All cells must sustain ionic motive forces (IMFs) -- the electrochemical gradients of permeant ions, together with the membrane potential they produce -- to regulate intracellular pH, drive secondary transport, and power ATP synthesis. Because membranes are imperfectly impermeable, IMFs continuously dissipate through passive leakage, and active transport must compensate at an energetic cost that competes with growth and biosynthesis. How environmental conditions set this cost, and why cells across the tree of life share a common ionic logic yet deploy strikingly diverse transporter repertoires, has lacked a unifying quantitative account. Here we derive a thermodynamic lower bound on the power required to maintain IMFs at steady state. The bound equals the rate of free-energy dissipation by ion leakage, holds across a broad family of electrophysiological models, and is independent of organism, energy source, or transporter architecture. Cost minimization recovers, from first principles, the universal K+-rich, Na+-poor cytoplasm observed across taxa: asymmetric membrane permeabilities alone are sufficient to explain it. The same framework predicts that extremophiles face higher maintenance costs under extreme pH, salinity, and temperature, and that when sustaining a large proton motive force becomes prohibitive, cells should shift to metabolic regimes compatible with smaller PMF, providing a thermodynamic rationale for stress-induced metabolic reconfiguration. Finally, we show that perfect energetic efficiency is unattainable in practice, and that this very imperfection, combined with environmental variability, selects for the diversity of transport architectures observed in nature: each architecture is optimal within a discrete regime of environmental constraints.

Cell-cell adhesion is widely hypothesised to maintain cohesion within the long streams of follower cells that trail leader subpopulations during collective migration, including in neural crest cell migration, angiogenesis, and cancer cell invasion. Mathematically, non-local advection-diffusion equations provide the canonical continuum framework within which to study such adhesive cell-cell interactions. Here, we study a minimal model of leader-follower migration within this framework, in which leaders migrate at constant velocity while followers are attracted to leaders and to one another over a finite spatial interaction range. Numerical simulations reveal that, although the model can maintain small cohorts of travelling follower cells, the size of these cohorts is limited by the adhesive interaction lengthscale, and is far below what is needed to reproduce the extended streams observed in vivo. This points to a structural limitation of the standard non-local adhesion formulation and highlights the need for the development of extended continuum models capable of sustaining long, coherent migratory streams through purely mass-conserving collective cell movement.

We introduce `Goxpyriment', a new open-source software framework for programming behavioral and cognitive experiments using the Go programming language. The library is designed to address some limitations of existing Python-based experiment tools, particularly the runtime environment complexity that frequently complicates deployment across laboratories. Because Go is a compiled language that can natively embed assets (e.g., graphics, audio files, and stimulus lists), Goxpyriment compiles entire experiments into single, self-contained executable binaries with zero runtime dependencies. This drastically simplifies distribution to collaborators and testing computers. The programming interface, inspired by Expyriment (Krause & Lindemann, 2014), was designed to be human friendly. The library includes an array of visual stimuli (text, shapes, images, Gabor patches, motion clouds, ...) and audio capabilities (WAV playback and tone generation). While developing Goxpyriment, we focused on timing reliability. Input events are timestamped by the operating system at hardware-interrupt time, so reaction times are computed by subtracting two OS-level timestamps rather than relying on continuous polling. Go's garbage collector can be disabled, greatly reducing the probability of unpredictable pauses that could corrupt stimulus timing. Finally, a set of over forty psychology experiments implemented in Goxpyriment are provided that promote not only learning by humans but also improve the ability of modern AI-assisted coding tools to help program experiments. The framework is released under the GNU General Public License v3 and is freely available at https://github.com/chrplr/goxpyriment.

Large language models can be aligned with human preferences through offline reinforcement learning (RL) on small labeled datasets. While single-objective alignment is well-studied, many real-world applications demand the simultaneous optimization of multiple conflicting rewards, e.g. optimizing both catalytic activity and specificity in protein engineering, or helpfulness and harmlessness for chatbots. Prior work has largely relied on linear reward scalarization, but this approach provably fails to recover non-convex regions of the Pareto front. In this paper, instead of scalarizing the rewards directly, we frame multi-objective RL itself as an optimization problem to be scalarized via smooth Tchebysheff scalarization, a recent technique that overcomes the shortcomings of linear scalarization. We use this formulation to derive Smooth Tchebysheff Optimization of Multi-Objective Preferences (STOMP), a novel offline RL algorithm that extends direct preference optimization to the multi-objective setting in a principled way by standardizing the individual rewards based on their observed distributions. We empirically validate STOMP on a range of protein engineering tasks by aligning three autoregressive protein language models on three laboratory datasets of protein fitness. Compared to state-of-the-art baselines, STOMP achieves the highest hypervolumes in eight of nine settings according to both offline off-policy and generative evaluations. We thus demonstrate that STOMP is a powerful, robust multi-objective alignment algorithm that can meaningfully improve post-trained models for multi-attribute protein optimization and beyond.

Scientists have long been fascinated by magnetoreception, the innate capacity of many animals to sense and use the Earth's magnetic field for navigation. In eusocial insects like honey bees, magnetoreception has been linked to communication and foraging. However, little is known about magnetoreception's phylogenetic patterns and relationship to species traits and natural history. Here, we demonstrate that putative magnetoreception based on ferromagnetic particles is widespread across a diversity of bee species (72 out of 96 species tested), with no phylogenetic signal. We also detected such putative magnetoreception in non-bee outgroups, suggesting this magnetic capacity predates the evolution of the Anthophila. While magnetic signals were found across a diversity of life history traits, the strength of the magnetic signal varied within and between species, and increased with body size and social behavior.

Designing RNA molecules that interact with specific proteins is a critical challenge in experimental and computational biology. Existing computational approaches require a substantial amount of previously known interacting RNA sequences for each specific protein or a detailed knowledge of RNA structure, restricting their utility in practice. To address this limitation, we develop RNA-BAnG, a deep learning-based model designed to generate RNA sequences for protein interactions without these requirements. Central to our approach is a novel generative method, Bidirectional Anchored Generation (BAnG), which leverages the observation that protein-binding RNA sequences often contain functional binding motifs embedded within broader sequence contexts. We first validate our method on generic synthetic tasks involving similar localized motifs to those appearing in RNAs, demonstrating its benefits over existing generative approaches. We then evaluate our model on biological sequences, showing its effectiveness for conditional RNA sequence design given a binding protein.

Many complex systems, ranging from migrating cells to animal groups, exhibit stochastic dynamics described by the underdamped Langevin equation. Inferring such an equation of motion from experimental data can provide profound insight into the physical laws governing the system. Here, we derive a principled framework to infer the dynamics of underdamped stochastic systems from realistic experimental trajectories, sampled at discrete times and subject to measurement errors. This framework yields an operational method, Underdamped Langevin Inference (ULI), which performs well on experimental trajectories of single migrating cells and in complex high-dimensional systems, including flocks with Viscek-like alignment interactions. Our method is robust to experimental measurement errors, and includes a self-consistent estimate of the inference error.

Proteins carry out biological functions through the coordinated action of groups of residues organized into structural arrangements. These arrangements, which we refer to as protein units, exist at an intermediate scale, being larger than individual residues yet smaller than entire proteins. A deeper understanding of protein function can be achieved by identifying these units and their associations with function. However, existing approaches either focus on residue-level signals, rely on curated annotations, or segment protein structures without incorporating functional information, thereby limiting interpretable analysis of structure-function relationships. We introduce PUFFIN, a data-driven framework for discovering protein units by jointly learning structural partitioning and functional supervision. PUFFIN represents proteins as residue-level structure graphs and applies a graph neural network with a structure-aware pooling mechanism that partitions each protein into multi-residue units, with functional supervision that shapes the partition. We show that the learned units are structurally coherent, exhibit organized associations with molecular function, and show meaningful correspondence with curated InterPro annotations. Together, these results demonstrate that PUFFIN provides an interpretable framework for analyzing structure-function relationships using learned protein units and their statistical function associations. We made our source code available at https://github.com/boun-tabi-lifelu/puffin.

Encoding models enable measurement of how our brains represent sensory inputs using electro-and magneto-encephalography (MEEG). Evaluating how closely encoding models reflect the underlying brain functions is a crucial premise for model interpretation and hypothesis testing. However, the ground-truth neural activity is unknown, preventing model evaluation with respect to the target neural signal. Existing evaluation metrics must therefore relate model's predictions to noisy MEEG measurements, where most variance is stimulus-unrelated. Here, I introduce an evaluation framework where model predictions are compared to a ground-truth approximation, obtained by aligning MEEG signals with predictions using canonical correlation analysis and via participant averaging. The resulting metric (CPA-PA) yields single-participant evaluations outperforming conventional scores by 300-1000% on synthetic EEG data and 250% on 34 real MEEG datasets (818 datapoints). These gains reflect increased sensitivity to stimulus-relevant neural activity and reduced dependence on SNR, establishing ground-truth approximation as a robust framework for evaluating encoding models.

The spread of infectious disease is strongly influenced by social dynamics. In addition to infection risk, individuals vaccination decisions depend on prevailing social behavior: high infection levels and widespread vaccination can increase vaccine uptake, which in turn suppresses infection. This feedback can generate sustained oscillations in disease prevalence and vaccination behavior. Here, we study two such populations undergoing the same behavioral epidemiological limit cycle and introduce weak coupling between them through social influence. We show that coupling leads to synchronization of disease dynamics between the two groups. Moreover, we find that different payoff sensitivity may lead to synchronization or anti synchronization.

Targeted amplicon panels are widely used in oncology diagnostics, but providing per-gene performance guarantees for copy number variant (CNV) detection remains challenging due to amplification artifacts, process-mismatch heterogeneity, and limited validation sample sizes. While Bayesian CNV callers naturally quantify per-sample uncertainty, translating this into the frequentist population-level guarantees required for clinical validation, coverage rates, false-positive bounds, and minimum detectable copy-number changes, is a fundamentally different inferential problem. We show empirically that even robust Bayesian credible intervals, including coarsened posteriors and sandwich-adjusted intervals, are severely miscalibrated on panels with small amplicon counts per gene. To address this, we propose a hybrid framework that evaluates Bayesian posterior functionals on validation samples and models the resulting squared losses with a Gamma distribution, yielding tolerance intervals with valid frequentist coverage. Three components make the method practical under real-world constraints: (1) imputation that removes the influence of true CNV-positive samples without requiring known ground truth, (2) regularization to address small sample variability, and (3) evidence-based stratification on the log model evidence to accommodate non-exchangeable noise profiles arising from process mismatch. Evaluated on two targeted amplicon panels using leave-one-out cross-validation, the proposed method achieves single-digit mean absolute coverage error across all genes under both process-matched and unmatched conditions, whereas Bayesian comparators exhibit mean absolute errors exceeding 60\% on clinically relevant genes such as ERBB2.

Accurate detection and segmentation of glomeruli in kidney tissue are essential for diagnostic applications. Traditional deep learning methods primarily rely on semantic segmentation, which often fails to precisely delineate adjacent glomeruli. To address this challenge, we propose a novel glomerulus detection and segmentation model that emphasises boundary separation. Leveraging pathology foundation models, the proposed U-Net-based architecture incorporates a specialised attention decoder designed to highlight critical regions and improve instancelevel segmentation. Experimental evaluations demonstrate that our approach surpasses state-of-the-art methods in both Dice score and Intersection over Union, indicating superior performance in glomerular delineation.

Functional magnetic resonance imaging (fMRI) is widely used for studying and diagnosing brain disorders, with functional connectivity (FC) matrices providing powerful representations of large-scale neural interactions. However, existing diagnostic models are trained either on a single site or under full multi-site access, making them unsuitable for real-world scenarios where clinical data arrive sequentially from different institutions. This results in limited generalization and severe catastrophic forgetting. This paper presents the first continual learning framework specifically designed for fMRI-based diagnosis across heterogeneous clinical sites. Our framework introduces a structure-aware variational autoencoder that synthesizes realistic FC matrices for both patient and control groups. Built on this generative backbone, we develop a multi-level knowledge distillation strategy that aligns predictions and graph representations between new-site data and replayed samples. To further enhance efficiency, we incorporate a hierarchical contextual bandit scheme for adaptive replay sampling. Experiments on multi-site datasets for major depressive disorder (MDD), schizophrenia (SZ), and autism spectrum disorder (ASD) show that the proposed generative model enhances data augmentation quality, and the overall continual learning framework substantially outperforms existing methods in mitigating catastrophic forgetting. Our code is available at https://github.com/4me808/FORGE.

The classic paradigm of structural biology is that the sequence of a biomolecule (protein, nucleic acid, lipid, etc) determines its conformation (shape) which determines its biological function. Protein folding programs like AlphaFold address this paradigm by predicting the single best conformation given a sequence that defines the molecule. However, biomolecules are not static structures, and their conformational ensemble determines their function. We present the Polyformer -- a generative framework for thermodynamic modeling of polymeric molecules. Given the sequence and temperature (or another thermodynamic variable), the Polyformer generates conformations faithful to the molecule's thermodynamic conformational ensemble. It is the first generative model that solves three problems simultaneously: how does a molecule fold, what is its conformational ensemble, and how does the conformational ensemble change as we change physical temperature. As a concrete test case, we apply Polyformer to protein domains with 50-111 residues and report good agreement of model predictions to Molecular Dynamics (MD) trajectories.

Electroencephalography (EEG) has become one of the key modalities underpinning brain-computer interfaces (BCIs) due to its high temporal resolution, rapid responsiveness, non-invasiveness, low cost, and portability. However, EEG signals are substantially inferior to intracranial EEG (iEEG) in signal-to-noise ratio and local spatial resolution, whereas iEEG suffers from extremely limited clinical accessibility owing to its invasive nature, hindering widespread application. To address this challenge, this study proposes a unified data-and prior knowledge-driven framework for EEG-iEEG representational enhancement. Guided by the principle that "geometric structure dictates function", the framework maps static cortical anatomy onto dynamic constraints governing neural signal propagation and integrates general-purpose neural representations extracted by a pre-trained large EEG model to explicitly model signal transmission through the brain. Enhanced EEG signals are then synthesized via a multidimensional representation diffusion process. Numerous experimental results demonstrate that the generated enhanced EEG signals effectively recover the neural activity patterns lost during propagation through the brain. This finding indicates that the performance ceiling of BCIs is constrained not only by acquisition hardware but also by the depth to which the generative model resolves the mechanisms of neural signal propagation. Collectively, the proposed framework provides a viable pathway toward acquiring high-fidelity neural signals at low cost.

Deep Neural Networks (DNNs) are vulnerable to elaborately designed adversarial noise, although they have achieved extraordinary success in many tasks. Compared with DNNs, the human visual system is highly robust. However, it is unclear how the human visual system defends against adversarial attacks, especially the role of the early visual system and its influence on the brain manifold. Due to retina gap junctions being crucial for the denoising function in the early visual system, we combine a retina gap junction-based filter, G-filter, with DNN as an abstract human visual system model called the biological hybrid model. We adopt this model to study the defense performance of retina gap junctions and their impact on the brain manifold. Compared with other defense methods, the biological hybrid model is more robust and can be further improved by introducing noise during training. Next, we analyze the manifold and its decision boundary of the biological hybrid model from a geometry perspective. The results show that the biological hybrid model has a unique 2D decision boundary with high nonlinearity and a lower curvature of the decision boundary of the manifold compared to other defense methods. The transforming manifold may account for the high robustness of the biological hybrid model. Finally, to dissect G-filter and clarify its internal mechanism, we borrow the Neural Ordinary Differential Equation (ODE) concept and rewrite G-filter into an equivalent recurrent neural network. The results show that the decision boundary of the model's manifold will gradually change with time and eventually reach a steady state, which is modulated by gap junction conductance, revealing the influence of retina gap junctions on the brain manifold is a gradually evolving process.

Large Language Model (LLM) agents have demonstrated remarkable capabilities in reasoning and tool use, yet they often suffer from rigid, reactive control flows that limit their adaptability and efficiency. Most existing frameworks rely on fixed pipelines or failure-triggered reflection, causing agents to act impulsively or correct errors only after they occur. In this paper, we introduce Heartbeat-Driven Autonomous Thinking Activity Scheduling, a mechanism that enables proactive, adaptive, and continuous self-regulation. Mirroring the natural rhythm of human cognition, our system employs a periodic ``heartbeat'' mechanism to orchestrate a dynamic repertoire of cognitive modules (e.g., Planner, Critic, Recaller, Dreamer). Unlike traditional approaches that rely on hard-coded symbolic rules or immediate reactive triggers, our scheduler learns to determine when to engage specific thinking activities -- such as recalling memories, summarizing experiences, or strategic planning -- based on temporal patterns and historical context. This functional approach allows cognitive modules to be dynamically added or removed without structural reengineering. Meanwhile, we propose a meta-learning strategy for continual policy adaptation, where the scheduler optimizes its cognitive strategy over time using historical interaction logs. Evaluation results demonstrate that our approach effectively learns to schedule cognitive activities based on historical data and can autonomously integrate new thinking modules.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; yet substantial proportion of patients exhibit intrinsic or acquired resistance, making accurate pre-treatment response prediction a critical unmet need. Transcriptomics-based biomarkers derived from bulk and single-cell RNA sequencing (scRNA-seq) offer a promising avenue for capturing tumour-immune interactions, yet the cross-cohort generalisability of existing prediction models remains unclear.We systematically benchmark nine state-of-the-art transcriptomic ICI response predictors, five bulk RNA-seq-based models (COMPASS, IRNet, NetBio, IKCScore, and TNBC-ICI) and four scRNA-seq-based models (PRECISE, DeepGeneX, Tres and scCURE), using publicly available independent datasets unseen during model development. Overall, predictive performance was modest: bulk RNA-seq models performed at or near chance level across most cohorts, while scRNA-seq models showed only marginal improvements. Pathway-level analyses revealed sparse and inconsistent biomarker signals across models. Although scRNA-seq-based predictors converged on immune-related programs such as allograft rejection, bulk RNA-seq-based models exhibited little reproducible overlap. PRECISE and NetBio identified the most coherent immune-related themes, whereas IRNet predominantly captured metabolic pathways weakly aligned with ICI biology. Together, these findings demonstrate the limited cross-cohort robustness and biological consistency of current transcriptomic ICI prediction models, underscoring the need for improved domain adaptation, standardised preprocessing, and biologically grounded model design.

Objectives: To externally validate targeted T2 fluid-attenuated inversion recovery (T2-FLAIR) dropout for robust automated glioblastoma segmentation and whole-tumor volumetry without T2-FLAIR, while preserving performance when the full MRI protocol is available. Methods: In this retrospective multi-dataset study, 3D nnU-Net models were developed on BraTS 2021 (n=848) and externally validated on an independent University of Pennsylvania glioblastoma cohort (n=403). Models were trained with or without targeted T2-FLAIR dropout, zeroing the T2-FLAIR channel during training. Testing used prespecified T2-FLAIR-present and T2-FLAIR-absent scenarios; the absent scenario was simulated by zeroing the T2-FLAIR channel at inference. The primary endpoint was per-patient overall region-wise Dice similarity coefficient (DSC). Secondary endpoints were region-specific DSC, 95th percentile Hausdorff distance, and Bland-Altman whole-tumor volume bias. Results: In external validation, performance was preserved with the full MRI protocol: overall median DSC was 94.8% (interquartile range [IQR] 90.0%-97.1%) with dropout and 95.0% (IQR 90.3%-97.1%) without dropout. In the T2-FLAIR-absent scenario, targeted dropout improved overall median DSC from 81.0% (IQR 75.1%-86.4%) to 93.4% (IQR 89.1%-96.2%). Whole-tumor DSC improved from 60.4% to 92.6%, whole-tumor 95th percentile Hausdorff distance from 17.24 mm to 2.45 mm, and whole-tumor volume bias from -45.6 mL to 0.83 mL. Conclusions: In an independent external test cohort, targeted T2-FLAIR dropout preserved glioblastoma segmentation performance with the full MRI protocol and substantially reduced whole-tumor segmentation error and volumetric bias when T2-FLAIR was absent. These findings support targeted sequence dropout as a practical robustness strategy for automated glioblastoma analysis in retrospective and heterogeneous clinical workflows.

Phylogenetic trees and networks are graphs used to model evolutionary relationships, with trees representing strictly branching histories and networks allowing for events in which lineages merge, called reticulation events. While the question of data sufficiency has been studied extensively in the context of trees, it remains largely unexplored for networks. In this work we take a first step in this direction by establishing bounds on the amount of genomic data required to reconstruct binary level-$1$ semi-directed phylogenetic networks, which are binary networks in which reticulation events are indicated by directed edges, all other edges are undirected, and cycles are vertex-disjoint. For this class, methods have been developed recently that are statistically consistent. Roughly speaking, such methods are guaranteed to reconstruct the correct network assuming infinitely long genomic sequences. Here we consider the question whether networks from this class can be uniquely and correctly reconstructed from finite sequences. Specifically, we present an inference algorithm that takes as input genetic sequence data, and demonstrate that the sequence length sufficient to reconstruct the correct network with high probability, under the CFN model of evolution, scales logarithmically, polynomially, or polylogarithmically with the number of taxa, depending on the parameter regime. As part of our contribution, we also present novel inference rules for quartet data in the semi-directed phylogenetic network setting.

Current work on forecasting emergency department (ED) admissions focuses on disease aggregates or singular disease types. However, given differences in the dynamics of individual diseases, it is unlikely that any single forecasting model would accurately account for each disease and for all time, leading to significant forecast model uncertainty. Yet, forecasting models for ED admissions to-date do not explore the utility of forecast combinations to improve forecast accuracy and stability. It is also unknown whether improvements in forecast accuracy can be yield from (1) incorporating a large number of environmental and anthropogenic covariates or (2) forecasting total ED causes by aggregating cause-specific ED forecasts. To address this gap, we propose high-dimensional forecast combination schemes to combine a large number of forecasting individual models for forecasting cause-specific ED admissions over multiple causes and forecast horizons. We use time series data of ED admissions with an extensive set of explanatory lagged variables at the national level, including meteorological/ambient air pollutant variables and ED admissions of all 16 causes studied. We show that the simple forecast combinations yield forecast accuracies of around 3.81%-23.54% across causes. Furthermore, forecast combinations outperform individual forecasting models, in more than 50% of scenarios (across all ED admission categories and horizons) in a statistically significant manner. Inclusion of high-dimensional covariates and aggregating cause-specific forecasts to provide all-cause ED forecasts provided modest improvements in forecast accuracy. Forecasting cause-specific ED admissions can provide fine-scale forward guidance on resource optimization and pandemic preparedness and forecast combinations can be used to hedge against model uncertainty when forecasting across a wide range of admission categories.

The brain is not only constrained by energy needed to fuel computation, but it is also constrained by energy needed to form memories. Experiments have shown that learning simple conditioning tasks already carries a significant metabolic cost. Yet, learning a task like MNIST to 95% accuracy appears to require at least 10^{8} synaptic updates. Therefore the brain has likely evolved to be able to learn using as little energy as possible. We explored the energy required for learning in feedforward neural networks. Based on a parsimonious energy model, we propose two plasticity restricting algorithms that save energy: 1) only modify synapses with large updates, and 2) restrict plasticity to subsets of synapses that form a path through the network. Combining these two methods leads to substantial energy savings while only incurring a small increase in learning time. In biology networks are often much larger than the task requires. In particular in that case, large savings can be achieved. Thus competitively restricting plasticity helps to save metabolic energy associated to synaptic plasticity. The results might lead to a better understanding of biological plasticity and a better match between artificial and biological learning. Moreover, the algorithms might also benefit hardware because in electronics memory storage is energetically costly as well.

Most functional magnetic resonance imaging studies rely on estimates of hierarchically organized functional brain networks whose segregation and integration reflect the cognitive and behavioral changes in humans. However, most existing methods for estimating the community structure of networks from both individual and group-level analysis methods do not account for the variability between subjects. In this paper, we develop a new multilayer community detection method based on Bayesian latent block model (LBM). The method can robustly detect the community structure of weighted functional networks with an unknown number of communities at both individual and group levels and retain the variability of the individual networks. For validation, we propose a new community structure-based multivariate Gaussian generative model to simulate synthetic signal. Our simulation study shows that the community memberships estimated by hierarchical Bayesian inference are consistent with the predefined node labels in the generative model. The method is also tested via split-half reproducibility using working memory task fMRI data of 100 unrelated healthy subjects from the Human Connectome Project. Analyses using both synthetic and real data show that our proposed method is more accurate and reliable compared with the commonly used (multilayer) modularity models.