We consider the SEIRS epidemiology model with such features of the COVID-19 outbreak as: abundance of unidentified infected individuals, limited time of immunity and a possibility of vaccination. The control of the pandemic dynamics is possible by restricting the transmission rate, increasing identification and isolation rate of infected individuals, and via vaccination. For the compartmental version of this model, we found stable disease-free and endemic stationary states. The basic reproductive number is analysed with respect to balancing quarantine and vaccination measures. The positions and heights of the first peak of outbreak are obtained numerically and fitted to simple in usage algebraic forms. Lattice-based realization of this model is studied by means of the asynchronous cellular automaton algorithm. This permitted to study the effect of social distancing by varying the neighbourhood size of the model. The attempt is made to match the quarantine and vaccination effects.

The dynamics of simple two-alternative forced-choice (2AFC) decisions are well-modeled by a class of random walk models (e.g. Laming, 1968; Ratcliff, 1978; Usher & McClelland, 2001; Bogacz et al., 2006). However, in real-life, even simple decisions involve dynamically changing influence of additional information. In this work, we describe a computational theory of decision making from multiple sources of information, grounded in Bayesian inference and consistent with a simple neural network. This Contextual Diffusion Decision Model (CDDM) is a formal generalization of the Diffusion Decision Model (DDM), a popular existing model of fixed-context decision making (Ratcliff, 1978), and shares with it both a mechanistic and a probabilistic motivation. Just as the DDM is a model for a variety of simple two-alternative forced-choice (2AFC) decision making tasks, we demonstrate that the CDDM supports a variety of simple context-dependent tasks of longstanding interest in psychology, including the Flanker (Eriksen & Eriksen, 1974), AX-CPT (Servan-Schreiber et al., 1996), Stop-Signal (Logan & Cowan, 1984), Cueing (Posner, 1980), and Prospective Memory paradigms (Einstein & McDaniel, 2005). Further, we use the CDDM to perform a number of normative rational analyses exploring optimal response and memory allocation policies. Finally, we show how the use of a consistent model across tasks allows us to recover consistent qualitative data patterns in multiple tasks, using the same model parameters.

Randomly-assembled dynamical systems are theoretically predicted to be unstable upon crossing a critical threshold of complexity, as first shown by May. Yet, empirical complex systems exhibit remarkable stability, indicating the presence of additional mechanisms playing a stabilizing role. The relation between complexity and stability is typically assessed by assuming fixed interactions, whereas real systems often evolve in intrinsically time-dependent states. To understand how this affects stability, we linearize a general non-autonomous dynamics around a reference operating state and model the resulting parameters as stochastic processes, which represent the minimal extension of static random interactions to time-varying ones. We derive exact stability bounds that generalize complexity-stability theory to dynamically varying systems. Notably, we find that temporal variability allows systems to remain stable even when their instantaneous Jacobian would predict instability. We compare our results against a non-linear neural network model, where our theory applies exactly, and the generalized Lotka-Volterra equations, where we numerically find that time-varying interactions systematically postpone the onset of replica-symmetry breaking. Overall, our results indicate that temporal variability systematically improves stability, demonstrating a general mechanism by which complex systems can violate classical complexity-stability bounds.

We analyse the global dynamics of a Susceptible--Vaccinated--Exposed--Infected--Recovered (SVEIR) epidemic model with demographic turnover, imperfect vaccination, and two transmission routes: direct host-to-host contagion and indirect transmission via contaminated fomites. Indirect transmission is described through an environmental pathogen concentration and a Holling-type dose--response function, accounting for nonlinear incidence at high contamination levels. Threshold conditions separating disease elimination from long-term persistence are expressed in terms of the control reproduction number $\mathcal R_c$, and the classical threshold condition $\mathcal R_c<1$ is derived for the local asymptotic stability of the disease-free equilibrium. For the Holling type~II case, we further obtain an explicit closed-form sufficient condition for the global asymptotic stability of the disease-free equilibrium by applying the Kamgang--Sallet approach for monotone systems with a Metzler infected subsystem. In the absence of vaccination, this criterion recovers the sharp threshold $\mathcal R_0\le 1$ for the global asymptotic stability of the disease-free equilibrium, where $\mathcal R_0$ denotes the basic reproduction number. Conversely, when $\mathcal R_c>1$, we establish uniform persistence of the infection and the existence of at least one endemic equilibrium using persistence theory for semiflows and an acyclicity analysis of the boundary dynamics. Overall, our results quantify the combined impact of vaccination and saturating fomite-mediated transmission on the global behaviour of the model.

Guiding collective motion in biological groups is a fundamental challenge in understanding social interaction rules and developing automated systems for animal management. In this study, we propose a deep reinforcement learning (RL) framework for the closed-loop guidance of fish schools using virtual agents. These agents are controlled by policies trained via Proximal Policy Optimization (PPO) in simulation and deployed in physical experiments with rummy-nose tetras (Petitella bleheri), enabling real-time interaction between artificial agents and live individuals. To cope with the stochastic behavior of live individuals, we design a composite reward function to balance directional guidance with social cohesion. Our systematic evaluation of visual parameters shows that a white background and larger stimulus sizes maximize guidance efficacy in physical trials. Furthermore, evaluation across group sizes revealed that while the system demonstrates effective guidance for groups of five individuals, this capability markedly degrades as group size increases to eight. This study highlights the potential of deep RL for automated guidance of biological collectives and identifies challenges in maintaining artificial influence in larger groups.

This report presents three proofs showing that idealized architectures capable of navigation guided by allocentric maps with landmark structure can be computationally universal. The navigation may occur either online (in the environment) or offline (in the animal's head). The first proof proceeds from a universal two-counter machine by encoding counters as the positions of two movable markers on orthogonal coordinate axes. The second proof directly simulates an ordinary one-tape Turing machine by using a writable tape-path embedded in the map. The third proof strengthens locality by replacing the globally designated path with a two-dimensional field of landmarks that carries only local predecessor/successor information. These constructions are mathematically close to classical graph-based models in computability theory, including Kolmogorov-Uspensky machines, storage-modification machines, graph Turing machines, and related navigation-on-graphs models. Accordingly, the bare universality results are mathematically unsurprising. Nevertheless, the present treatment is, as far as I know, the first self-contained reconstruction of such universality demonstrations in the idiom of allocentric cognitive maps and offline navigation, that is, within an architecture whose core representational and computational primitives are drawn from a body of empirical and theoretical work on spatial navigation. The report therefore reframes known computability-theoretic ideas to show that an allocentric navigation-based architecture can be computationally universal.

Cardiovascular-Kidney-Metabolic (CKM) syndrome represents a growing public health crisis, yet the subclinical heterogeneity of its component systems remains underexplored. Early detection of physiological deviation is critical for preventing irreversible organ damage and mortality. Here, we characterize the prevalence and interplay of CKM impairment in a US cohort (N=841) by integrating continuous wearable data with clinical biomarkers. We assessed cardiovascular, kidney via clinical biomarkers, namely Chol/HDL, eGFR, as well as metabolic health risk through Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We show that while metabolic and cardiovascular disruptions are significantly associated (r=0.26, p<0.001), early-stage kidney impairment manifests independently. Utilizing a normalized deviance score, we identified significant health impairments in 29.0% of the cohort. Cardiovascular deviation was the most prevalent singular phenotype (13.3%), followed by metabolic (9.1%) and renal (6.25%) deviations, with dual metabolic-cardiovascular impairment occurring in only 2.2% of participants. These findings suggest that high system-specific deviance may serve as an indicator for accelerated physiological aging within the respective organ system. Furthermore, feature ablation analysis revealed that step count, Active Zone Minutes, and resting heart rate are the most potent wearable-derived predictors of cardiovascular and metabolic decline. These findings underscore the necessity of a multi-system subtyping approach, demonstrating that wearable-derived phenotypes can facilitate the early, targeted interventions required to manage the complex landscape of CKM syndrome.

Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening.

Growth and decay are system-level properties of chemical reaction networks (CRNs) relevant from prebiotic chemistry to cellular metabolism. Their properties are typically analyzed through the kinetics of particular models, which requires specification of the full set of kinetic laws and parameters. In this work, we derive stoichiometry-based constraints on the growth (or shrinkage) rate, in the balanced-growth regime of scalable CRNs. The resulting bounds are controlled by a topological quantity, the maximum amplification factor, defined via a von Neumann max-min problem over feasible fluxes as illustrated by numerical tests on random-network ensembles of CRNs. We argue for the relevance of our results in the context of origin of life studies but also for designing synthetic chemical reaction networks.

We propose a multi-scale lung model to investigate spatio-temporal distributions of ventilation variables. Lung envelope and large airway geometries are derived from CT scans; smaller airways are generated using a physiologically consistent algorithm. Tissue mechanics is modeled using nonlinear elasticity under small deformations, coupled with local air pressure from fluid dynamics within the bronchial tree. Airflow accounts for inertia and static airway compliance. Simulations employ finite elements. Using this model, we explore spatio-temporal airflows and shear stresses distributions.

Mathematical models support inference and forecasting in ecology and epidemiology, but results depend on the estimation framework. We compare Bayesian and Frequentist approaches across three biological models using four datasets: Lotka-Volterra predator-prey dynamics (Hudson Bay), a generalized logistic model (lung injury and 2022 U.S. mpox), and an SEIUR epidemic model (COVID-19 in Spain). Both approaches use a normal error structure to ensure a fair comparison. We first assessed structural identifiability to determine which parameters can theoretically be recovered from the data. We then evaluated practical identifiability and forecasting performance using four metrics: mean absolute error (MAE), mean squared error (MSE), 95 percent prediction interval (PI) coverage, and weighted interval score (WIS). For the Lotka-Volterra model with both prey and predator data, we analyzed three scenarios: prey only, predator only, and both. The Frequentist workflow used QuantDiffForecast (QDF) in MATLAB, which fits ODE models via nonlinear least squares and quantifies uncertainty through parametric bootstrap. The Bayesian workflow used BayesianFitForecast (BFF), which employs Hamiltonian Monte Carlo sampling via Stan to generate posterior distributions and diagnostics such as the Gelman-Rubin R-hat statistic. Results show that Frequentist inference performs best when data are rich and fully observed, while Bayesian inference excels when latent-state uncertainty is high and data are sparse, as in the SEIUR COVID-19 model. Structural identifiability clarifies these patterns: full observability benefits both frameworks, while limited observability constrains parameter recovery. This comparison provides guidance for choosing inference frameworks based on data richness, observability, and uncertainty needs.

Cryo-electron microscopy (cryo-EM) enables the atomic-resolution visualization of biomolecules; however, modern direct detectors generate data volumes that far exceed the available storage and transfer bandwidth, thereby constraining practical throughput. We introduce cryoSENSE, the computational realization of a hardware-software co-designed framework for compressive cryo-EM sensing and acquisition. We show that cryo-EM images of proteins lie on low-dimensional manifolds that can be independently represented using sparse priors in predefined bases and generative priors captured by a denoising diffusion model. cryoSENSE leverages these low-dimensional manifolds to enable faithful image reconstruction from spatial and Fourier-domain undersampled measurements while preserving downstream structural resolution. In experiments, cryoSENSE increases acquisition throughput by up to 2.5$\times$ while retaining the original 3D resolution, offering controllable trade-offs between the number of masked measurements and the level of downsampling. Sparse priors favor faithful reconstruction from Fourier-domain measurements and moderate compression, whereas generative diffusion priors achieve accurate recovery from pixel-domain measurements and more severe undersampling. Project website: https://cryosense.github.io.

Medical image segmentation using deep learning (DL) has enabled the development of automated analysis pipelines for large-scale population studies. However, state-of-the-art DL methods are prone to hallucinations, which can result in anatomically implausible segmentations. With manual correction impractical at scale, automated quality control (QC) techniques have to address the challenge. While promising, existing QC methods are organ-specific, limiting their generalizability and usability beyond their original intended task. To overcome this limitation, we propose no-new Quality Control (nnQC), a robust QC framework based on a diffusion-generative paradigm that self-adapts to any input organ dataset. Central to nnQC is a novel Team of Experts (ToE) architecture, where two specialized experts independently encode 3D spatial awareness, represented by the relative spatial position of an axial slice, and anatomical information derived from visual features from the original image. A weighted conditional module dynamically combines the pair of independent embeddings, or opinions to condition the sampling mechanism within a diffusion process, enabling the generation of a spatially aware pseudo-ground truth for predicting QC scores. Within its framework, nnQC integrates fingerprint adaptation to ensure adaptability across organs, datasets, and imaging modalities. We evaluated nnQC on seven organs using twelve publicly available datasets. Our results demonstrate that nnQC consistently outperforms state-of-the-art methods across all experiments, including cases where segmentation masks are highly degraded or completely missing, confirming its versatility and effectiveness across different organs.

High failure rates in cardiac drug development necessitate virtual clinical trials via electrocardiogram (ECG) generation to reduce risks and costs. However, existing ECG generation models struggle to balance morphological realism with pathological flexibility, fail to disentangle demographics from genuine drug effects, and are severely bottlenecked by early-phase data scarcity. To overcome these hurdles, we propose the Multimodal Drug-Aware Diffusion Model (MM-DADM), the first generative framework for generating individualized drug-induced ECGs. Specifically, our proposed MM-DADM integrates a Dynamic Cross-Attention (DCA) module that adaptively fuses External Physical Knowledge (EPK) to preserve morphological realism while avoiding the suppression of complex pathological nuances. To resolve feature entanglement, a Causal Feature Encoder (CFE) actively filters out demographic noise to extract pure pharmacological representations. These representations subsequently guide a Causal-Disentangled ControlNet (CDC-Net), which leverages counterfactual data augmentation to explicitly learn intrinsic pharmacological mechanisms despite limited clinical data. Extensive experiments on $9,443$ ECGs across $8$ drug regimens demonstrate that MM-DADM outperforms $10$ state-of-the-art ECG generation models, improving simulation accuracy by at least $6.13\%$ and recall by $5.89\%$, while providing highly effective data augmentation for downstream classification tasks.

We report the emergence of Log-normal Superstatistics in the collective motion of ants confined in a quasi-2D arena and exposed to a panic-inducing stimulus. A data-driven superstatistical Langevin model accurately reproduces the transition from stationary behavior to an organized escape response, characterized by non-Gaussian velocity distributions and a stochastic diffusion coefficient. Our findings show that danger information propagates via a memory-limited, cascade-like mechanism, resulting in a stable cluster formation despite individual memory constraints. These results indicate that a slowly varying diffusivity arises from the multiplicative combination of interaction-mediated processes under confinement, leading naturally to Log-normal fluctuations. The persistence of this statistical structure under panic reveals a form of collective resilience, establishing a mechanistic bridge between Superstatistics and living active matter in confined environments.

Neuromorphic engineering has matured over the past four decades and is currently experiencing explosive growth with the potential to transform biomedical engineering and neurotechnologies. Participants at the Neuromorphic Principles in Biomedicine and Healthcare (NPBH) Workshop (October 2024) -- representing a broad cross-section of the community, including early-career and established scholars, engineers, scientists, clinicians, industry, and funders -- convened to discuss the state of the field, current and future challenges, and strategies for advancing neuromorphic research and development for biomedical applications. Publicly approved recordings with transcripts (https://2024.neuro-med.org/program/session-video-and-transcripts) and slides (https://2024.neuro-med.org/program/session-slides) can be found at the workshop website.

Understanding how the human brain instantiates distinct emotional states is a key challenge in affective neuroscience. While network-based approaches have advanced emotion processing research,they remain largely descriptive,leaving the dynamical stability of emotional brain states unquantified.This study introduces a novel framework to quantify this stability by applying Hopfield network energy to empirically derived functional connectivity. High density EEG was recorded from 20 healthy adults during a happy versus sad facial expression discrimination task. Functional connectivity was estimated using the weighted Phase Lag Index to obtain artifact-robust,frequency-specific matrices, which served as coupling weights in a continuous Hopfield energy model to calculate a scalar energy value per trial. Statistical comparisons showed sad emotional processing was associated with significantly lower(more negative) energy in delta,theta,and alpha bands,with the strongest effect in the alpha band (Cohen's d =0.83). Energy correlated strongly negatively with global efficiency(r=-0.72),indicating hyperconnected,efficient networks correspond to more stable states.Additionally, alpha-band energy correlated positively with reaction time during sad trials(r=0.61),linking deeper network stability to increased cognitive effort. These findings demonstrate emotional valence corresponds to distinct attractor basins in the brain's functional landscape, with sadness occupying a deeper,more stable configuration than happiness.The Hopfield energy metric provides a principled, quantifiable measure of emotional brain state stability, opening new avenues for understanding affective dynamics in health and disease.

When a cognitive system modifies its own functioning, what exactly does it modify: a low-level rule, a control rule, or the norm that evaluates its own revisions? Cognitive science describes executive control, metacognition, and hierarchical learning with precision, but lacks a formal framework distinguishing these targets of transformation. Contemporary artificial intelligence likewise exhibits self-modification without common criteria for comparison with biological cognition. We show that the question of what counts as a self-modifying system entails a minimal structure: a hierarchy of rules, a fixed core, and a distinction between effective rules, represented rules, and causally accessible rules. Four regimes are identified: (1) action without modification, (2) low-level modification, (3) structural modification, and (4) teleological revision. Each regime is anchored in a cognitive phenomenon and a corresponding artificial system. Applied to humans, the framework yields a central result: a crossing of opacities. Humans have self-representation and causal power concentrated at upper hierarchical levels, while operational levels remain largely opaque. Reflexive artificial systems display the inverse profile: rich representation and causal access at operational levels, but none at the highest evaluative level. This crossed asymmetry provides a structural signature for human-AI comparison. The framework also offers insight into artificial consciousness, with higher-order theories and Attention Schema Theory as special cases. We derive four testable predictions and identify four open problems: the independence of transformativity and autonomy, the viability of self-modification, the teleological lock, and identity under transformation.

Recent work on artificial consciousness shifts evaluation from behaviour to internal architecture, deriving indicators from theories of consciousness and updating credences accordingly. This is progress beyond naive Turing-style tests. But the indicator-based programme remains epistemically under-calibrated: consciousness science is theoretically fragmented, indicators lack independent validation, and no ground truth of artificial phenomenality exists. Under these conditions, probabilistic consciousness attribution to current AI systems is premature. A more defensible near-term strategy is to redirect effort toward biologically grounded engineering -- biohybrid, neuromorphic, and connectome-scale systems -- that reduces the gap with the only domain where consciousness is empirically anchored: living systems.

Quantitatively mapping three-dimensional (3D) flow, diffusion, and particle density in crowded living cells remains challenging because most dynamic optical microscopy measurements are effectively planar and existing analysis methods struggle with dense, noisy volumetric data. We introduce volumetric spatio-temporal image correlation spectroscopy (vSTICS), a framework that recovers voxel-resolved flow, diffusion coefficients, and particle densities from 3D fluorescence time series. Growing Camellia japonica pollen tubes were imaged with field-synthesis lattice light-sheet microscopy, and localized 3D spatio-temporal correlation analysis was applied to overlapping volumetric samples to generate maps of velocity, diffusion, and density. Validation with synthetic flow-diffusion simulations showed accurate recovery of seeded transport parameters, including velocities near $3$ $μ$m s$^{-1}$ and diffusion near $10^{-3}$ $μ$m$^2$ s$^{-1}$. Fluorescent microsphere experiments verified particle number and point spread function readouts and measured diffusion coefficients of $0.3 \pm 0.1$ $μ$m$^2$ s$^{-1}$ in gel, consistent with imaging-FCS measurements of $0.5 \pm 0.2$ $μ$m$^2$ s$^{-1}$. Applied to mitochondria in pollen tubes, vSTICS resolved a bidirectional reverse-fountain pattern with slower anterograde transport ($0.1$-$1$ $μ$m s$^{-1}$) and faster retrograde motion peaking near $3$ $μ$m s$^{-1}$, plus a retrograde corridor about $2$ $μ$m wide. Density and diffusion maps indicated a denser, more advective core and higher peripheral diffusion. High-density sub-diffraction vesicle mapping produced similar velocity landscapes with about ten-fold higher particle densities. These results establish vSTICS as a practical method for quantitative 3D mapping of intracellular transport and refines the reverse-fountain model by revealing asymmetric, predominantly transverse circulation.

People infer rich social information from others' actions. These inferences are often constrained by the physical world: what agents can do, what obstacles permit, and how the physical actions of agents causally change an environment and other agents' mental states and behavior. We propose that such rich social perception is more than visual pattern matching, but rather a reasoning process grounded in an integration of intuitive psychology with intuitive physics. To test this hypothesis, we introduced PHASE (PHysically grounded Abstract Social Events), a large dataset of procedurally generated animations, depicting physically simulated two-agent interactions on a 2D surface. Each animation follows the style of the Heider and Simmel movie, with systematic variation in environment geometry, object dynamics, agent capacities, goals, and relationships (friendly/adversarial/neutral). We then present a computational model, SIMPLE, a physics-grounded Bayesian inverse planning model that integrates planning, probabilistic planning, and physics simulation to infer agents' goals and relations from their trajectories. Our experimental results showed that SIMPLE achieved high accuracy and agreement with human judgments across diverse scenarios, while feedforward baseline models -- including strong vision-language models -- and physics-agnostic inverse planning failed to achieve human-level performance and did not align with human judgments. These results suggest that our model provides a computational account for how people understand physically grounded social scenes by inverting a generative model of physics and agents.

Quantitative estimation of information flow in early vision with psychophysically realistic networks is still an open issue. This is because, up to date, the necessary elements (general and plausible network, accurate noise, and reliable information measures) have not been put together. As a result, previous works made different approximations that limit the generality of their results. This work combines the following elements for the first time: (1) General and plausible recurrent net: a cascade of linear+nonlinear psychophysically tuned layers [IEEE TIP.06, J.Neurophysiol.19, J.Math.Neurosci.20, Neurocomp.24], augmented to consider top-down feedback following [Nat.Neurosci.21,Neurips.22]. (2) Accurate noise in every layer, which is tuned to reproduce psychometric functions both in contrast detection and discrimination following [J.Vision 25]. (3) Reliable information measures that have been checked with analytical results, both in general [IEEE PAMI 24], and in similar visual neuroscience contexts [Neurocomp.24], and hence can be applied in this (more general) case where analytical results are difficult to obtain. The joint use of these elements allows a reliable study of information flow depending on different connectivity schemes (different nonlinearities and interactions), different noise sources, and different stimuli. Results show the benefits of feedback in two ways: (1) the information loss in the data processing inequality along the pathway is reduced by the V1 -- > LGN recurrence for values of feedback that give stable steady state solutions, and (2) the stability of the net is assessed though standard Poincaré analysis and we find an optimal value for the feedback in terms of the accuracy of the reconstructed signal from the cortical representation.

Protein scientific discovery is bottlenecked by the manual orchestration of information and algorithms, while general agents are insufficient in complex domain projects. VenusFactory2 provides an autonomous framework that shifts from static tool usage to dynamic workflow synthesis via a self-evolving multi-agent infrastructure to address protein-related demands. It outperforms a set of well-known agents on the VenusAgentEval benchmark, and autonomously organizes the discovery and optimization of proteins from a single natural language prompt.

Although many phenotypic traits are determined by a large number of genetic variants, the behavior of allele frequencies in a polygenic trait is not completely understood. The problem is especially challenging when the quantitative trait of interest is under epistatic selection as the allele frequency at a locus is affected by those at other loci. Here, we consider a panmictic, diploid finite population evolving under stabilizing selection and symmetric mutations when the population is in linkage equilibrium. In the stationary state, using a diffusion theory, we calculate the marginal distribution of allele frequency, and find parameter regimes where fitness epistasis can not be ignored for an accurate description of the frequency distribution. For such parameters, the mean deviation in the phenotypic optimum and genic variance are, however, found to be well captured even when epistatic interactions are neglected. Thus, while the presence of epistasis may not be evident in phenotypic quantities, it can strongly affect the allele frequency distribution.We also find that the allele frequency distribution at a locus is unimodal if its effect size is below a threshold effect and bimodal otherwise; these results are the stochastic analog of the deterministic ones where the stable allele frequency becomes bistable when the effect size exceeds a threshold. Our analytical results are verified against Monte Carlo simulations and numerical integration of a Langevin equation.

Dissipative cognitive architectures maintain computation through continuous energy expenditure, where units that exhaust their energy are stochastically replaced with fresh random state. This creates a fundamental challenge: how can persistent, context-specific memory survive when all learnable state is periodically destroyed? Existing memory mechanisms -- including elastic weight consolidation, synaptic intelligence, and surprise-driven gating -- rely on gradient computation and are inapplicable to non-gradient dissipative systems. We introduce Deep Memory (DM), a non-gradient persistent memory mechanism operating through a triple-loop consolidation cycle: (1) recording of expert-specific content centroids, (2) seeding of replaced units with stored representations, and (3) stabilization through continuous re-entry. We demonstrate that discrete expert routing via Mixture-of-Experts (MoE) gating is a causal prerequisite for DM, preventing centroid convergence that would render stored memories identical. Across ${\sim}970$ simulation runs spanning thirteen experimental blocks: (i) discrete routing is causally necessary for specialization ($\text{MI}=1.10$ vs. $0.001$; $n=91$); (ii) DM achieves $R=0.984$ vs. $0.385$ without memory ($n=16$); (iii) continuous seeding reconstructs representations after interference ($R_\mathrm{recon}=0.978$; one-shot fails; $n=30$); (iv) the mechanism operates within a characterized $(K,p)$ envelope ($n=350$); (v) recording $\times$ seeding is the minimal critical dyad ($n=40$); (vi) DM outperforms non-gradient baselines (Hopfield, ESN) under matched turnover ($n=370$). These results establish DM as a falsifiable mechanism for persistent memory in non-gradient cognitive systems, with functional parallels to hippocampal consolidation.

As immunotherapies become standard cancer treatments, it is increasingly important to identify a patient's immune profile, which encompasses the activity of immune cells within the tumor microenvironment and the presence of specific biomarkers. However, we lack mechanistic explanations drivers of immune phenotypes. Despite advances in immune profiling with high-throughput sequencing, the mechanisms driving them remain unclear. This study aimed to identify novel, robust immune-related gene clusters (metagenes) and evaluate their prognostic significance and functional relevance across various pan-cancer types using a comprehensive computational pipeline. We acquired pan-cancer bulk RNA-seq and established immune subtypes from The Cancer Genome Atlas (TCGA). Using expression-based filtering and clustering of genes with ANOVA and Gaussian Mixture Model (GMM), we identified 48 unique metagenes. These metagenes achieved 87% accuracy in predicting the established subtypes. SHAP analysis revealed the most predictive metagenes per subtype, while functional enrichment analysis identified their associated pathways. Genes were ranked by differential expression between high- and low-expression groups. The metagenes revealed insights, including co-expression of immune activation and regulatory factors, links between cell cycle regulation and immune evasion, and dynamic microenvironment remodeling signatures. Kaplan-Meier survival analysis and multivariate Cox Regression revealed that many metagenes had prognostic value for overall survival. Overall, the metagenes represent coordinated biological programs across diverse cancer types, providing a foundation for developing robust, broadly applicable immuno-oncology biomarkers that extend beyond single-gene markers. They demonstrate prognostic value across cancer types and hold potential to guide immunotherapy treatment decisions.

Background: Medical Digital Twins (MDTs) are computational representations of individual patients that integrate clinical, genomic, and physiological data to support diagnosis, treatment planning, and outcome prediction. However, most MDTs remain static or passively updated, creating a critical synchronization gap, especially in rare genetic disorders where phenotypes, genomic interpretations, and care guidelines evolve over time. Methods: We propose an agent-orchestrated digital twin framework using OpenClaw's proactive "heartbeat" mechanism and modular Agent Skills. This Autonomous Agent-orchestrated Digital Twin (AADT) system continuously monitors local and external data streams (e.g., patient-reported phenotypes and updates in variant classification databases) and executes automated workflows for data ingestion, normalization, state updates, and trigger-based analysis. Results: A prototype implementation demonstrates that agent orchestration can continuously synchronize MDT states with both longitudinal phenotype updates and evolving genomic knowledge. In rare disease settings, this enables earlier diagnosis and more accurate modeling of disease progression. We present two case studies, including variant reinterpretation and longitudinal phenotype tracking, highlighting how AADTs support timely, auditable updates for both research and clinical care. Conclusion: The AADT framework addresses the key bottleneck of real-time synchronization in MDTs, enabling scalable and continuously updated patient models. We also discuss data security considerations and mitigation strategies through human-in-the-loop system design.

T cells are a critical component of the adaptive immune system, playing a role in infectious disease, autoimmunity, and cancer. T cell function is mediated by the T cell receptor (TCR) protein, a highly diverse receptor targeting specific peptides presented by the major histocompatibility complex (pMHCs). Predicting the specificity of TCRs for their cognate pMHCs is central to understanding adaptive immunity and enabling personalized therapies. However, accurate prediction of this protein-protein interaction remains challenging due to the extreme diversity of both TCRs and pMHCs. Here, we present ImmSET (Immune Synapse Encoding Transformer), a novel sequence-based architecture designed to model interactions among sets of variable-length biological sequences. We train this model across a range of dataset sizes and compositions and study the resulting models' generalization to pMHC targets. We describe a failure mode in prior sequence-based approaches that inflates previously reported performance on this task and show that ImmSET remains robust under stricter evaluation. In systematically testing the scaling behavior of ImmSET with training data, we show that performance scales consistently with data volume across multiple data types and compares favorably with the pre-trained protein language model ESM2 fine-tuned on the same datasets. Finally, we demonstrate that ImmSET can outperform AlphaFold2 and AlphaFold3-based pipelines on TCR-pMHC specificity prediction when provided sufficient training data. This work establishes ImmSET as a scalable modeling paradigm for multi-sequence interaction problems, demonstrated in the TCR-pMHC setting but generalizable to other biological domains where high-throughput sequence-driven reasoning complements structure prediction and experimental mapping.

Cooperating first then mimicking the partner's act has been proven to be effective in utilizing reciprocity in social dilemmas. However, the extent to which this, called Tit-for-Tat strategy, should be regarded as equivalent to unconditional cooperators remains controversial. Here, we introduce a biased Tit-for-Tat (T) strategy that cooperates differently toward unconditional cooperators (C) and fellow T players through independent bias parameters. The results show that, even under strong dilemmas in the donation game framework, this three-strategy system can exhibit diverse phase diagrams on the parameter plane. In particular, when T-bias is small and C-bias is large, a ``hidden T phase'' emerges, in which the weakest T strategy dominates. The dominance of the weakened T strategy originates from a counterintuitive mechanism characterizing non-transitive ecological systems: T suppresses its relative fitness to C, rapidly eliminates the cyclic dominance clusters, and subsequently expands slowly to take over the entire population. Analysis in well-mixed populations confirms that this phenomenon arises from structured populations. Our study thus reveals the subtle role of bias regulation in cooperative modes by emphasizing the ``survival of the weakest'' effect in a broader context.

The branching geometry of biological transport networks is characterized by a diameter scaling exponent $α$. Two structural attractors compete: impedance matching ($α\sim 2$) for pulsatile flow and viscous-metabolic minimization ($α= 3$) for steady flow. Neither predicts the empirically observed $α_{\mathrm{exp}} = 2.70 \pm 0.20$ in mammalian arterial trees. Incorporating sub-linear vessel-wall scaling $h(r) \propto r^p$ ($p = 0.77$) into a three-term metabolic cost rigorously breaks Murray's cubic law -- via Cauchy's functional equation -- bounding the static optimum to $α_t \in [2.90, 2.94]$. We formulate a unified network-level Lagrangian balancing wave-reflection penalties against transport-metabolic costs. Because the operational duty cycle $η$ is uncertain over developmental timescales, we cast the optimization as a zero-sum game between network architecture and environment. Von Neumann's minimax theorem -- proved via strict monotonicity of the cost curves -- yields a unique saddle point $(α^, η^)$ satisfying an exact equal-cost condition. We further prove $N = 2$ uniquely maximizes the network stiffness ratio $κ_{\mathrm{eff}}(N)$, deriving binary branching as a structural consequence of the framework. For the porcine coronary tree ($G = 11$ generations), $α^* = 2.72$, within $0.1σ$ of morphometric data. Sensitivity analysis confirms $|Δα^*| < 0.01$ across physiological metabolic ranges; the prediction depends critically only on the histological exponent $p$ -- a zero-parameter derivation from fundamental scaling principles that simultaneously recovers a cumulative wave dissipation of 6.3%, consistent with independent clinical estimates.