The brain interprets visual information through learned regularities, a computation formalized as probabilistic inference under a prior. The visual cortex establishes priors for this inference, some delivered through established top-down connections that inform low-level cortices about statistics represented at higher levels in the cortical hierarchy. While evidence shows that adaptation leads to priors reflecting the structure of natural images, it remains unclear whether similar priors can be flexibly acquired when learning a specific task. To investigate this, we built a generative model of V1 optimized for a simple discrimination task and analyzed it together with large-scale recordings from mice performing an analogous task. In line with recent approaches, we assumed that neuronal activity in V1 corresponds to latent posteriors in the generative model, enabling investigation of task-related priors in neuronal responses. To obtain a flexible test bed, we extended the VAE formalism so that a task can be acquired efficiently by reusing previously learned representations. Task-specific priors learned by this Task-Amortized VAE were used to investigate biases in mice and model when presenting stimuli that violated trained task statistics. Mismatch between learned task statistics and incoming sensory evidence produced signatures of uncertainty in stimulus category in the TAVAE posterior, reflecting properties of bimodal response profiles in V1 recordings. The task-optimized generative model accounted for key characteristics of V1 population activity, including within-day updates to population responses. Our results confirm that flexible task-specific contextual priors can be learned on demand by the visual system and deployed as early as the entry level of visual cortex.

How do social animals make effective decisions in the absence of a leader? While coordination can improve accuracy, it also introduces delays as information propagates through the group. In changing environments, these delays can outweigh the benefits of globally coordinated decisions, even when local interactions remain tightly organized. This raises a key question: how can groups implement efficient collective decision-making without central coordination? We address this question using a collective foraging model in which individuals share information and rewards, but each must choose whether to bear the cost of exploring or to remain idle. We show that decentralized collectives can match the performance of centrally controlled groups through a division of labor: a small, heterogeneous subset explores even when expected rewards are negative, acquiring information to enable future foraging, while a coordinated majority forages only when expected rewards are positive. Information redundancy causes the optimal number of explorers to grow sublinearly with group size, so that larger groups need proportionally fewer explorers. The heterogeneity of the group is maximized at intermediate ecological pressures, but optimal groups are homogeneous when costs or fluctuations are extreme. Crucially, these group-level policies do not require central coordination, emerging instead from agents following simple threshold-based decision rules. We thus demonstrate a mechanism through which leaderless collectives can make effective decisions under uncertainty and show how ecological pressures can drive changes in the distribution of strategies employed by the group.

This study investigates how listeners perceive consonance and dissonance in dyads composed of simple (sine) tones, focusing on the effects of frequency ratio ($R$) and mean frequency ($F$). Seventy adult participants - categorized by musical training, gender, and age group - rated randomly ordered dyads using binary preference responses (``like'' or ``dislike''). Dyads represented standard Western intervals but were constructed with sine tones rather than musical notes, preserving interval ratios while varying absolute pitch. Statistical analyses reveal a consistent decrease in preference with increasing mean frequency, regardless of interval class or participant group. Octaves, fifths, fourths, and sixths showed a nearly linear decline in preference with increasing $F$. Major seconds were among the least preferred. Musicians rated octaves and certain consonant intervals more positively than non-musicians, while gender and age groups exhibited different sensitivity to high frequencies. The findings suggest that both interval structure and pitch range shape the perception of consonance in simple-tone dyads, with possible psychoacoustic explanations involving frequency sensitivity and auditory fatigue at higher frequencies.

Foundation models are transforming neuroscience but are often prohibitively large, data-hungry, and difficult to deploy. Here, we introduce BrainSymphony, a lightweight and parameter-efficient foundation model with plug-and-play integration of fMRI time series and diffusion-derived structural connectivity, allowing unimodal or multimodal training and deployment without architectural changes while requiring substantially less data compared to the state-of-the-art. The model processes fMRI time series through parallel spatial and temporal transformer streams, distilled into compact embeddings by a Perceiver module, while a novel signed graph transformer encodes anatomical connectivity from diffusion MRI. These complementary representations are then combined through an adaptive fusion mechanism. Despite its compact design, BrainSymphony consistently outperforms larger models on benchmarks spanning prediction, classification, and unsupervised network discovery. Highlighting the model's generalizability and interpretability, attention maps reveal drug-induced context-dependent reorganization of cortical hierarchies in an independent psilocybin neuroimaging dataset. BrainSymphony delivers accessible, interpretable, and clinically meaningful results and demonstrates that architecturally informed, multimodal models can surpass much larger counterparts and advance applications of AI in neuroscience.

Function diversity, the range of tasks individuals perform, and specialization, the distribution of function abundances, are fundamental to complex adaptive systems. In the absence of overarching principles, these properties have appeared domain-specific. Here, we introduce an empirical framework and a mathematical model for the diversification and specialization of functions across disparate systems, including bacteria, federal agencies, universities, corporations, and cities. We find that the number of functions grows sublinearly with system size, with exponents from 0.35 to 0.57, consistent with Heaps' Law. In contrast, cities exhibit logarithmic scaling. To explain these empirical findings, we generalize the Yule-Simon model by introducing two key parameters: a diversification parameter that characterizes how existing functions inhibit the creation of new ones, and a specialization parameter that describes how a function's attractiveness depends on its abundance. Our model enables cross-system comparisons, from microorganisms to metropolitan areas. The analysis suggests that what drives the creation of new functions depends on the system's goals and structure: federal agencies tend to ensure comprehensive coverage of necessary functions; cities tend to slow the creation of new occupations as existing ones expand; and cells occupy an intermediate position. Once functions are introduced, their growth follows a remarkably universal pattern across all systems.

Biological neural networks (BNNs) are increasingly explored for their rich dynamics, parallelism, and adaptive behavior. Beyond understanding their function as a scientific endeavour, a key focus has been using these biological systems as a novel computing substrate. However, BNNs can only function as reliable information-processing systems if inputs are delivered in a temporally and structurally consistent manner. In practice, this requires stimulation with precisely controlled structure, microsecond-scale timing, multi-channel synchronization, and the ability to observe and respond to neural activity in real-time. Existing approaches to interacting with BNNs face a fundamental trade-off: they either depend on low-level hardware mechanisms, imposing prohibitive complexity for rapid iteration, or they sacrifice temporal and structural control, undermining consistency and reproducibility - particularly in closed-loop experiments. The Cortical Labs Application Programming Interface (CL API) enables real-time, sub-millisecond closed-loop interactions with BNNs. Taking a contract-based API design approach, the CL API provides users with precise stimulation semantics, transactional admission, deterministic ordering, and explicit synchronization guarantees. This contract is presented through a declarative Python interface, enabling non-expert programmers to express complex stimulation and closed-loop behavior without managing low-level scheduling or hardware details. Ultimately, the CL API provides an accessible and reproducible foundation for real-time experimentation with BNNs, supporting both fundamental biological research and emerging neurocomputing applications.

We present scPilot, the first systematic framework to practice omics-native reasoning: a large language model (LLM) converses in natural language while directly inspecting single-cell RNA-seq data and on-demand bioinformatics tools. scPilot converts core single-cell analyses, i.e., cell-type annotation, developmental-trajectory reconstruction, and transcription-factor targeting, into step-by-step reasoning problems that the model must solve, justify, and, when needed, revise with new evidence. To measure progress, we release scBench, a suite of 9 expertly curated datasets and graders that faithfully evaluate the omics-native reasoning capability of scPilot w.r.t various LLMs. Experiments with o1 show that iterative omics-native reasoning lifts average accuracy by 11% for cell-type annotation and Gemini-2.5-Pro cuts trajectory graph-edit distance by 30% versus one-shot prompting, while generating transparent reasoning traces explain marker gene ambiguity and regulatory logic. By grounding LLMs in raw omics data, scPilot enables auditable, interpretable, and diagnostically informative single-cell analyses. Code, data, and package are available at https://github.com/maitrix-org/scPilot

We present a collaboration ring model -- a network of players playing the prisoner's dilemma game and collaborating among the nearest neighbours by forming coalitions. The microscopic stochastic updating of the players' strategies are driven by their innate nature of seeking selfish gains and shared intentionality. Cooperation emerges in such a structured population through non-equilibrium phase transitions driven by propensity of the players to collaborate and by the benefit that a cooperator generates. The robust results are qualitatively independent of number of neighbours and collaborators.

Reaction-diffusion equations describe various spatially extended processes that unfold as traveling fronts moving at constant velocity. We introduce and solve analytically a model that, besides such fronts, supports solutions advancing as the square root of time. These sublinear fronts preserve an invariant shape, with an effective diffusion constant that diverges at the transition to linear spreading. The model applies to dense cellular aggregates of nonmotile cells consuming a diffusible nutrient. The sublinear spread results from biomass redistribution slowing due to nutrient depletion, a phenomenon supported experimentally but often neglected. Our results provide a potential explanation for the linear rather than quadratic increase of colony area with time, which has been observed for many microbes.

Homologous proteins have similar three-dimensional structures and biological functions that shape their sequences. The resulting coevolution-driven correlations underlie methods from Potts models to AlphaFold, which infer protein structure and function from sequences. Using a minimal model, we show that fluctuating selection strength and the onset of new selection pressures improve coevolution-based inference of structural contacts. Our conclusions extend to realistic synthetic data and to the inference of interaction partners. Out-of-equilibrium noise arising from ubiquitous variations in natural selection thus enhances, rather than hinders, the success of inference from protein sequences.

Epidemic and pandemic preparedness with rapid outbreak response rely on timely, trustworthy evidence. Mathematical models are crucial for supporting timely and reliable evidence generation for public health decision-making with models spanning approaches from compartmental and metapopulation models to detailed agent-based simulations. Yet, the accompanying software ecosystem remains fragmented across model types, spatial resolutions, and computational targets, making models harder to compare, extend, and deploy at scale. Here we present MEmilio, a modular, high-performance framework for epidemic simulation that harmonizes the specification and execution of diverse dynamic epidemiological models within a unified and harmonized architecture. MEmilio couples an efficient C++ simulation core with coherent model descriptions and a user-friendly Python interface, enabling workflows that run on laptops as well as high-performance computing systems. Standardized representations of space, demography, and mobility support straightforward adaptations in resolution and population size, facilitating systematic inter-model comparisons and ensemble studies. The framework integrates readily with established tools for uncertainty quantification and parameter inference, supporting a broad range of applications from scenario exploration to calibration. Finally, strict software-engineering practices, including extensive unit and continuous integration testing, promote robustness and minimize the risk of errors as the framework evolves. By unifying implementations across modeling paradigms, MEmilio aims to lower barriers to reuse and generalize models, enable principled comparisons of implicit assumptions, and accelerate the development of novel approaches that strengthen modeling-based outbreak preparedness.

On exposure to 1,2-propanediol (1,2-PD), Salmonella enterica serovar Typhimurium LT2 produces 1,2-PD utilization (Pdu) microcompartments (MCPs), nanoscale protein-bound shells that encapsulate metabolic enzymes. MCPs serve as a bioengineering platform to study reaction organization and enhance flux through specific pathways. However, a recently published assay of purified wild-type (WT) MCPs reported metabolic activity that differed markedly from that observed in vivo. Using kinetic modeling, we attribute these discrepancies to in vivo cell growth and to the cytosolic presence of MCP-associated enzymes and promiscuous alcohol dehydrogenases, which are not present in the purified MCPs. Assays of purified MCPs in E. coli lysate, together with an LT2 growth assay in which the native Pdu MCP-associated alcohol dehydrogenase, PduQ, was knocked out, support the conclusion that exogenous Pdu cytosolic enzyme activity can narrow the gap between in vitro and in vivo experiments. Our modeling further suggests that MCP-localized enzymes contribute little to in vivo metabolic flux downstream of PduCDE. We therefore propose a revised in vivo model of WT growth on 1,2-PD in which PduCDE is fully encapsulated, while much of the downstream Pdu activity occurs in the cytosol.

Accurate prognosis for Glioblastoma (GBM) using deep learning (DL) is hindered by extreme spatial and structural heterogeneity. Moreover, inconsistent MRI acquisition protocols across institutions hinder generalizability of models. Conventional transformer and DL pipelines often fail to capture the multi-scale morphological diversity such as fragmented necrotic cores, infiltrating margins, and disjoint enhancing components leading to scanner-specific artifacts and poor cross-site prognosis. We propose TopoGBM, a learning framework designed to capture heterogeneity-preserved, scanner-robust representations from multi-parametric 3D MRI. Central to our approach is a 3D convolutional autoencoder regularized by a topological regularization that preserves the complex, non-Euclidean invariants of the tumor's manifold within a compressed latent space. By enforcing these topological priors, TopoGBM explicitly models the high-variance structural signatures characteristic of aggressive GBM. Evaluated across heterogeneous cohorts (UPENN, UCSF, RHUH) and external validation on TCGA, TopoGBM achieves better performance (C-index 0.67 test, 0.58 validation), outperforming baselines that degrade under domain shift. Mechanistic interpretability analysis reveals that reconstruction residuals are highly localized to pathologically heterogeneous zones, with tumor-restricted and healthy tissue error significantly low (Test: 0.03, Validation: 0.09). Furthermore, occlusion-based attribution localizes approximately 50% of the prognostic signal to the tumor and the diverse peritumoral microenvironment advocating clinical reliability of the unsupervised learning method. Our findings demonstrate that incorporating topological priors enables the learning of morphology-faithful embeddings that capture tumor heterogeneity while maintaining cross-institutional robustness.

Spiking Neural Networks (SNNs) offer energy-efficient, biologically plausible computation but suffer from non-differentiable spike generation, necessitating reliance on heuristic surrogate gradients. This paper introduces UltraLIF, a principled framework that replaces surrogate gradients with ultradiscretization, a mathematical formalism from tropical geometry providing continuous relaxations of discrete dynamics. The central insight is that the max-plus semiring underlying ultradiscretization naturally models neural threshold dynamics: the log-sum-exp function serves as a differentiable soft-maximum that converges to hard thresholding as a learnable temperature parameter $\eps \to 0$. Two neuron models are derived from distinct dynamical systems: UltraLIF from the LIF ordinary differential equation (temporal dynamics) and UltraDLIF from the diffusion equation modeling gap junction coupling across neuronal populations (spatial dynamics). Both yield fully differentiable SNNs trainable via standard backpropagation with no forward-backward mismatch. Theoretical analysis establishes pointwise convergence to classical LIF dynamics with quantitative error bounds and bounded non-vanishing gradients. Experiments on six benchmarks spanning static images, neuromorphic vision, and audio demonstrate improvements over surrogate gradient baselines, with gains most pronounced in single-timestep ($T{=}1$) settings on neuromorphic and temporal datasets. An optional sparsity penalty enables significant energy reduction while maintaining competitive accuracy.

Fluid-structure interaction (FSI) simulation of biological systems presents significant computational challenges, particularly for applications involving large structural deformations and contact mechanics, such as heart valve dynamics. Traditional ALE methods encounter fundamental difficulties with such problems due to mesh distortion, motivating immersed techniques. This work presents a novel open-source immersed FSI framework that strategically couples two mature finite element libraries: MFEM, a GPU-ready and scalable library with state-of-the-art parallel performance developed at LLNL, and FEBio, a nonlinear finite element solver with sophisticated solid mechanics capabilities designed for biomechanics applications developed at the University of Utah and Columbia University. This coupling creates a unique synergy wherein the fluid solver leverages MFEM's distributed-memory parallelization and pathway to GPU acceleration, while the immersed solid exploits FEBio's comprehensive suite of hyperelastic and viscoelastic constitutive models and advanced solid mechanics modeling targeted for biomechanics applications. FSI coupling is achieved using a fictitious domain methodology with variational multiscale stabilization for enhanced accuracy on under-resolved grids expected with unfitted meshes used in immersed FSI. A fully implicit, monolithic scheme provides robust coupling for strongly coupled FSI characteristic of cardiovascular applications. The framework's modular architecture facilitates straightforward extension to additional physics and element technologies. Several test problems are considered to demonstrate the capabilities of the proposed framework, including a 3D semilunar heart valve simulation. This platform addresses a critical need for open-source immersed FSI software combining advanced biomechanics modeling with high-performance computing infrastructure.

Synthetic molecular communication (MC) in the cardiovascular system is a key enabler for many envisioned medical applications inside the human body, such as targeted drug delivery, early disease detection, and continuous health monitoring. The design of synthetic MC systems for such applications requires suitable models for the signaling molecule propagation through complex vessel networks (VNs). Existing theoretical models offer limited analytical tractability and lack closed-form solutions, making the analysis of realistic large-scale VNs either infeasible or not insightful. To overcome these limitations, in this paper, we propose a novel closed-form physical model, termed mixture of inverse Gaussians for hemodynamic transport (MIGHT), for the advection-diffusion-driven transport of signaling molecules through complex VNs. The model represents the received molecule flux as a weighted sum of inverse Gaussian distributions, parameterized by the physical properties of the underlying VN. We show that MIGHT is capable of accurately representing the transport dynamics of signaling molecules in large-scale VNs ranging from simple single-input single-output (SISO) to complex multiple-input multiple-output (MIMO) network topologies. The accuracy of the proposed model is validated by comparison to the results from an existing convolution-based model and numerical finite-element simulations, with all finite-element simulation data available on Zenodo. Furthermore, we investigate three applications of the model, namely the reduction of SISO-VNs to obtain simplified representations preserving the essential transport dynamics, the identification and analysis of network regions that are most important for molecule transport in MIMO-VNs comprising multiple transmitters and multiple receivers, and the estimation of representative SISO-VNs that can reproduce the received signal of an unknown SISO-VN.

Chemical language models (CLMs) are increasingly used for molecular design and property prediction. Because these models learn from textual encodings of molecules, differences in how such encodings are generated may affect their behavior. In cheminformatics, the term canonical SMILES implies a single standardized notation, yet different toolkits define distinct canonicalization rules, yielding multiple canonical strings for the same molecule. To examine how this variability arises and why it matters, we surveyed 264 CLM papers in PubMed and found that about half did not specify their canonicalization procedure, limiting transparency and reproducibility. Using a molecular translation framework, we show that when multiple valid notations are mixed or left undocumented, inconsistent notations distort latent representations and, in some benchmarks, can spuriously inflate predictive accuracy, a phenomenon we term notation-level confounding. These findings demonstrate how subtle differences in SMILES generation can mislead CLMs and highlight the importance of explicitly reporting preprocessing tools and settings.

We develop a neurogeometric model for the arm area of motor cortex, which encodes complex motor primitives, ranging from simple movement features like movement direction, to short hand trajectories, termed fragments, and ultimately to more complex patterns known as neural states (Georgopoulos, Hatsopoulos, Kadmon-Harpaz et al). Based on the sub-riemannian framework introduced in 2023, we model the space of fragments as a set of short curves defined by kinematic parameters. We then introduce a geometric kernel that serves as a model for cortical connectivity and use it in a differential equation to describe cortical activity. By applying a grouping algorithm to this cortical activity model, we successfully recover the neural states observed in Kadmon-Harpaz et al, which were based on measured cortical activity. This confirms that the choice of kinematic variables and the distance metric used here are sufficient to explain the phenomena of neural state formation. The modularity of our model reflects the brain's hierarchical structure, where initial groupings in the kinematic space $\mathcal{M}$ lead to more abstract representations. This approach mimics how the brain processes stimuli at different scales, extracting both local and global properties.

Spoken language is often, if not always, understood in a context formed by the identity of the speaker. For example, we can easily make sense of an utterance such as "I'm going to have a manicure this weekend" or "The first time I got pregnant I had a hard time" when spoken by a woman, but it would be harder to understand when it is spoken by a man. Previous ERP studies have shown mixed results regarding the neurophysiological responses to such speaker-content mismatches, with some reporting an N400 effect and others a P600 effect. In an EEG experiment involving 64 participants, we used social and biological mismatches as test cases to demonstrate how these distinct ERP patterns reflect different aspects of rational inference. We showed that when the mismatch involves social stereotypes (e.g., men getting a manicure), listeners can arrive at a "literal" interpretation by integrating the content with their social knowledge, though this integration requires additional effort due to stereotype violations-resulting in an N400 effect. In contrast, when the mismatch involves biological knowledge (e.g., men getting pregnant), a "literal" interpretation becomes highly implausible or impossible, leading listeners to treat the input as potentially containing errors and engage in correction processes-resulting in a P600 effect. Supporting this rational inference framework, we found that the social N400 effect decreased as a function of the listener's personality trait of openness (as more open-minded individuals maintain more flexible social expectations), while the biological P600 effect remained robust (as biological constraints are recognized regardless of individual personalities). Our findings help to reconcile empirical inconsistencies and reveal how rational inference shapes speaker-contextualized language comprehension.