithm known to scale to human-level intelligence; 2. Algorithmically, it must be implementable using known, well-established neural circuits within the neocortex and associated brain structures; 3. Implementationally, there must be a detailed account for how all of the algorithmic mechanisms actually function at a neurochemical level. At present, there is only one framework that meets all of these criteria: error-driven predictive learning via temporal derivatives, driven by corticothalamic circuits, based on competitive kinase synaptic plasticity induction mechanisms. This has been implemented in the Axon neural simulation framework using spiking neurons, and demonstrated to learn across a wide range of challenging cognitively motivated tasks.

Fundamental investigations into how different molecular encoding methods affect molecular property prediction remain relatively limited. In this study, we extensively examined the optimal molecular encoding methods for molecular properties prediction using two prevalent structure designs: a classical neural network model (MLP) and a Transformer encoder-based model (MLP+TL). For molecular encoding methods, we investigated several types of fingerprints, including traditional topological fingerprints, substructure-based fingerprints, and string-based representations. These two models were trained on seven well-known molecular datasets to evaluate different input molecular encoding methods based on evaluation metrics. On several biologically relevant classification tasks, including toxicity, mutagenicity, and side-effect prediction, our models consistently achieved average AUC values above 0.9. Rather than relying on external post-hoc explanation methods such as the local interpretable model-agnostic explanation (LIME) or the Deep SHapley Additive exPlanations (SHAP), we leveraged the model's intrinsic attention weights as an internal interpretability signal for identifying potentially important feature. The MLP+TL model using MACCS and PubChem as input can capture chemically interpretable groups that determined the major blood-brain barrier (BBB) permeability and mutagenicity in Salmonella typhimurium. In particular, a comparison between Morphine and Heroin highlighted the role of hydroxyl-related substructures in BBB permeability prediction, which was consistently reflected in the attention weights. Overall, our findings provide practical guidance for selecting effective molecular encoding methods and contribute to the development of interpretable molecular informatics approaches for drug discovery.

Living organisms, from bacteria to humans, are more likely to survive if their traits enhance fitness. In populations well adapted to their environmental niches, natural selection proceeds via rarely beneficial mutations. But when a catastrophe wipes out niche diversity, sudden adaptation often follows. Here, we present a data-validated theory of natural selection in the wake of catastrophe and unveil a simple law that emerges during recovery: the mean fitness relaxes inversely with time, with a prefactor proportional to the number of traits coupled to the post-catastrophe environment. We put our approach to test using experimental fitness landscapes measured following antibiotic administration to E. coli. The resulting mean trait adaptation is not described by gradient ascent on a fitness landscape, instead it follows an algorithm known as Levenberg-Marquardt optimization. Near fitness peaks, evolutionary trajectories are biased against greediness - from an optimization perspective, post-catastrophic selection is optimistic.

Ecological communities with structured interactions exhibit collective phenomena such as percolation and clustering of occupied sites. While these effects have been documented in experiments and simulations, systematic analytical understanding has remained limited. In this paper, we develop a dynamical theory of these phenomena for competitive ecological systems defined on random interaction graphs. We introduce a discrete version of the generalized Lotka-Volterra model that preserves key macroscopic features of continuous ecological dynamics while enabling analytical treatment. Within this framework, we characterize the emergence of percolating clusters and describe the spatial organization of surviving sites. Our analysis uncovers which equilibria can be reached by the dynamics and shows how this dynamical accessibility governs the onset of clustering and percolation. In doing so, our framework complements classical Lotka-Volterra theory by providing a dynamical perspective on the collective organization of structured communities.

Motivation: Transformer-based models are increasingly applied to large-scale single-cell transcriptomics, showing strong performance through self-supervised learning on millions of cells. However, most existing approaches treat genes as independent features, and largely ignore prior biological knowledge, which limits interpretability and robustness. In this paper, we explore whether explicitly incorporating gene regulatory information can improve both model performance and biological insight. Results: We present scTransformer, the first Transformer-based approach that builds a priori knowledge of biological mechanisms into the model's attention patterns. By constraining information flow according to known regulatory structures, the model learns representations that are more biologically meaningful. We evaluate scTransformer on a disease-relevant single-nucleus RNA-seq dataset using supervised cell-type classification. Compared to standard Transformers, our approach improves classification accuracy, enhances separation of cell types in embedding space, and produces attention patterns consistent with known regulatory programs. Overall, our results demonstrate that embedding biological structure into Transformer models can enhance interpretability without sacrificing performance, offering a principled step toward biologically grounded foundation models for single-cell omics.

Spatially resolved transcriptomics (SRT) is transforming how we study tissues by measuring gene expression in cells in their spatial context. However, the field lacks robust methodological guidance on one of its most fundamental analytical steps: how to accurately segment cells and assign spatially localized transcripts to them. Major technical challenges include sparse molecular signals, transcript displacement, complex cellular morphologies, and the projection of three-dimensional tissue architecture onto two-dimensional imaging planes. These challenges make segmentation a major source of uncertainty, with errors that can propagate through downstream analyses and ultimately lead to misleading biological interpretations. Here, we argue that segmentation should be treated as a central unresolved problem in spatial omics rather than a routine preprocessing step. We review current approaches, highlight key methodological limitations, including the lack of appropriate metrics and gold-standard benchmarks, and propose a community-driven path forward. Establishing shared evaluation frameworks, scalable benchmark datasets, and transparent reporting standards will be essential for transforming SRT into a robust and reproducible foundation for biological discovery and clinical translation.

Nearby neurons in cortex share similar response profiles, producing systematic spatial organization across sensory and cognitive systems. Recent topographic models reproduce aspects of this structure but remain unimodal and spatially constrain each layer separately, yielding fragmented maps that capture neither the contiguity of cortical processing streams nor their integration across modalities. We introduce Topo-Omni, a topographic multimodal model in which visual, auditory, and language/cognitive processing share a single contiguous in-silico sheet. Built by fine-tuning a pretrained foundation model with a spatial smoothness objective, this architecture develops clusters across modalities that are consistent with human neuroimaging, from sensory to cognitive systems. Driving or suppressing a cluster selectively biases or impairs perception, paralleling human intervention studies. Finally, we use our model to screen for novel clusters in-silico and discover new natural landscape and animal networks which we validate in human data. A single spatial principle thus organizes representations across modalities and processing stages, yielding testable hypotheses about cortical organization.

Advances in machine learning and computational power have unlocked the predictive potential of the human genome, yet biologists now demand that these models also elucidate the underlying biological mechanisms. While interpretable machine learning (IML) techniques have been increasingly applied to bridge this gap, there has been a pervasive reliance on anecdotal validation: the vast majority of research relies on a single IML method and reports only isolated successful instances. Through a benchmarking study on transcription factor binding, we demonstrate the risks of current practices. We show that different IML methods can often (1) yield contradictory explanations for the same predictions, (2) fail to localize known regulatory motifs, and (3) fail to faithfully reflect the model's internal decision process. In light of this, we argue for a validation framework analogous to clinical trials: just as trials require rigorous design and adverse-event reporting, genomic interpretability must move beyond cherry-picked plausibility toward systematic assessment of consistency, faithfulness, and biological validity. To facilitate this, we propose a tiered framework to guide rigorous evaluation and reporting of genomic IML methods.

Objective: To develop and externally test a video-based framework for simultaneous detection of hyperkinetic MDs phenomenologies: dystonia, tremor, myoclonus, chorea, athetosis, ballismus, stereotypies, and tics using routine clinical recordings, with explicit testing of external, cross-cohort transfer from adult to pediatric populations. Methods: In this proof-of-concept study, the framework combines markerless pose estimation, kinematic descriptors, and a pretrained fondation model. A shared predictive backbone was developed on 21 adults with confirmed hyperkinetic MDs and 4 healthy controls assessed under a standardized protocol. External validation was performed on an independent external cohort: a real-world pediatric sample (n=12, monogenic combined MDs). For the external dataset, the backbone was deployed without retraining; lightweight calibration adjusted only the final subject-level decision step using a small labeled subset of patients selected by clinicians as representative of the cohort's phenotypic range. Results: After local calibration of the decision layer on the clinician-selected subset, performance improved consistently on the held-out pediatric patients (n=7): Hamming accuracy rose from 0.804 to 0.839 and the Jaccard index from 0.548 to 0.633. This calibrated performance was preserved, and the Jaccard index further improved, when the evaluation was restricted to the phenomenologies with more definite clinician agreement (Hamming accuracy 0.9, Jaccard index 0.786), indicating that the gains did not rest on the least-reliable labels.

Alzheimer's disease is a progressive neurodegenerative disorder, and its progression varies substantially across patients. Existing work aims to forecast patients' future cognitive state, with minimal focus on reconstructing the state from past visits. Furthermore, in current research, quantifying predictive uncertainty remains underexplored and relies on costly modalities such as MRI, PET, and CSF, limiting their deployment in resource-limited settings. In this research, our primary objectives are: First, bidirectional prediction of cognitive scores from irregular visits to present the complete disease trajectory. Second, to enable interpolation and extrapolation capabilities to assist clinicians in informed prognostic decision making, and third, to provide a well-calibrated uncertainty estimate for all predictions, and finally, to achieve the objectives using the modalities available during routine visits. We propose a unified framework, GNOVA: A GRU-Neural ODE Variational Autoencoder. The architecture combines a Gated Recurrent Unit encoder and a Neural ODE decoder within a variational autoencoder framework. In our work, we forecast the CDR-SB and MMSE Scores. The GRU encoder allows for any number of inputs at any time point. The Neural-ODE decoder performs continuous estimation, allowing interpolation and extrapolation at any desired time point. The Variational autoencoder allows for uncertainty estimation in predictions. We worked with 1,727 patients from the ADNI dataset over 10 years; the model achieved mean absolute errors of 1.35 and 2.28 for CDR-SB and MMSE scores, respectively, without requiring any neuroimaging or biomarker data. Feature-ablation studies revealed that age, BMI, and APOE4 status were strong predictors. The proposed framework enables the reconstruction of incomplete patient histories and the anticipation of future cognitive states.

Eukaryotic DNA replication must remain robust under thermal, chemical, and genotoxic stress despite large fluctuations in replication dynamics. Here, we develop a lattice-based stochastic Monte Carlo framework for whole-genome replication in Saccharomyces cerevisiae at single base-pair resolution, incorporating probabilistic origin firing, replication fork-speed distributions, and a time-dependent limiting factor that governs the availability of cellular replication resources. The model is benchmarked quantitatively against experimental replication profiles before being applied to stress conditions, and reproduces diverse replication stress responses using only two effective parameters. Importantly, the analysis reveals that replication fork-speed heterogeneity underlies the emergence of Erlang-distributed S-phase durations and rare, anomalously prolonged replication events observed experimentally in Escherichia coli and human cell lines, while predicting similar behavior in S. cerevisiae. The framework further predicts non-monotonic thermal behavior, power-law scaling under hydroxyurea stress, and total replication-time dynamics under diverse genotoxic conditions.

Token aggregation is a common bottleneck in models that map token representations to sample-level predictions, yet most pooling methods operate only in the original token domain. We propose FLaG, a plug-in aggregation module that transforms token representations with the real FFT, summarizes spectral components with learnable latent queries, applies a channel-wise gate, and reconstructs enhanced time-domain tokens for final pooling. We evaluate FLaG on antimicrobial peptide (AMP) activity prediction with ESM2, image classification with ResNet18 on CIFAR-10 and CIFAR-100, and text classification with RoBERTa on IMDB and GLUE. FLaG achieves its clearest gains on the ESM2-8M antimicrobial peptide tasks and on CIFAR-100, while remaining competitive with strong text baselines on IMDB and GLUE. Then we probe its behavior on the AMP setting with band knockouts, gate summaries, residue perturbations, latent-query readouts, and structure-proxy stratification. We find that low-frequency bands contribute the most overall, and the remaining higher-band pattern is more sample-specific. The gate acts as a broadly shared spectral reweighting stage and the cross-attention patterns are sample-specific with mild query-wise differentiation, and higher-helix peptides exhibit stronger average spectral sensitivity in both bacteria. The supplementary materials, source code and data are released at this https URL and this https URL.

Most statistical and machine learning methods for directed interactions focus on pairwise effects among variables. Even existing cyclic models represent feedback primarily through node-level dependencies, making large-scale recurrent organization difficult to estimate and compare. This limitation is particularly acute in biological and neural systems, where interactions are highly recurrent and involve many overlapping cycles. We introduce a variational framework for statistical inference on cyclic interactions. Directed interactions are represented as edge flows on a simplicial complex and evolved under an energy-minimizing dynamical system. The resulting dynamics separate transient interaction components from persistent harmonic flows, yielding a low-dimensional cycle space that captures stable recurrent organization. Rather than enumerating individual cycles, the proposed framework represents cyclic interactions as elements of a Hilbert space, enabling projection, averaging, comparison, and population-level statistical inference. We establish theoretical properties of the harmonic projection, including characterization of the cycle space, variance reduction, and population inference. Simulations demonstrate substantially improved recovery of cyclic structure in dense recurrent systems compared with existing directed-interaction methods. Applied to resting-state fMRI from 400 human subjects, the framework reveals reproducible large-scale cyclic organization that is not detectable through edgewise averaging. These results provide a scalable statistical framework for studying recurrent interactions in high-dimensional dynamical systems.

Phylogenetic networks are graphs inferred from molecular sequence data that represent ancestral histories shaped by reticulate processes such as recombination, hybridization, and horizontal gene transfer. We introduce a family of distance metrics for rooted, ranked, unlabeled phylogenetic networks, extending a previously developed distance for ranked trees. Our approach relies on a bijective triangular matrix representation of phylogenetic networks that captures the temporal order of internal events, speciations, and hybridizations. Our metrics, defined as standard matrix norms, allow efficient quantitative comparisons of network topologies, timed networks and networks with differing numbers of hybridizations. Our distance can be used for both isochronous networks where all tips are sampled at one time point, and heterochronous networks where tips are allowed to be sampled at different time points. We show that our metrics capture biologically meaningful differences among evolutionary histories in both simulations and empirical posterior distributions of viral phylogenetic networks. These tools fill a methodological gap, enabling principled comparisons of ranked, unlabeled phylogenetic networks, including ancestral recombination graphs.

Dynamical mean-field theory recasts deterministic chaos in random recurrent networks as an effective stochastic process. We show that for analytic nonlinearities with sufficiently fast Fourier decay, this stochasticity is only apparent: the continuous past of a realized mean-field trajectory uniquely determines its future. The mean-field theory is therefore not merely an ensemble description, but a conditional prediction theory for individual trajectories. Unfolding the power spectrum into a Krylov state space exposes how this latent determinism is organized across an infinite hierarchy of temporal modes. The associated Krylov growth rate sets the complexity of finite-resolution prediction and upper-bounds the largest Lyapunov exponent in this class of networks. Thus, microscopic sensitivity and predictive complexity are distinct aspects of mean-field chaos. Our results extend Krylov growth ideas developed for Hamiltonian chaotic dynamics to classical dissipative systems.

When do three-dimensional conformer ensembles improve molecular property prediction beyond two-dimensional fingerprints? We provide the first systematic, mechanistically grounded answer. Through ~1,000 experiments spanning 13 model configurations, 14 regression targets, and 2 classification targets across MoleculeNet, QM9, and MARCEL benchmarks, we discover selective complementarity: conformer ensemble statistics extracted via Distribution Kernel Operators (DKOs) yield statistically significant RMSE reductions on solvation-dependent properties (ESOL -11.0%, p < 10^{-9}; FreeSolv -13.5%, p < 3x10^{-5}; 10-seed paired validation) while providing no benefit for electronic or steric tasks. Three lines of evidence confirm this selectivity has a physical rather than statistical basis: improvement is larger under scaffold splits than random splits (+11.9% vs. +8.5% on ESOL), concentrates on large, flexible molecules (+18.9% for heaviest quartile), and grows monotonically with training data. We establish a four-tier performance hierarchy: end-to-end 3D GNNs (SchNet, PaiNN; 21-42% over fingerprints) >= engineered physicochemical descriptors (PMI/SASA/USR) > Morgan fingerprints + XGBoost > all neural conformer ensemble methods, confirmed by two architecturally diverse GNNs and revealing that the pre-computed feature bottleneck limits ensemble approaches. Feature attribution and mutual information analysis expose the mechanistic asymmetry: conformer mean features carry 2-8x more information per feature than fingerprint bits, yet covariance features contribute <2% of model signal, explaining why five simple scalar invariants outperform all complex covariance architectures (p < 0.001). These findings yield an empirical property taxonomy and a practical decision framework for when conformer generation is worth the investment.

Spinal pathology is a leading cause of pain and disability worldwide. Spine MRI is central to clinical evaluation, yet its interpretation remains complex and time-consuming, requiring integration of information across multiple imaging sequences and anatomical regions. Despite recent advances in automated MRI analysis, effectively combining multi-sequence data while preserving sequence-specific diagnostic information remains an open challenge. Here we present SpineAgent, a multi-agent framework for spine MRI report generation built upon a multi-sequence foundation model trained on routine clinical data from 32,047 patients and 453,683 MRI series, comprising a total of 13,441,191 MRI slices. To accommodate diverse modalities of sequences, we first pre-train two DINOv3-based encoders separately on T1- and T2-weighted sequences. We then introduce a continual training strategy that learns a synthesizer to embed images of other sequences using the T1 and T2 encoders, producing patient-level embedding that integrates various signals across MRI sequences. Using these embeddings, SpineAgent achieves state-of-the-art performance, and demonstrates strong generalizability under cross-manufacturer and cross-cohort evaluation. Beyond classification, SpineAgent enables pathology localization by identifying findings-relevant slices and segmenting pathological regions. It also supports multimodal image-report retrieval, providing a solid foundation for scalable and explainable MRI report generation. We further integrate these validated capabilities of SpineAgent into 37 specialized agents. Finally, we incorporate their outputs as structured tokens within a Medical Report Agent trained end-to-end for report generation. Through both automated metrics and expert evaluation by five radiologists, SpineAgent achieves leading performance in spine MRI report generation.

Ask a pretrained biomedical language model whether "cortisol 28 ug/dL" and "stock-market volatility" are related, and it returns a cosine similarity of 0.83 on a scale where 1.0 means identical. The two share no mechanism. This is not a corner case: every off-the-shelf biomedical encoder we tested (BioBERT, PubMedBERT, BioM-ELECTRA) scores unrelated cross-domain pairs between 0.76 and 0.92 when the answer should be near zero. Accuracy on cross-domain discrimination is 0%. Retrieval systems survive this, because a language model downstream filters the noise. A Large Behavioural Model (LBM), a foundation model whose subject is a person rather than a sentence, does not: it reasons over a graph of a user's life and treats embedding proximity as evidence that two events are causally linked. False proximity writes a false causal edge, and everything downstream inherits the error. Here, embedding geometry is not a tuning knob; it is correctness. We report the fix. A contrastive pass over 72,034 pairs raises PubMedBERT BIOSSES correlation from 0.633 to 0.828 and within-vs-across-domain separation from 1.05x to 1.63x. A second pass, BODHI, mines hard negatives from edges absent in a biomedical knowledge graph and lifts separation to 2.30x and the discrimination gap to +0.392, at a 4.5% BIOSSES cost. On an Intel Xeon 6737P with AMX, OpenVINO cuts single-query latency from 1367 ms to 10 ms (133x) and reaches 555 sentences/sec. One finding contradicts standard advice: FP16 beats INT8 on this silicon at every serving batch size, and we explain why. The same model on a no-AMX Ice Lake instance runs 13-27x slower. We release the benchmark suite, training corpora, the BODHI generator, and the OpenVINO scripts.

Learning recurrent connectivity that supports memory over long intrinsic timescales is a basic problem in the theory of dynamical computation. While continuous attractor and integrator models describe how tuned recurrent circuits can maintain information, less is known about how such slow modes are acquired by gradient-based learning. Here we study this question in an analytically tractable setting: we build a mathematical theory of the learning dynamics of linear RNNs trained to integrate white noise. We show that when the initial recurrent weights are small, the dynamics of learning are described by a low-dimensional system that tracks a single outlier eigenvalue of the recurrent weights. This reveals the precise manner in which the long timescale associated with white noise integration is learned. We extend our analyses to RNNs learning a damped oscillatory filter, and find low-dimensional effective dynamical equations for the evolution of a conjugate pair of outlier eigenvalues. Taken together, our analyses build a rich mathematical framework for studying dynamical learning problems relevant to both machine learning and neuroscience.

Decoding sensory experiences from neural activity to reconstruct human-perceived visual stimuli and semantic content remains a challenge in neuroscience and artificial intelligence. Despite notable progress in current brain decoding models, a critical gap still persists in their systematic integration with established neuroscientific theories and the exploration of underlying neural mechanisms. Here, we present a novel framework that directly decodes fMRI signals into textual descriptions of viewed natural images. Our novel deep learning model, trained without visual information, achieves state-of-the-art semantic decoding performance, generating meaningful captions that capture the core semantic content of complex scenes. Neuroanatomical analysis reveals the critical role of higher-level visual cortices, including MT+ complex, ventral stream visual cortex, and inferior parietal cortex, in visual semantic processing. Furthermore, category-specific analysis demonstrates nuanced neural representations for semantic dimensions like animacy and motion. This work provides a more direct and interpretable framework to the brain's semantic decoding, offering a powerful new methodology for probing the neural basis of complex semantic processing, refining the understanding of the distributed semantic network, and potentially developing brain-inspired language models.

Neural recording technologies now enable simultaneous recording of population activity across many brain regions, motivating the development of data-driven models of inter-regional communication. However, existing models can struggle to disentangle the influences that drive recorded population activity, leading to inaccurate portraits of communication. Here, we introduce Multi-Region Latent Factor Analysis via Dynamical Systems (MR-LFADS), a sequential variational autoencoder designed to disentangle inter-regional communication, inputs from unobserved regions, and local neural population dynamics. We show that MR-LFADS outperforms existing approaches at identifying communication across dozens of simulations of task-trained multi-region networks. When applied to large-scale electrophysiology, MR-LFADS predicts brain-wide effects of circuit perturbations that were held out during model fitting. These validations on synthetic and real neural data position MR-LFADS as a promising tool for discovering principles of brain-wide information processing.

We introduce AMix-1, a powerful protein foundation model built on Bayesian Flow Networks and empowered by a systematic training methodology, encompassing pretraining scaling laws, emergent capability analysis, in-context learning mechanism, and test-time scaling algorithm. To guarantee robust scalability, we establish a predictive scaling law and reveal the progressive emergence of structural understanding via loss perspective, culminating in a strong 1.7-billion model. Building on this foundation, we devise a multiple sequence alignment (MSA)-based in-context learning strategy to unify protein design into a general framework, where AMix-1 recognizes deep evolutionary signals among MSAs and consistently generates structurally and functionally coherent proteins. This framework enables the successful design of a dramatically improved AmeR variant with an up to $50\times$ activity increase over its wild type. Pushing the boundaries of protein engineering, we further empower AMix-1 with an evolutionary test-time scaling algorithm for in silico directed evolution that delivers substantial, scalable performance gains as verification budgets are intensified, laying the groundwork for next-generation lab-in-the-loop protein design.

Chronic Wasting Disease (CWD) is a neurological disease impacting deer, elk, moose, and other cervid populations and is caused by a misfolded protein known as a prion. CWD is difficult to control due to the persistence of prions in the environment. Prions can remain infectious for more than a decade and have been found in soil as well as other environmental vectors, such as ticks and plants. Here, we provide a bifurcation analysis of a simple mathematical model of CWD spread in a cervid population and use a modification of the Gillespie algorithm to explore if predators can be used as an ecological control strategy to limit the spread of the disease in several relevant scenarios. We then use several analytical probabilistic arguments to show that lowering the susceptible population is also beneficial to controlling CWD outbreaks. Finally, we consider a more complex model of CWD spread in a cervid population in which predators are assumed to be dynamic. Here, we find that, again, predators may be used to control CWD outbreaks, assuming they selectively prey upon infected cervids at a sufficiently high rate. From our analysis, we conclude that wolves may be used as an effective control strategy to limit the spread of CWD in cervid populations, and hunting or other means of lowering the susceptible population are beneficial to controlling CWD.

Understanding the growth and form of complex morphological structures is one of the most fundamental problems in biology. While many prior works have analyzed the beak morphology of Darwin's finches, other cranial features are relatively less explored. In this work, we develop geometric and statistical methods for analyzing the skull morphology of Darwin's finches and their relatives, focusing on the relationship between their skull dimensions, orbit curvature, and neurocranial geometries. Unlike traditional landmark-based approaches that scale linearly with human labor, our framework is fully unsupervised. Specifically, by utilizing tools in computational geometry, differential geometry, and numerical optimization, we develop efficient algorithms for quantifying various key geometric features of the skull. We then perform a statistical analysis and discover a strong correlation between skull size and orbit curvature. Based on our findings, we further establish a predictive model that can estimate the orbit curvature using easily obtainable linear skull measurements. Our results show that the predictive model is highly effective and capable of explaining 85.48\% of the variance in curvature with an average prediction error of only 6.35\%. Altogether, our work establishes a rigorous foundation for the digital estimation and high-throughput phenotyping of large-scale museum collections, overcoming the scalability bottlenecks of manual methods.

RFdiffusion is a popular and well-established model for generation of protein structures. However, this generative process offers limited insight into its internal representations and how they contribute to the final protein structure. Concurrently, recent work in mechanistic interpretability has successfully used Sparse Autoencoders (SAEs) to discover interpretable features within neural networks. We combine these concepts by applying SAE to the internal representations of RFdiffusion to uncover secondary structure-specific features and establish a relationship between them and generated protein structures. Building on these insights, we introduce a novel steering mechanism that enables precise control of secondary structure formation through a tunable hyperparameter, while simultaneously revealing interpretable block and neuron-level representations within RFdiffusion. Our work pioneers a new framework for making RFdiffusion more interpretable, demonstrating how understanding internal features can be directly translated into precise control over the protein design process.

Representations pervade our daily experience, from letters representing sounds to bit strings encoding digital files. While such representations require externally defined decoders to convey meaning, conscious experience is fundamentally different: a neural state corresponding to perceiving a red square cannot alternatively encode the experience of a green triangle. This intrinsic property of consciousness suggests that conscious representations must be unambiguous in a way that conventional representations are not. We formalize this intuition using information theory, defining representational ambiguity as the conditional entropy H(I|R) over possible interpretations I given a representation R. Through experiments on neural networks trained to classify MNIST digits, we demonstrate that relational structures in network connectivity can unambiguously encode representational content. From relational structure alone, we achieve perfect (100%) accuracy for dropout-trained networks and 38% for standard backpropagation (chance: 10%) in identifying output neuron class identity, despite identical task performance, demonstrating that representational ambiguity can arise orthogonally to behavioral accuracy. We further show that spatial position of input neurons, relevant to phenomenal properties like visual field location, can be decoded from network connectivity with R^2 up to 0.844. These results provide a quantitative method for measuring representational ambiguity in neural systems and demonstrate that neural networks can exhibit the low-ambiguity representations posited as necessary (though not sufficient) by theoretical accounts such as narrow representationalism and IIT.

This study aims to better understand the functional geometry of the motor cortex, starting from different sources of experimental evidence. Recent studies have proved that cells of the primary motor cortex (M1) are sensitive to short hand trajectories called fragments. Here, we propose a sub-Riemannian higher-dimensional geometry accounting for geometric and kinematic properties. Due to the constraints of the geometry, horizontal curves naturally satisfy a relation between geometric and kinematic properties experimentally observed. In the space of trajectories, we also apply a clustering algorithm based on the Wasserstein distance: we obtain a grouping which nicely fits the observed experimental data much more efficiently than the Sobolev distance.

Alzheimer's disease (AD) develops over a prolonged preclinical phase, during which neuropathological changes accumulate long before cognitive symptoms appear. Identifying cognitive functions affected at early stages is critical for the preclinical detection of asymptomatic individuals at-risk of AD. Early risk identification could enable timely interventions aimed at mitigating the development of significant future cognitive impairment. While episodic memory decline typically appears after substantial medial temporal lobe damage, spatial navigation has emerged as a particularly sensitive cognitive function in preclinical AD. In this review, we provide an overview of spatial navigation computations and the tasks used to assess them, highlighting how spatial navigation relies on neural circuits corresponding to the earliest sites of AD pathology. We synthesize evidence from cognitively unimpaired individuals with AD biomarkers, i.e. individuals at-risk of AD, and discuss future research directions. Overall, performance on spatial navigation tasks, particularly path integration and wayfinding, correlates with plasma and CSF biomarkers of AD pathology, notably p-tau. Spatial navigation assessment can represent a sensitive and scalable approach for early detection of individuals at-risk of AD in preclinical stages, and will inform future interventions to mitigate the progression toward clinically significant cognitive impairment.

Parkinsons disease (PD) alters cortical neural dynamics, yet reliable non-invasive electrophysiological biomarkers remain elusive. This study examined whether interpretable EEG features capturing complementary aspects of neural dynamics can discriminate Parkinsonian neural states. A comprehensive set of interpretable features was extracted and grouped into Standard descriptors (spectral power, phase synchronization, time-domain statistics) and Dynamical descriptors (aperiodic activity, cross-frequency coupling, scale-free dynamics, neuronal avalanche statistics, and instantaneous frequency measures). A multi-head attention transformer classifier was trained using strict LOSO validation. Group-level comparisons were performed to identify electrophysiological differences associated with disease and medication state. Standard feature sets achieved strongest performance in discriminating medication states (PDoff vs PDon), whereas Dynamical performed competitively in contrasts between PD patients and healthy controls. Random feature ablation analyses indicated that Dynamical descriptors provide complementary information distributed across features while correlation analysis revealed low redundancy within both feature sets. Group-level comparisons revealed medication-sensitive reductions in delta power and voltage variance, modulation of neuronal avalanche statistics, persistent increases in theta phase synchronization in PD patients, and disease-related alterations in cross-frequency interactions. Traditional spectral and synchronization features primarily reflect medication-related neural modulation, whereas dynamical descriptors reveal broader alterations in cortical network organization associated with disease but also with medication. These findings support multivariate EEG representations as a promising framework for developing non-invasive biomarkers of PD.

Proteolysis-targeting chimeras (PROTACs) represent a promising therapeutic modality that induces targeted protein degradation by hijacking the ubiquitin-proteasome system. However, rational PROTAC design remains challenging due to the complex interplay between molecular structure, target proteins, E3 ligases, and the cellular context. We present TACK, a statistical evaluation of degradation activity on a novel TArgeting Chimeras Knowledge dataset of 3,514 PROTACs and 6,561 degradation endpoints aggregated from three major repositories with standardized molecular representations, protein annotations, and experimental conditions. Using scaffold-based 5x5 cross-validation, we perform a rigorous statistical comparison of three machine learning methods to predict PROTAC degradation activity across three tasks: $DC_{50}$ and Dmax regression, and binary activity classification. Feature ablation demonstrates that cellular context features and simple protein representations rival complex ESM protein embeddings, highlighting the importance of feature engineering over architectural sophistication. Models trained on the best performing features show that potency ($pDC_{50}$, $R^2=0.66$) is substantially more predictable than maximum degradation (Dmax, $R^2=0.36$). In activity prediction, statistical tests support that classical methods (XGBoost and MLP) significantly outperform PROTAC-STAN, a domain-specific graph neural network model (ROC-AUC: 0.85 vs. 0.75, p<0.001). Finally, we propose an ensemble-based uncertainty quantification approach showing that prediction variance correlates with prediction error ($pDC_{50}$: Spearman $\rho = 0.36$, p<0.001; Dmax: $\rho=0.69$, p<0.001), enabling confidence-aware experimental prioritization. Our findings challenge assumptions about specialized architectures for degradation prediction and provide evidence-based guidance for ML-driven PROTAC assessment.

Large language models are moving scientific research from text assistance toward agentic workflows, yet biological research requires strong object validation, methodological suitability, reproducibility, and auditability. Prompt engineering, general RAG, or tool use alone cannot reliably produce domain-specific scientific judgment. Here, we present PRAXIS, a verifiable biological research agent framework driven by literature learning and case distillation. PRAXIS converts research experience, failure boundaries, domain rules, and executable procedures into structured long-term memory. By coordinating successful cases, negative cases, rules, and skills, PRAXIS supports problem definition, object validation, method selection, workflow execution, result interpretation, and review feedback across diverse biocomputational tasks. We instantiated PRAXIS as an agent suite for biomedical computing and evaluated it through object validation, case retrieval, memory ablation, public benchmarks, and cross-agent workflows. The results show that case-based learning improves method selection, error suppression, and workflow organization in complex biological research tasks. Rather than replacing scientists, PRAXIS provides a general pathway for transforming research experience into executable, auditable, and transferable agent capabilities.

In stochastic evolutionary dynamics, the replacement of an existing genotype or cultural trait by a newly introduced mutant is typically characterized by the quantities of fixation probability and fixation time. But in a structured population, the disappearance of a lineage occurs at a specific place. For evolutionary dynamics on graphs, we define the fixation location as the node occupied by the last wild-type individual immediately before mutant fixation. Conditional on fixation, this location is described by a probability distribution over the nodes of the graph. We study the fixation location for neutral evolution, for the colonization process, and, more generally, for constant selection on small graphs, cycles, tori, random graphs, and island populations. We find that the distribution of the fixation location is often highly nonuniform, depends strongly on the graph structure and the selection strength, and can differ sharply even when classical fixation statistics are similar. For many graphs, some nodes can never be fixation locations. Our results identify fixation location as a fundamental aspect of evolutionary dynamics and suggest new ways to understand, monitor, and potentially mitigate extinction events in biological and social settings.

Landscape dynamics are key drivers of the movement and distribution of sylvatic hematophagous disease vectors and their (wild) animal hosts. Their habitats are undergoing increasing change, particularly fragmentation, through anthropogenic activity. In this article, we present and analyse a novel mathematical model that explicitly combines anthropization-induced landscape dynamics with the population dynamics of hematophagous vectors and (wild) animals dynamics. We develop a phenomenological and analytically tractable two-patch model in which the migration terms between the patches nonlinearly depend on the anthropization level of the patches. Our model analysis comprising analytical stability analysis and numerical bifurcation analysis provides information on how changes in model parameters, especially anthropization levels, shape the long-term dynamics in the model. Precisely, we find that low anthropogenic activity allows for a vector-animal coexistence state, while high anthropization leads to a vector extinction state. However, we establish that for intermediate anthropization levels, the transition between the two states is not necessarily monotonic, but may instead occur via a sequence of concurrent bifurcations along the anthropization axis.

Across biological and social systems, cooperation often depends on phenotypic cues rather than random encounters. To account for real-world interactions unfolding across multiple, simultaneous dimensions, here we develop a general framework for the evolution of cooperation in multiplex networks governed by multi-phenotype homophily. We derive analytical conditions for natural selection to favor cooperation across phenotypic traits that are independent or exhibit epistasis and under different modes of mutation coupling. Despite the integration of fitness across layers, the conditions for cooperation resolve into layer-specific $\sigma$-rules, depending only on the local payoff structure, the effective number of phenotypes, and the mutation rates. We show that phenotypic diversity fosters cooperation by partitioning populations into assortative niches. Furthermore, in finite populations, intensifying the prisoner's dilemma shifts the dependence of cooperation on strategy mutation from monotonically decreasing, through U-shaped, to monotonically increasing. Our work provides a unified account of how multi-phenotype homophily underpins the evolutionary dynamics of cooperation in heterogeneous populations.

SFILES are a text-based notation for chemical process flowsheets. They were originally proposed by d'Anterroches (Process flow sheet generation & design through a group contribution approach) who was inspired by the text-based SMILES notation for molecules. The text-based format has several advantages compared to flowsheet images regarding the storage format, computational accessibility, and eventually for data analysis and processing. However, the original SFILES version cannot describe essential flowsheet configurations unambiguously, such as the distinction between top and bottom products. Neither is it capable of describing the control structure required for the safe and reliable operation of chemical processes. Also, there is no publicly available software for decoding or encoding chemical process topologies to SFILES. We propose the SFILES 2.0 with a complete description of the extended notation and naming conventions. Additionally, we provide open-source software for the automated conversion between flowsheet graphs and SFILES 2.0 strings. This way, we hope to encourage researchers and engineers to publish their flowsheet topologies as SFILES 2.0 strings. The ultimate goal is to set the standards for creating a FAIR database of chemical process flowsheets, which would be of great value for future data analysis and processing.

This paper introduces Reflective Empiricism, an extension of empirical science that incorporates subjective perception and consciousness processes as equally valid sources of knowledge. It views reality as an interplay of subjective experience and objective laws, comprehensible only through systematic introspection, bias reflection, and premise-based logical-explorative modeling. This approach overcomes paradigmatic blindness arising from unreflected subjective filters in established paradigms, promoting an adaptable science. Innovations include a method for bias recognition, premise-based models grounded in observed phenomena to unlock new conceptual spaces, and Eureka moments - intuitive insights - as starting points for hypotheses, subsequently tested empirically. The author's self-observation, such as analyzing belief formation, demonstrates its application and transformative power. Rooted in philosophical and scientific-historical references (e.g., Archimedes' intuition, quantum observer effect), Reflective Empiricism connects physics, psychology, and philosophy, enhancing interdisciplinary synthesis and accelerating knowledge creation by leveraging anomalies and subjective depth. It does not seek to replace empirical research but to enrich it, enabling a more holistic approach to phenomena that have not yet been fully grasped. A subsequent body of the author's work is presented as case studies demonstrating the application of the method introduced here.

To investigate the mechanical correlations between intraocular pressure (IOP) variations and glaucoma, this study presents a linear transversely isotropic poroelastic model of the lamina cribrosa (LC) based on Reissner-Mindlin plate theory. A key feature of the proposed framework is its analytical tractability, which allows the governing poroelastic equations to be solved in closed form under appropriate mechanical and hydraulic boundary conditions. Within this setting, linearity is used to capture the reversible component of the tissue response, providing a baseline description of the coupled solid-fluid feedback on which more complex time-dependent phenomena, such as viscoelastic effects and remodelling, may this http URL results indicate that both strain and stress measures (in the form of shear strain and deviatoric stress measures) peak in the peripheral region of the LC, which is currently suspected to be the initial site of glaucomatous damage. These quantities increase with IOP, suggesting a pressure-dependent mechanical insult to the retinal ganglion cell (RGC) axons. In parallel, the model predicts a monotonic reduction in fluid content as IOP rises, which may contribute to ischemic phenomena and disc haemorrhages. The influence of material anisotropy was also examined, revealing that isotropic assumptions tend to overestimate the fluid content while underestimating shear strain. Given the current experimental challenges in measuring blood flow within the LC, the proposed model provides a valuable framework for exploring the coupled mechanical-hemodynamic behavior of the tissue and for inverse estimation of its mechanical parameters, such as the stiffness of the opening for the central retinal vessels.

Neural scaling laws -- power-law relationships between loss, model size, and data -- have been extensively documented for language and vision transformers, yet their existence in single-cell genomics remains largely unexplored. We present the first systematic study of scaling behaviour for masked-reconstruction transformers trained on single-cell RNA sequencing (scRNA-seq) data. Using expression profiles from the CELLxGENE Census, we construct two experimental regimes: a data-rich regime (512 highly variable genes, 200,000 cells) and a data-limited regime (1,024 genes, 10,000 cells). Across seven model sizes spanning three orders of magnitude in parameter count (533 to 3.4 x 10^8 parameters), we fit the parametric scaling law to validation mean squared error (MSE). The data-rich regime exhibits clear power-law scaling with an irreducible loss floor of c ~ 1.44, while the data-limited regime shows negligible scaling, indicating that model capacity is not the binding constraint when data are scarce. These results establish that scaling laws analogous to those observed in natural language processing do emerge in single-cell transcriptomics when sufficient data are available, and they identify the data-to-parameter ratio as a critical determinant of scaling behaviour. A preliminary conversion of the data-rich asymptotic floor to information-theoretic units yields an estimate of approximately 2.30 bits of entropy per masked gene position. We discuss implications for the design of single-cell foundation models and outline the additional measurements needed to refine this entropy estimate.

Multi-task learning shows strikingly inconsistent results -- sometimes joint training helps substantially, sometimes it actively harms performance -- yet the field lacks a principled framework for predicting these outcomes. We identify a fundamental but unstated assumption underlying gradient-based task analysis: tasks must share training instances for gradient conflicts to reveal genuine relationships. When tasks are measured on the same inputs, gradient alignment reflects shared mechanistic structure; when measured on disjoint inputs, any apparent signal conflates task relationships with distributional shift. We discover this sample overlap requirement exhibits a sharp phase transition: below 30% overlap, gradient-task correlations are statistically indistinguishable from noise; above 40%, they reliably recover known biological structure. Comprehensive validation across multiple datasets achieves strong correlations and recovers biological pathway organization. Standard benchmarks systematically violate this requirement -- MoleculeNet operates at <5% overlap, TDC at 8-14% -- far below the threshold where gradient analysis becomes meaningful. This provides the first principled explanation for seven years of inconsistent MTL results.

Large nonlinear recurrent neural networks with random couplings generate rich, potentially chaotic activity and are of interest in neuroscience and other fields. A key object encoding the structure of activity is the $N \times N$ covariance matrix. Recent work proposed an ansatz in which, at large $N$ and for typical quenched couplings, this covariance matrix matches that of a linear network with the same couplings, driven by independent noise. We derive this ansatz using a two-site cavity method that gives access to the joint statistics of activities at a pair of sites without disorder averaging. Specifically, we decompose each unit's activity into a linear response to its local field and a nonlinear residual; using the cavity method, we show that cross covariances of residuals at distinct sites are strongly suppressed, so that the residuals act as independent noise driving a linear network. In an alternative derivation, we construct a self-consistent equation for the covariance matrix in which non-Gaussian contributions supply cross terms that, in a linear network, would correspond to an external drive. Higher-order cross-site moments admit a Wick decomposition into pairwise covariances at leading order, reducing them to the linear-equivalent ansatz. We confirm the results in simulations and discuss their neuroscience implications.

The rapid growth of molecular foundation models and large language models (LLMs) has encouraged a scale centred view of AI in drug discovery, in which larger pretrained models are expected to supersede compact cheminformatics models. We test this assumption across 26 ADME, toxicity and bioactivity endpoints, covering 165,541 endpoint level compound label records. The benchmark contains 78 endpoint and split entries evaluated under random, Murcko scaffold and structure separated 5-fold cross validation protocols, representing increasing chemical generalization difficulty. Across 156 task and metric comparisons, classical machine learning (ML) provides the largest share of best performing entries (47.4%), followed by pretrained molecular sequence models (28.8%), graph neural networks (21.8%) and LLM based SAR baselines (1.9%). Classical ML dominates random split interpolation and remains the largest winner family overall. GNN and sequence models are competitive in selected harder splits, but their strict winner shares decrease under a fixed final-window readout, indicating sensitivity to training settings and model selection. Paired bootstrap analyses show that small numerical differences between individual models should not be read as decisive victories. SAR knowledge from training folds improves GPT5.5-SAR and Opus4.7-SAR metrics but does not make rule based reasoning a universal substitute for supervised predictors. Compact specialized models remain highly effective, and predictive performance depends on the fit among model, task and validation scenario, not on scale alone.

Coherence resonance (CR) characterizes noise-induced regularity in excitable systems, yet its evaluation in quiescent biological media is often obscured by flattened energy landscapes and complex nonlinear dynamics. In this study, we investigate the stochastic dynamics of a 3D Sherman-Rinzel-Keizer (SRK) model driven by multiplicative Feller noise. We show that traditional extremal evaluations of CR encounter a "bathtub effect", a broad resonance valley that can lead to statistical inaccuracies. To address this, we propose a logarithmic centroid extraction method, which filters out stochastic jitter and recovers the underlying adiabatic Kramers scaling with high linearity. Furthermore, we identify the physical boundary where this adiabatic approximation breaks down under the strong-noise limit. Extending our analysis to gap-junction coupled systems, we observe a noise-induced transition from sub-threshold physiological shivering (characterized by statistical correlation but negligible functional output) to macroscopic functional synchronization. Our results provide a mathematical framework for extracting optimal noise intensities in broad energy valleys and offer insights into how quiescent biological systems utilize stochastic fluctuations for functional recovery.

A long standing challenge in computational chemistry and biophysics is efficiently sampling the Boltzmann distribution of molecules. Advances in generative modeling have been proposed to address the limitations of conventional sampling techniques by eliminating the computational cost of simulation. A promising direction is iteratively finetuning diffusion models along a temperature ladder whereby training data is generated via importance sampling during inference-time annealing. Unfortunately, these methods require computing a divergence over the score field to estimate importance weights, rendering them intractable for larger systems. Here we present scalable inference-time annealing (SITA), which retrains flow-based models to generate samples at progressively lower temperatures using an energy-based model to facilitate fast surrogate likelihoods. We demonstrate state-of-the-art performance on both Alanine Dipeptide and Alanine Tripeptide while avoiding costly divergence terms. Our code is available at this https URL