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2602.03779 2026-02-04 q-bio.BM

Generative AI for Enzyme Design and Biocatalysis

Lasse Middendorf, Noelia Ferruz

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Sparked by innovations in generative artificial intelligence (AI), the field of protein design has undergone a paradigm shift with an explosion of new models for optimizing existing enzymes or creating them from scratch. After more than one decade of low success rates for computationally designed enzymes, generative AI models are now frequently used for designing proficient enzymes. Here, we provide a comprehensive overview and classification of generative AI models for enzyme design, highlighting models with experimental validation relevant to real-world settings and outlining their respective limitations. We argue that generative AI models now have the maturity to create and optimize enzymes for industrial applications. Wider adoption of generative AI models with experimental feedback loops can speed up the development of biocatalysts and serve as a community assessment to inform the next generation of models.

2506.04536 2026-02-04 cs.LG cs.AI q-bio.NC

NOBLE -- Neural Operator with Biologically-informed Latent Embeddings to Capture Experimental Variability in Biological Neuron Models

Luca Ghafourpour, Valentin Duruisseaux, Bahareh Tolooshams, Philip H. Wong, Costas A. Anastassiou, Anima Anandkumar

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Characterizing the cellular properties of neurons is fundamental to understanding their function in the brain. In this quest, the generation of bio-realistic models is central towards integrating multimodal cellular data sets and establishing causal relationships. However, current modeling approaches remain constrained by the limited availability and intrinsic variability of experimental neuronal data. The deterministic formalism of bio-realistic models currently precludes accounting for the natural variability observed experimentally. While deep learning is becoming increasingly relevant in this space, it fails to capture the full biophysical complexity of neurons, their nonlinear voltage dynamics, and variability. To address these shortcomings, we introduce NOBLE, a neural operator framework that learns a mapping from a continuous frequency-modulated embedding of interpretable neuron features to the somatic voltage response induced by current injection. Trained on synthetic data generated from bio-realistic neuron models, NOBLE predicts distributions of neural dynamics accounting for the intrinsic experimental variability. Unlike conventional bio-realistic neuron models, interpolating within the embedding space offers models whose dynamics are consistent with experimentally observed responses. NOBLE enables the efficient generation of synthetic neurons that closely resemble experimental data and exhibit trial-to-trial variability, offering a $4200\times$ speedup over the numerical solver. NOBLE is the first scaled-up deep learning framework that validates its generalization with real experimental data. To this end, NOBLE captures fundamental neural properties in a unique and emergent manner that opens the door to a better understanding of cellular composition and computations, neuromorphic architectures, large-scale brain circuits, and general neuroAI applications.

1902.11214 2026-02-04 nlin.AO cond-mat.stat-mech cs.DM nlin.CG q-bio.MN

A Multilayer Structure Facilitates the Production of Antifragile Systems in Boolean Network Models

Hyobin Kim, Omar K. Pineda, Carlos Gershenson

Comments 15 pages, 8 figures

Journal ref Complexity, 2019:11

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Antifragility is a property from which systems are able to resist stress and furthermore benefit from it. Even though antifragile dynamics is found in various real-world complex systems where multiple subsystems interact with each other, the attribute has not been quantitatively explored yet in those complex systems which can be regarded as multilayer networks. Here we study how the multilayer structure affects the antifragility of the whole system. By comparing single-layer and multilayer Boolean networks based on our recently proposed antifragility measure, we found that the multilayer structure facilitated the production of antifragile systems. Our measure and findings will be useful for various applications such as exploring properties of biological systems with multilayer structures and creating more antifragile engineered systems.

1812.06760 2026-02-04 nlin.AO cond-mat.stat-mech cs.DM nlin.CG q-bio.MN

A Novel Antifragility Measure Based on Satisfaction and Its Application to Random and Biological Boolean Networks

Omar K. Pineda, Hyobin Kim, Carlos Gershenson

Comments 15 pages, 7 figures

Journal ref Complexity, 2019:10

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Antifragility is a property that enhances the capability of a system in response to external perturbations. Although the concept has been applied in many areas, a practical measure of antifragility has not been developed yet. Here we propose a simply calculable measure of antifragility, based on the change of "satisfaction" before and after adding perturbations, and apply it to random Boolean networks (RBNs). Using the measure, we found that ordered RBNs are the most antifragile. Also, we demonstrated that seven biological systems are antifragile. Our measure and results can be used in various applications of Boolean networks (BNs) including creating antifragile engineering systems, identifying the genetic mechanism of antifragile biological systems, and developing new treatment strategies for various diseases.

2602.03477 2026-02-04 cs.LG cs.AI q-bio.GN

ScDiVa: Masked Discrete Diffusion for Joint Modeling of Single-Cell Identity and Expression

Mingxuan Wang, Cheng Chen, Gaoyang Jiang, Zijia Ren, Chuangxin Zhao, Lu Shi, Yanbiao Ma

Comments 19 pages, 11 figures

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Single-cell RNA-seq profiles are high-dimensional, sparse, and unordered, causing autoregressive generation to impose an artificial ordering bias and suffer from error accumulation. To address this, we propose scDiVa, a masked discrete diffusion foundation model that aligns generation with the dropout-like corruption process by defining a continuous-time forward masking mechanism in token space. ScDiVa features a bidirectional denoiser that jointly models discrete gene identities and continuous values, utilizing entropy-normalized serialization and a latent anchor token to maximize information efficiency and preserve global cell identity. The model is trained via depth-invariant time sampling and a dual denoising objective to simulate varying sparsity levels while ensuring precise recovery of both identity and magnitude. Pre-trained on 59 million cells, scDiVa achieves strong transfer performance across major benchmarks, including batch integration, cell type annotation, and perturbation response prediction. These results suggest that masked discrete diffusion serves as a biologically coherent and effective alternative to autoregression.

2602.03343 2026-02-04 stat.CO q-bio.GN q-bio.QM

MARADONER: Motif Activity Response Analysis Done Right

Georgy Meshcheryakov, Andrey I. Buyan

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Inferring the activities of transcription factors from high-throughput transcriptomic or open chromatin profiling, such as RNA-/CAGE-/ATAC-Seq, is a long-standing challenge in systems biology. Identification of highly active master regulators enables mechanistic interpretation of differential gene expression, chromatin state changes, or perturbation responses across conditions, cell types, and diseases. Here, we describe MARADONER, a statistical framework and its software implementation for motif activity response analysis (MARA), utilizing the sequence-level features obtained with pattern matching (motif scanning) of individual promoters and promoter- or gene-level activity or expression estimates. Compared to the classic MARA, MARADONER (MARA-done-right) employs an unbiased variance parameter estimation and a bias-adjusted likelihood estimation of fixed effects, thereby enhancing goodness-of-fit and the accuracy of activity estimation. Further, MARADONER is capable of accounting for heteroscedasticity of motif scores and activity estimates.

2602.03269 2026-02-04 q-bio.NC

Systematic review of self-supervised foundation models for brain network representation using electroencephalography

Hannah Portmann, Yosuke Morishima

Comments 19 pages, 1 figure, 3 tables

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Automated analysis of electroencephalography (EEG) has recently undergone a paradigm shift. The introduction of transformer architectures and self-supervised pretraining (SSL) has led to the development of EEG foundation models. These models are pretrained on large amounts of unlabeled data and can be adapted to a range of downstream tasks. This systematic review summarizes recent SSL-trained EEG foundation models that learn whole-brain representations from multichannel EEG rather than representations derived from a single channel. We searched PubMed, IEEE Xplore, Scopus, and arXiv through July 21, 2025. Nineteen preprints and peer-reviewed articles met inclusion criteria. We extracted information regarding pretraining datasets, model architectures, pretraining SSL objectives, and downstream task applications. While pretraining data heavily relied on the Temple University EEG corpus, there was significant heterogeneity in model architecture and training objectives across studies. Transformer architectures were identified as the predominant pretraining architecture with state-space models such as MAMBA and S4 as emerging alternatives. Concerning SSL objectives, masked auto-encoding was most common, and other studies incorporate contrastive learning. Downstream tasks varied widely and implemented diverse fine-tuning strategies, which made direct comparison challenging. Furthermore, most studies used single-task fine-tuning, and a generalizable EEG foundation model remains lacking. In conclusion, the field is advancing rapidly but still limited by limited dataset diversity and the absence of standardized benchmarks. Progress will likely depend on larger and more diverse pretraining datasets, standardized evaluation protocols, and multi-task validation. The development will advance EEG foundation models towards robust and general-purpose relevant to both basic and clinical applications.

2602.03240 2026-02-04 q-bio.NC cs.IT math.IT

Estimating measures of information processing during cognitive tasks using functional magnetic resonance imaging

Chetan Gohil, Oliver M. Cliff, James M. Shine, Ben D. Fulcher, Joseph T. Lizier

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Cognition is increasingly framed in terms of information processing, yet most fMRI analyses focus on activation or functional connectivity rather than quantifying how information is stored and transferred. To remedy this problem, we propose a framework for estimating measures of information processing: active information storage (AIS), transfer entropy (TE), and net synergy from task-based fMRI. AIS measures information maintained within a region, TE captures directed information flow, and net synergy contrasts higher-order synergistic to redundant interactions. Crucially, to enable this framework we utilised a recently developed approach for calculating information-theoretic measures: the cross mutual information. This approach combines resting-state and task data to address the challenges of limited sample size, non-stationarity and context in task-based fMRI. We applied this framework to the working memory (N-back) task from the Human Connectome Project (470 participants). Results show that AIS increases in fronto-parietal regions with working memory load, TE reveals enhanced directed information flows across control pathways, and net synergy indicates a global shift to redundancy. This work establishes a novel methodology for quantifying information processing in task-based fMRI.

2602.03172 2026-02-04 cs.LG q-bio.NC

Adversarial construction as a potential solution to the experiment design problem in large task spaces

Prakhar Godara, Frederick Callaway, Marcelo G. Mattar

Comments 7 pages, 7 figures

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Despite decades of work, we still lack a robust, task-general theory of human behavior even in the simplest domains. In this paper we tackle the generality problem head-on, by aiming to develop a unified model for all tasks embedded in a task-space. In particular we consider the space of binary sequence prediction tasks where the observations are generated by the space parameterized by hidden Markov models (HMM). As the space of tasks is large, experimental exploration of the entire space is infeasible. To solve this problem we propose the adversarial construction approach, which helps identify tasks that are most likely to elicit a qualitatively novel behavior. Our results suggest that adversarial construction significantly outperforms random sampling of environments and therefore could be used as a proxy for optimal experimental design in high-dimensional task spaces.

2602.02920 2026-02-04 cs.LG cs.CV q-bio.NC q-bio.QM

A Reproducible Framework for Bias-Resistant Machine Learning on Small-Sample Neuroimaging Data

Jagan Mohan Reddy Dwarampudi, Jennifer L Purks, Joshua Wong, Renjie Hu, Tania Banerjee

Comments Accepted to ISBI 2026, 5 pages with 1 figure

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We introduce a reproducible, bias-resistant machine learning framework that integrates domain-informed feature engineering, nested cross-validation, and calibrated decision-threshold optimization for small-sample neuroimaging data. Conventional cross-validation frameworks that reuse the same folds for both model selection and performance estimation yield optimistically biased results, limiting reproducibility and generalization. Demonstrated on a high-dimensional structural MRI dataset of deep brain stimulation cognitive outcomes, the framework achieved a nested-CV balanced accuracy of 0.660\,$\pm$\,0.068 using a compact, interpretable subset selected via importance-guided ranking. By combining interpretability and unbiased evaluation, this work provides a generalizable computational blueprint for reliable machine learning in data-limited biomedical domains.

2602.02918 2026-02-04 cs.CV cs.AI cs.LG q-bio.TO

A Multi-scale Linear-time Encoder for Whole-Slide Image Analysis

Jagan Mohan Reddy Dwarampudi, Joshua Wong, Hien Van Nguyen, Tania Banerjee

Comments Accepted to ISBI 2026, 4 pages with 2 figures

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We introduce Multi-scale Adaptive Recurrent Biomedical Linear-time Encoder (MARBLE), the first \textit{purely Mamba-based} multi-state multiple instance learning (MIL) framework for whole-slide image (WSI) analysis. MARBLE processes multiple magnification levels in parallel and integrates coarse-to-fine reasoning within a linear-time state-space model, efficiently capturing cross-scale dependencies with minimal parameter overhead. WSI analysis remains challenging due to gigapixel resolutions and hierarchical magnifications, while existing MIL methods typically operate at a single scale and transformer-based approaches suffer from quadratic attention costs. By coupling parallel multi-scale processing with linear-time sequence modeling, MARBLE provides a scalable and modular alternative to attention-based architectures. Experiments on five public datasets show improvements of up to \textbf{6.9\%} in AUC, \textbf{20.3\%} in accuracy, and \textbf{2.3\%} in C-index, establishing MARBLE as an efficient and generalizable framework for multi-scale WSI analysis.

2602.02825 2026-02-04 stat.AP q-bio.QM stat.ME

On the consistent and scalable detection of spatial patterns

Jiayu Su, Jun Hou Fung, Haoyu Wang, Dian Yang, David A. Knowles, Raul Rabadan

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Detecting spatial patterns is fundamental to scientific discovery, yet current methods lack statistical consensus and face computational barriers when applied to large-scale spatial omics datasets. We unify major approaches through a single quadratic form and derive general consistency conditions. We reveal that several widely used methods, including Moran's I, are inconsistent, and propose scalable corrections. The resulting test enables robust pattern detection across millions of spatial locations and single-cell lineage-tracing datasets.

2602.02638 2026-02-04 cs.LG q-bio.QM

hSNMF: Hybrid Spatially Regularized NMF for Image-Derived Spatial Transcriptomics

Md Ishtyaq Mahmud, Veena Kochat, Suresh Satpati, Jagan Mohan Reddy Dwarampudi, Humaira Anzum, Kunal Rai, Tania Banerjee

Comments The paper is accepted to the 2026 IEEE 23rd International Symposium on Biomedical Imaging (ISBI); 5 pages, 1 figure

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High-resolution spatial transcriptomics platforms, such as Xenium, generate single-cell images that capture both molecular and spatial context, but their extremely high dimensionality poses major challenges for representation learning and clustering. In this study, we analyze data from the Xenium platform, which captures high-resolution images of tumor microarray (TMA) tissues and converts them into cell-by-gene matrices suitable for computational analysis. We benchmark and extend nonnegative matrix factorization (NMF) for spatial transcriptomics by introducing two spatially regularized variants. First, we propose Spatial NMF (SNMF), a lightweight baseline that enforces local spatial smoothness by diffusing each cell's NMF factor vector over its spatial neighborhood. Second, we introduce Hybrid Spatial NMF (hSNMF), which performs spatially regularized NMF followed by Leiden clustering on a hybrid adjacency that integrates spatial proximity (via a contact-radius graph) and transcriptomic similarity through a tunable mixing parameter alpha. Evaluated on a cholangiocarcinoma dataset, SNMF and hSNMF achieve markedly improved spatial compactness (CHAOS < 0.004, Moran's I > 0.96), greater cluster separability (Silhouette > 0.12, DBI < 1.8), and higher biological coherence (CMC and enrichment) compared to other spatial baselines. Availability and implementation: https://github.com/ishtyaqmahmud/hSNMF

2602.02587 2026-02-04 physics.soc-ph cond-mat.stat-mech cs.GT q-bio.PE

The Evolution of Lying in a Spatially-Explicit Prisoner's Dilemma Model

Gregg Hartvigsen

Comments 18 pages, 11 figures

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I present the results from a spatial model of the prisoner's dilemma, played on a toroidal lattice. Each individual has a default strategy of either cooperating ($C$) or defecting ($D$). Two strategies were tested, including ``tit-for-tat'' (TFT), in which individuals play their opponent's last play, or simply playing their default play. Each individual also has a probability of telling the truth ($0 \leq P_{truth} \leq 1$) about their last play. This parameter, which can evolve over time, allows individuals to be, for instance, a defector but present as a cooperator regarding their last play. This leads to interesting dynamics where mixed populations of defectors and cooperators with $P_{truth} \geq 0.75$ move toward populations of truth-telling cooperators. Likewise, mixed populations with $P_{truth} < 0.7$ become populations of lying defectors. Both such populations are stable because they each have higher average scores than populations with intermediate values of $P_{truth}$. Applications of this model are discussed with regards to both humans and animals.

2602.02562 2026-02-04 physics.soc-ph math.DS q-bio.NC

A Distinct Communication Strategies Model of the Double Empathy Problem

Enrique Calderoli, Maria Cristina Varriale, Flávio Kapczinski

Comments 16 pages, 5 figures

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The double empathy problem recasts the difficulty of forming empathy bonds in social interactions between autistic and neurotypical individuals as a bidirectional problem, rather than due to a deficit exclusive to the person on the spectrum. However, no explicit mechanism to explain such a phenomenon has been proposed. Here we build a feedback-loop mathematical model that would theoretically induce the empathy degradation observed during communication in neurotypical-autistic pairs solely due to differences in communication preferences between neurotypical and neurodivergent individuals. Numerical simulations of dyadic interactions show the model, whose mechanism is based solely on communication preferences, can illustrate the breakdown of empathic bonding observed clinically. Stability analysis of the model provides a way to predict the overall trajectory of the interaction in the empathy space. Furthermore, we suggest experimental designs to measure several parameters outlined here and discuss the future directions for testing the proposed model.

2602.02558 2026-02-04 cs.LG cs.AI q-bio.QM

PA-MIL: Phenotype-Aware Multiple Instance Learning Guided by Language Prompting and Genotype-to-Phenotype Relationships

Zekang Yang, Hong Liu, Xiangdong Wang

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Deep learning has been extensively researched in the analysis of pathology whole-slide images (WSIs). However, most existing methods are limited to providing prediction interpretability by locating the model's salient areas in a post-hoc manner, failing to offer more reliable and accountable explanations. In this work, we propose Phenotype-Aware Multiple Instance Learning (PA-MIL), a novel ante-hoc interpretable framework that identifies cancer-related phenotypes from WSIs and utilizes them for cancer subtyping. To facilitate PA-MIL in learning phenotype-aware features, we 1) construct a phenotype knowledge base containing cancer-related phenotypes and their associated genotypes. 2) utilize the morphological descriptions of phenotypes as language prompting to aggregate phenotype-related features. 3) devise the Genotype-to-Phenotype Neural Network (GP-NN) grounded in genotype-to-phenotype relationships, which provides multi-level guidance for PA-MIL. Experimental results on multiple datasets demonstrate that PA-MIL achieves competitive performance compared to existing MIL methods while offering improved interpretability. PA-MIL leverages phenotype saliency as evidence and, using a linear classifier, achieves competitive results compared to state-of-the-art methods. Additionally, we thoroughly analyze the genotype-phenotype relationships, as well as cohort-level and case-level interpretability, demonstrating the reliability and accountability of PA-MIL.

2602.02553 2026-02-04 physics.soc-ph math.DS q-bio.PE

Indirect Reciprocity with Environmental Feedback

Yishen Jiang, Xin Wang, Ming Wei, Wenqiang Zhu, Longzhao Liu, Hongwei Zheng, Shaoting Tang

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Indirect reciprocity maintains cooperation in stranger societies by mapping individual behaviors onto reputation signals via social norms. Existing theoretical frameworks assume static environments with constant resources and fixed payoff structures. However, in real-world systems, individuals' strategic behaviors not only shape their reputation but also induce collective-level resource changes in ecological, economic, or other external environments, which in turn reshape the incentives governing future individual actions. To overcome this limitation, we establish a co-evolutionary framework that couples moral assessment, strategy updating, and environmental dynamics, allowing the payoff structure to dynamically adjust in response to the ecological consequences of collective actions. We find that this environmental feedback mechanism helps lower the threshold for the emergence of cooperation, enabling the system to spontaneously transition from a low-cooperation state to a stable high-cooperation regime, thereby reducing the dependence on specific initial conditions. Furthermore, while lenient norms demonstrate adaptability in static environments, norms with strict discrimination are shown to be crucial for curbing opportunism and maintaining evolutionary resilience in dynamic settings. Our results reveal the evolutionary dynamics of coupled systems involving reputation institutions and environmental constraints, offering a new theoretical perspective for understanding collective cooperation and social governance in complex environments.

2602.01751 2026-02-04 cs.LG q-bio.QM

MGKAN: Predicting Asymmetric Drug-Drug Interactions via a Multimodal Graph Kolmogorov-Arnold Network

Kunyi Fan, Mengjie Chen, Longlong Li, Cunquan Qu

Comments This paper has been accepted by ICASSP 2026

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Predicting drug-drug interactions (DDIs) is essential for safe pharmacological treatments. Previous graph neural network (GNN) models leverage molecular structures and interaction networks but mostly rely on linear aggregation and symmetric assumptions, limiting their ability to capture nonlinear and heterogeneous patterns. We propose MGKAN, a Graph Kolmogorov-Arnold Network that introduces learnable basis functions into asymmetric DDI prediction. MGKAN replaces conventional MLP transformations with KAN-driven basis functions, enabling more expressive and nonlinear modeling of drug relationships. To capture pharmacological dependencies, MGKAN integrates three network views-an asymmetric DDI network, a co-interaction network, and a biochemical similarity network-with role-specific embeddings to preserve directional semantics. A fusion module combines linear attention and nonlinear transformation to enhance representational capacity. On two benchmark datasets, MGKAN outperforms seven state-of-the-art baselines. Ablation studies and case studies confirm its predictive accuracy and effectiveness in modeling directional drug effects.

2602.00197 2026-02-04 q-bio.QM cs.AI cs.CL

Rank-and-Reason: Multi-Agent Collaboration Accelerates Zero-Shot Protein Mutation Prediction

Yang Tan, Yuanxi Yu, Can Wu, Bozitao Zhong, Mingchen Li, Guisheng Fan, Jiankang Zhu, Yafeng Liang, Nanqing Dong, Liang Hong

Comments 22 pages, 5 figures, 15 tables

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Zero-shot mutation prediction is vital for low-resource protein engineering, yet existing protein language models (PLMs) often yield statistically confident results that ignore fundamental biophysical constraints. Currently, selecting candidates for wet-lab validation relies on manual expert auditing of PLM outputs, a process that is inefficient, subjective, and highly dependent on domain expertise. To address this, we propose Rank-and-Reason (VenusRAR), a two-stage agentic framework to automate this workflow and maximize expected wet-lab fitness. In the Rank-Stage, a Computational Expert and Virtual Biologist aggregate a context-aware multi-modal ensemble, establishing a new Spearman correlation record of 0.551 (vs. 0.518) on ProteinGym. In the Reason-Stage, an agentic Expert Panel employs chain-of-thought reasoning to audit candidates against geometric and structural constraints, improving the Top-5 Hit Rate by up to 367% on ProteinGym-DMS99. The wet-lab validation on Cas12i3 nuclease further confirms the framework's efficacy, achieving a 46.7% positive rate and identifying two novel mutants with 4.23-fold and 5.05-fold activity improvements. Code and datasets are released on GitHub (https://github.com/ai4protein/VenusRAR/).

2509.24926 2026-02-04 q-bio.MN physics.bio-ph q-bio.SC

Bifurcations and multistability in inducible three-gene toggle switch networks

Rebecca J. Rousseau, Rob Phillips

Comments 32 pages, 23 figures

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Control of transcription presides over a vast array of biological processes, including those mediated by gene regulatory circuits that exhibit multistability. Within these circuits, two- and three-gene network motifs are particularly critical to the repertoire of metabolic and developmental pathways. Theoretical models of these circuits, however, often vary parameters such as dissociation constants, transcription rates, and degradation rates without specifying precisely how these parameters are controlled biologically. In this study, we examine the role of effector molecules, which can alter the concentrations of the active transcription factors that control regulation, and are ubiquitous in regulatory processes across many biological settings. We specifically consider allosteric regulation in the context of extending the standard bistable switch to three-gene networks, and explore the rich multistable dynamics exhibited in these architectures as a function of effector concentrations. We then analyze how the dynamics evolve under various interpretations of regulatory circuit mechanics, underlying inducer activity, and perturbations thereof. Notably, the biological mechanism by which we model effector control over dual-function proteins transforms not only the phenotypic trend of dynamic tuning but also the set of available dynamic regimes. In this way, we determine key parameters and regulatory features that drive phenotypic decisions, and offer an experimentally tunable structure for encoding inducible multistable behavior arising from both single and dual-function allosteric transcription factors.

2508.15784 2026-02-04 q-bio.NC cs.LG

Emergent time-keeping mechanisms in a deep reinforcement learning agent performing an interval timing task

Amrapali Pednekar, Alvaro Garrido, Pieter Simoens, Yara Khaluf

Comments Accepted at 2025 Artificial Life Conference

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Drawing parallels between Deep Artificial Neural Networks (DNNs) and biological systems can aid in understanding complex biological mechanisms that are difficult to disentangle. Temporal processing, an extensively researched topic, is one such example that lacks a coherent understanding of its underlying mechanisms. In this study, we investigate temporal processing in a Deep Reinforcement Learning (DRL) agent performing an interval timing task and explore potential biological counterparts to its emergent behavior. The agent was successfully trained to perform a duration production task, which involved marking successive occurrences of a target interval while viewing a video sequence. Analysis of the agent's internal states revealed oscillatory neural activations, a ubiquitous pattern in biological systems. Interestingly, the agent's actions were predominantly influenced by neurons exhibiting these oscillations with high amplitudes and frequencies corresponding to the target interval. Parallels are drawn between the agent's time-keeping strategy and the Striatal Beat Frequency (SBF) model, a biologically plausible model of interval timing. Furthermore, the agent maintained its oscillatory representations and task performance when tested on different video sequences (including a blank video). Thus, once learned, the agent internalized its time-keeping mechanism and showed minimal reliance on its environment to perform the timing task. A hypothesis about the resemblance between this emergent behavior and certain aspects of the evolution of biological processes like circadian rhythms, has been discussed. This study aims to contribute to recent research efforts of utilizing DNNs to understand biological systems, with a particular emphasis on temporal processing.

2505.13197 2026-02-04 cs.LG physics.bio-ph q-bio.QM

Inferring stochastic dynamics with growth from cross-sectional data

Stephen Zhang, Suryanarayana Maddu, Xiaojie Qiu, Victor Chardès

Comments 10 pages, 5 figures, NeurIPS 2025

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Time-resolved single-cell omics data offers high-throughput, genome-wide measurements of cellular states, which are instrumental to reverse-engineer the processes underpinning cell fate. Such technologies are inherently destructive, allowing only cross-sectional measurements of the underlying stochastic dynamical system. Furthermore, cells may divide or die in addition to changing their molecular state. Collectively these present a major challenge to inferring realistic biophysical models. We present a novel approach, unbalanced probability flow inference, that addresses this challenge for biological processes modelled as stochastic dynamics with growth. By leveraging a Lagrangian formulation of the Fokker-Planck equation, our method accurately disentangles drift from intrinsic noise and growth. We showcase the applicability of our approach through evaluation on a range of simulated and real single-cell RNA-seq datasets. Comparing to several existing methods, we find our method achieves higher accuracy while enjoying a simple two-step training scheme.

2505.12387 2026-02-04 cs.LG cond-mat.dis-nn cond-mat.stat-mech math-ph math.MP q-bio.NC stat.ML

Neural Thermodynamics: Entropic Forces in Deep and Universal Representation Learning

Liu Ziyin, Yizhou Xu, Isaac Chuang

Comments Published at NeurIPS 2025

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With the rapid discovery of emergent phenomena in deep learning and large language models, understanding their cause has become an urgent need. Here, we propose a rigorous entropic-force theory for understanding the learning dynamics of neural networks trained with stochastic gradient descent (SGD) and its variants. Building on the theory of parameter symmetries and an entropic loss landscape, we show that representation learning is crucially governed by emergent entropic forces arising from stochasticity and discrete-time updates. These forces systematically break continuous parameter symmetries and preserve discrete ones, leading to a series of gradient balance phenomena that resemble the equipartition property of thermal systems. These phenomena, in turn, (a) explain the universal alignment of neural representations between AI models and lead to a proof of the Platonic Representation Hypothesis, and (b) reconcile the seemingly contradictory observations of sharpness- and flatness-seeking behavior of deep learning optimization. Our theory and experiments demonstrate that a combination of entropic forces and symmetry breaking is key to understanding emergent phenomena in deep learning.

2505.08677 2026-02-04 q-bio.PE math.PR

Evolving genealogies in cultural evolution, the descendant process, and the number of cultural traits

Joe Yuichiro Wakano, Hisashi Ohtsuki, Yutaka Kobayashi, Ellen Baake

Comments 46 pages, 16 figures

Journal ref Theor. Popul. Biol. 168 (2026) 1-18

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We consider a Moran-type model of cultural evolution, which describes how traits emerge, are transmitted, and get lost in populations. Our analysis focuses on the underlying cultural genealogies; they were first described by Aguilar and Ghirlanda (2015) and are closely related to the ancestral selection graph of population genetics, wherefore we call them ancestral learning graphs. We investigate their dynamical behaviour, that is, we are concerned with evolving genealogies. In particular, we consider the total length of the genealogy of the entire population as a function of the (forward) time where we start looking back. This quantity shows a sawtooth-like dynamics with linear increase interrupted by collapses to near-zero at random times. We relate this to the metastable behaviour of the stochastic logistic model, which describes the evolution of the number of ancestors as well as the number of descendants of a given sample. We superpose types to the model by assuming that new inventions appear independently in every individual, and all traits of the cultural parent are transmitted to the learner in any given learning event. The set of traits of an individual then agrees with the set of innovations along its genealogy. The properties of the genealogy thus translate into the properties of the trait set of a sample. In particular, the moments of the number of traits are obtained from the moments of the total length of the genealogy.

2502.07537 2026-02-04 q-bio.PE cond-mat.dis-nn nlin.AO

Evolution of cooperation in a bimodal mixture of conditional cooperators

Chenyang Zhao, Xinshi Feng, Guozhong Zheng, Weiran Cai, Jiqiang Zhang, Li Chen

Comments 11 pages, 14 figures, comments are appreciated

Journal ref Physical Review E 112, 054309 (2025)

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Extensive behavioral experiments reveal that conditional cooperation is a prevalent phenomenon. Previous game-theoretical studies have predominantly relied on hard-manner models, where cooperation is triggered only upon reaching a specific threshold. However, this approach contrasts with the observed flexibility of human behaviors, where individuals adapt their strategies dynamically based on their surroundings. To capture this adaptability, we introduce a soft form of conditional cooperation by integrating the Q-learning algorithm from reinforcement learning. In this form, players not only reciprocate mutual cooperation but may also defect in highly cooperative environments or cooperate in less cooperative settings to maximize rewards. To explore the effects of hard and soft conditional cooperators, we examine their interactions in two scenarios: structural mixture (SM) and probabilistic mixture (PM), where the two behavioral modes are fixed and probabilistically adopted, respectively. In SM, hard conditional cooperators enhance cooperation when the threshold is low but hinder it otherwise. Surprisingly, in PM, the cooperation prevalence exhibits two first-order phase transitions as the probability is varied, leading to high, low, and vanishing levels of cooperation. Analysis of Q-tables offers insights into the "psychological shifts" of soft conditional cooperators and the overall evolutionary dynamics. Model extensions confirm the robustness of our findings. These results highlight the novel complexities arising from the diversity of conditional cooperators.

2412.16249 2026-02-04 cs.LG cond-mat.dis-nn nlin.AO physics.soc-ph q-bio.PE

Decoding fairness: a reinforcement learning perspective

Guozhong Zheng, Jiqiang Zhang, Xin Ou, Shengfeng Deng, Li Chen

Comments 12 pages, 13 figures. Comments are appreciated

Journal ref Physical Review E 111, 064307 (2025)

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英文摘要

Behavioral experiments on the ultimatum game (UG) reveal that we humans prefer fair acts, which contradicts the prediction made in orthodox Economics. Existing explanations, however, are mostly attributed to exogenous factors within the imitation learning framework. Here, we adopt the reinforcement learning paradigm, where individuals make their moves aiming to maximize their accumulated rewards. Specifically, we apply Q-learning to UG, where each player is assigned two Q-tables to guide decisions for the roles of proposer and responder. In a two-player scenario, fairness emerges prominently when both experiences and future rewards are appreciated. In particular, the probability of successful deals increases with higher offers, which aligns with observations in behavioral experiments. Our mechanism analysis reveals that the system undergoes two phases, eventually stabilizing into fair or rational strategies. These results are robust when the rotating role assignment is replaced by a random or fixed manner, or the scenario is extended to a latticed population. Our findings thus conclude that the endogenous factor is sufficient to explain the emergence of fairness, exogenous factors are not needed.

2407.19634 2026-02-04 q-bio.PE cond-mat.stat-mech nlin.AO

Evolution of cooperation with Q-learning: the impact of information perception

Guozhong Zheng, Zhenwei Ding, Jiqiang Zhang, Shengfeng Deng, Weiran Cai, Li Chen

Comments 13pages, 13figures, comments are appreciated

Journal ref Chaos 35, 053129 (2025)

详情
英文摘要

The inherent complexity of human beings manifests in a remarkable diversity of responses to intricate environments, enabling us to approach problems from varied perspectives. However, in the study of cooperation, existing research within the reinforcement learning framework often assumes that individuals have access to identical information when making decisions, which contrasts with the reality that individuals frequently perceive information differently. In this study, we employ the Q-learning algorithm to explore the impact of information perception on the evolution of cooperation in a two-person Prisoner's Dilemma game. We demonstrate that the evolutionary processes differ significantly across three distinct information perception scenarios, highlighting the critical role of information structure in the emergence of cooperation. Notably, the asymmetric information scenario reveals a complex dynamical process, including the emergence, breakdown, and reconstruction of cooperation, mirroring psychological shifts observed in human behavior. Our findings underscore the importance of information structure in fostering cooperation, offering new insights into the establishment of stable cooperative relationships among humans.

2404.04604 2026-02-04 q-bio.NC

A diffusion MRI tractography atlas for concurrent white matter mapping across Eastern and Western populations

Yijie Li, Wei Zhang, Ye Wu, Li Yin, Ce Zhu, Yuqian Chen, Suheyla Cetin-Karayumak, Kang Ik K Cho, Leo R. Zekelman, Jarrett Rushmore, Yogesh Rathi, Nikos Makris, Lauren J. O'Donnell, Fan Zhang

详情
英文摘要

The study of brain differences across Eastern and Western populations provides vital insights for understanding potential cultural and genetic influences on cognition and mental health. Diffusion MRI (dMRI) tractography is an important tool in assessing white matter (WM) connectivity and brain tissue microstructure across different populations. However, a comprehensive investigation into WM fiber tracts between Eastern and Western populations is challenged due to the lack of a cross-population WM atlas and the large site-specific variability of dMRI data. This study presents a dMRI tractography atlas, namely the East-West WM Atlas, for concurrent WM mapping between Eastern and Western populations and creates a large, harmonized dMRI dataset (n=306) based on the Human Connectome Project and the Chinese Human Connectome Project. The curated WM atlas, as well as subject-specific data including the harmonized dMRI data, the whole brain tractography data, and parcellated WM fiber tracts and their diffusion measures, are publicly released. This resource is a valuable addition to facilitating the exploration of brain commonalities and differences across diverse cultural backgrounds.

2312.14970 2026-02-04 physics.soc-ph cond-mat.dis-nn nlin.AO q-bio.PE stat.ML

Optimal coordination of resources: A solution from reinforcement learning

Guozhong Zheng, Weiran Cai, Guanxiao Qi, Jiqiang Zhang, Li Chen

Comments 15 pages, 13 figures, 1 table, comments are appreciated

Journal ref Physical Review E 112, 064305 (2025)

详情
英文摘要

Efficient allocation is important in nature and human society, where individuals frequently compete for limited resources. The Minority Game (MG) is perhaps the simplest toy model to address this issue. However, most previous solutions assume that the strategies are provided a priori and static, failing to capture their adaptive nature. Here, we introduce the reinforcement learning (RL) paradigm to MG, where individuals adjust decisions based on accumulated experience and expected rewards dynamically. We find that this RL framework achieves optimal resource coordination when individuals balance the exploitation of experience with random exploration. Yet, the imbalanced strategies of the two lead to suboptimal partial coordination or even anti-coordination. Our mechanistic analysis reveals a symmetry-breaking in action preferences at the optimum, offering a fresh solution to the MG and new insights into the resource allocation problem.