Artificial vision models are often evaluated against the human visual cortex by measuring how accurately their internal representations predict brain responses. However, prediction accuracy alone does not indicate which dimensions of the target brain's response space are recovered. Here, we introduce a unified framework for evaluating both model-brain and brain-brain alignment by identifying the response dimensions recovered by prediction. Using repeated fMRI measurements, we first identify target-brain response dimensions that can be reproducibly predicted across independent trial splits. We then predict target-brain responses from either another subject's brain responses or a vision model's internal representations, and quantify how strongly each of these reproducible response dimensions is recovered. Applying this framework to a subset of the Natural Scenes Dataset, in which eight subjects viewed the same natural images during fMRI, we find that the early-to-intermediate visual-cortex responses contain a low-dimensional set of reproducible dimensions. Brain-to-brain comparisons identify which of these dimensions are consistently recoverable from other subjects' brains, providing a diagnostic human reference rather than only a scalar benchmark. In some cases, pretrained and randomly initialized models achieve similar prediction accuracy while showing distinct recovery profiles across these response dimensions. These results show that prediction accuracy alone can mask model-brain mismatches. By making explicit which reproducible brain response dimensions are recovered by prediction, our framework provides a more diagnostic evaluation of alignment between artificial vision models and the human visual cortex.

Background: Face morphometry has been shown to work as a diagnosis tool in a set of syndromes. Face similarities are usually indications of more complete genetic similarities. Purpose: To show preliminary results on the face morphometry profile of the Cuban population and to argue that it could be used to define early markers for diseases, like Alzheimer. Methods: A dataset composed of photos of 200000 men is processed. Facial landmarks are extracted by means of the DLIB library and distances between them are computed. By clustering samples with similar facial traits, groups are formed and their densities inside the population are computed. Results: The face morphometry profiles for two age cohorts are obtained, showing the population dynamics. Genes involved in facial development are shown to be related to Alzheimer's disease. Conclusions: Late multifactorial diseases develop against the genetic background of each individual, which is expressed by its face morphometry. The latter can be thus considered a risk marker.

Phylogenetic networks generalize phylogenetic trees by allowing reticulate evolutionary events such as horizontal gene transfer and hybridization. Among the many subclasses of phylogenetic networks, orchard networks have attracted increasing attention due to their structural and algorithmic properties. In this paper, we study the arc-deletion distance to orchard networks, defined as the minimum number of reticulate arcs whose deletion transforms a phylogenetic network into an orchard network. We prove that computing this distance is NP-hard via a polynomial-time reduction from the Degree-3 Vertex Cover problem. Our result establishes the computational intractability of this proximity measure and contributes to the complexity theory of phylogenetic network transformations.

Predicting protein-ligand binding affinity remains intractable for multi-domain proteins, where inter-domain dynamics govern molecular recognition. Existing geometric deep learning methods typically treat proteins as monolithic static graphs, suffering from rigid-body assumptions and aleatoric noise in flexible regions. To address this, we introduced HCLBind, a self-supervised framework that decouples geometric representation learning from affinity regression. HCLBind leverages a general-to-specific pre-training paradigm on the Q-BioLiP database to learn a robust physical grammar of binding. We propose a novel hierarchical decoy strategy: the model learns local physicochemical constraints through protein coordinate perturbation in single-domain proteins and global conformational geometry through inter-domain rotation in multi-domain complexes. Our hybrid architecture integrates a domain-gated graph attention network and cross-modal attention to explicitly prioritize domain interfaces. Furthermore, we employ LoRA on protein and ligand foundation models, ensuring efficient optimization while preserving evolutionary knowledge. Experiments on PDBBind demonstrate that HCLBind effectively learns discriminative interface features and provides robust uncertainty estimation, overcoming the limitations of standard supervised learning. The code is available at https://github.com/jiankliu/HCLBind.

Purpose: To investigate psychophysically the ability of low vision individuals with central visual field loss (CFL) to perform a visually-guided pointing task in a virtual reality environment. Methods: Patients with CFL (n=25, ages = 67-90 years) and normally-sighted controls (n=26, ages = 67-85 years) had to select a target (2{\textdegree} diameter dot) with a head-contingent cursor (6{\textdegree} diameter reticle). Target selection occurred when target was validly pointed at for 1.5 seconds. Pointing was valid when target was inside an invisible pointer activation zone (PAZ) centered on reticle. Task difficulty was decreased by increasing PAZ diameter from 0.5{\textdegree} to 8{\textdegree}. Performance was assessed by measuring the time needed to select the target. The task was also performed with an array of three simultaneously-displayed cursors. Results: Selection times decreased (from 14.1 and 8.4 seconds for patients and controls respectively) with increasing PAZ diameter and reached a similar asymptote for both groups (1.4 seconds). The rate of this decrease was smaller for patients so that PAZ diameter needed for their best performance was much larger than PAZ diameter needed for controls' best performance (average: 3.48{\textdegree} vs 1.32{\textdegree}). In the three-reticle condition, both groups tended to use the cursor closer to the target. Conclusions: Patients with CFL are able to point at a 2{\textdegree} target thanks to head-pointing. Their performance can get close to controls' best performance by increasing PAZ size. Translational relevance: This research suggests guidelines to improve the accessibility of visually-guided pointing tools for human-machine interfaces designed for low vision individuals.

Embryology has long played a foundational role in shaping our scientific understanding of animal evolution. In recent decades, growing evidence has also highlighted its role in cancer. Despite the indisputable similarities between embryonic development and cancer, there has been limited discussion on the profound embryological implications for the disease. This article explores the understanding of cancer as an embryological and evolutionary phenomenon, offering a fresh perspective on the disease and discussing immediate consequences in the search for therapeutic approaches

Short-term synaptic plasticity (STP) is often regarded as a presynaptic filter of spikes, independent of postsynaptic activity. Recent experiments, however, indicate an associative STP that depends on pre- and postsynaptic coactivation. We develop a normative, information-theoretic theory of associative STP. Extending Fisher-information-based learning to Tsodyks-Markram synapses, we derive learning rules for baseline weight and release probability that maximize stimulus information under resource constraints. The rules split into a postsynaptic term tracking local firing and a presynaptic, phase-advanced term that selectively detects stimulus onset. For slowly varying inputs, this onset sensitivity favors anti-causal connectivity and enhances response offset during drive and reverse replay after drive removal in recurrent circuits. Linear-response analysis shows that STP yields frequency-dependent phase selectivity and that release-probability constraints tune temporal asymmetry. These results identify release-probability plasticity as a principled substrate for rapidly reconfigurable temporal coding.

This paper introduces a nonstandard finite difference (NSFD) approach to a reaction-diffusion SEIQR epidemiological model, which captures the spatiotemporal dynamics of infectious disease transmission. Formulated as a system of semilinear parabolic partial differential equations (PDEs), the model extends classical compartmental models by incorporating spatial diffusion to account for population movement and spatial heterogeneity. The proposed NSFD discretization is designed to preserve the continuous model's essential qualitative features, such as positivity, boundedness, and stability, which are often compromised by standard finite difference methods. We rigorously analyze the model's well-posedness, construct a structure-preserving NSFD scheme for the PDE system, and study its convergence and local truncation error. Numerical simulations validate the theoretical findings and demonstrate the scheme's effectiveness in preserving biologically consistent dynamics.

Explainability is necessary for many tasks in biomedical research. Recent explainability methods have focused on attention, gradient, and Shapley value. These do not handle data with strong associated prior knowledge and fail to constrain explainability results based on known relationships between predictive features. We propose GraphPINE, a graph neural network (GNN) architecture leveraging domain-specific prior knowledge to initialize node importance optimized during training for drug response prediction. Typically, a manual post-prediction step examines literature (i.e., prior knowledge) to understand returned predictive features. While node importance can be obtained for gradient and attention after prediction, node importance from these methods lacks complementary prior knowledge; GraphPINE seeks to overcome this limitation. GraphPINE differs from other GNN gating methods by utilizing an LSTM-like sequential format. We introduce an importance propagation layer that unifies 1) updates for feature matrix and node importance and 2) uses GNN-based graph propagation of feature values. This initialization and updating mechanism allows for informed feature learning and improved graph representation. We apply GraphPINE to cancer drug response prediction using drug screening and gene data collected for over 5,000 gene nodes included in a gene-gene graph with a drug-target interaction (DTI) graph for initial importance. The gene-gene graph and DTIs were obtained from curated sources and weighted by article count discussing relationships between drugs and genes. GraphPINE achieves a PR-AUC of 0.894 and ROC-AUC of 0.796 across 952 drugs. Code is available at https://anonymous.4open.science/r/GraphPINE-40DE.

Cryomicroneedles offer a route to minimally invasive intradermal delivery of living cells, but their cryogenic formulations must reconcile cell protection with constraints on toxicity and device fabrication. Here we report an AI-assisted, closed-loop workflow for cryomicroneedle cryoprotectant discovery that combines literature curation, Gaussian-process surrogate modelling, Bayesian optimization, and sequential wet-lab validation. A curated dataset of 198 mesenchymal stem-cell cryopreservation formulations from 42 studies was converted into 21 ingredient features and used to train an uncertainty-aware literature prior. This model captured moderate structure in the literature data but failed prospectively, motivating iterative wet-lab correction. Across ten validation iterations and 106 wet-lab observations, the model progressively adapted to cryomicroneedle-specific outcomes: batch RMSE decreased from 41.21 to 6.86 percentage points, later-stage rank correlations became consistently positive, and the cumulative wet-lab predicted-versus-measured summary reached $R^2 = 0.942$. The best validated formulation achieved 95.15\% post-thaw viability with low DMSO, ectoin, ethylene glycol, and fetal bovine serum. However, high viability alone did not ensure intact cryomicroneedle formation, highlighting the need for future multi-objective optimization. These results demonstrate that agent-assisted computational infrastructure can make data-efficient formulation discovery more accessible to labs with minimal data expertise in-house. Project code is available at https://github.com/baitmeister/ML-for-CryoMN.

Advancements in clinical Brain-Computer Interfaces (BCIs) depend on precise and reliable signal interpretation. However, the high-dimensional and noisy nature of data captured from both implanted and non-implanted BCIs poses significant challenges, motivating the use of feature selection algorithms. We introduce BCI-sift (BCI Systematic and Interpretable Feature Tuning), a Python-based toolbox designed to streamline the application of diverse optimization algorithms to BCI datasets for identifying the most relevant features in machine learning tasks. Our scikit-learn-compatible toolbox (github.com/UMCU-RIBS/BCI-sift) simplifies feature selection in BCI tasks by integrating advanced optimization methods. We validated the toolbox on high-density electrocorticography (HD ECoG) data from eight able-bodied participants with 64-128 electrodes implanted over the sensorimotor cortex, who repeatedly spoke 12 words. BCI-sift identified informative neural features across electrode, temporal, and frequency dimensions. The anatomical locations of electrode selections were consistent across participants and aligned with known functional organization of the sensorimotor cortex. Relevant time points clustered around speech production, and the high-frequency band was identified as most informative, in line with prior work. Feature selection improved classification accuracy compared to using all features. BCI-sift provides an accessible and versatile platform for feature selection in BCI research, enabling improved decoding performance, automated feature analysis, and enhanced interpretability. While validated on HD ECoG data, the approach is broadly applicable to other BCI modalities. By enhancing classification accuracy and interpretability, BCI-sift addresses key challenges in developing efficient and transparent BCI systems.

Understanding how humans and artificial intelligence systems predict and plan by interacting with their environment is a fundamental challenge at the intersection of neuroscience and machine learning. Most brain-encoding studies focus on aligning artificial models with brain activity during language comprehension or passive visual processing, while interactive brain-alignment studies have to date been largely limited to reinforcement-learning (RL) agents and theory-based models. To address this gap, we study brain alignment of representative models from two foundation-model families, namely vision-language models (VLMs) and large-action models (LAMs), using fMRI recordings from participants playing naturalistic Atari-style video games. Specifically, we examine how action-focused and reasoning-focused prompts shape model's internal representations and align with fMRI brain activity. First, we find that both VLMs and LAMs exhibit significantly exhibit voxel-wise encoding performance than RL baselines, with the advantage holding even under matched feature dimensionality. Second, prompt-driven gains scale with the cortical processing hierarchy: the largest improvements appear in frontal-parietal and motor-planning regions, while early visual cortex gains roughly half as much. Third, variance partitioning reveals a qualitatively different representational organization: VLM is prompt-symmetric (12.5% unique action vs. 13.6% unique reasoning), whereas LAM is prompt-asymmetric (27% unique action vs. -5% unique reasoning), with the asymmetry strongest in frontal-motor cortex. Together, these results demonstrate that action-specialized fine-tuning reorganizes multimodal representations toward action-relevant neural computations even when whole-brain prediction accuracy is statistically equivalent between VLM and LAM.

Proteins are constructed from a limited alphabet of ~20 amino acids, yet the origins and selection of this specific alphabet are unresolved. One largely overlooked aspect is whether elemental composition constrains the range of viable proteomes. Here, we analyze the elemental composition of thousands of proteomes spanning cellular domains and viral realms. Despite evolutionary divergence and orders-of-magnitude variation in proteome size and gene content, proteomes exhibit strikingly consistent elemental composition. This consistency is substantially more constrained than amino acid frequencies or physicochemical properties and is not explained by evolutionary relatedness, biological function, or amino acid usage alone. Viral proteomes occupy the same elemental composition space observed in cellular organisms despite the absence of a single viral common ancestor, suggesting common biochemical constraints shape proteome organization across life. To investigate the evolutionary origins of this pattern, we compare modern proteomes with multiple independent reconstructions of the Last Universal Common Ancestor (LUCA) and with synthetic reduced-alphabet proteomes generated from primordial amino acid alphabets. LUCA proteomes occupy the same constrained elemental composition space observed in modern Bacteria and Archaea, whereas reduced primordial-like alphabets systematically generated alternative elemental regimes outside the modern range despite retaining high sequence similarity to extant proteins. Reduced alphabets disrupt fold space and reorganize relationships between elemental composition and predicted protein structural organization. Our results suggest that constrained elemental composition represents a fundamental organizational property of proteomes, which emerged early in evolution and may have contributed to the selection and stabilization of the modern amino acid alphabet.

The vast chemical space of possible small molecules, estimated at 10^60 compounds for molecules composed of just C, N, O, and S, is only sparsely occupied by biology. We propose that where life selects molecules within this space constitutes a detectable ecological signature: a fingerprint not of specific compounds, but of the statistical structure of elemental composition across molecules sam-pled from ecological systems. Here we introduce a framework combining Van Krevelen diagrams and element scaling laws to characterize the elemental composition of regions of chemical space occupied by biological systems and contrast them with other chemical systems. Applying this framework to 11,834 microbial metagenomic samples, we show that microbial metabolisms occupy a region of chemical space, which is enriched in heteroatoms such as P, S, N, and O relative to C, shifted toward higher O:C and H:C ratios. We observe sublinear element scaling with system size, yielding insights into how elemental constraints dictate how biological systems occupy chemical space. These patterns are distinct from a sample of 18,000 compounds from the comprehensive Reaxys synthetic chemical database. Critically, datasets from molecules detected in planetary science mission data occupy statistically distinct regions from both terrestrial biological and Reaxys distributions, demonstrating that with standardized methods for data collection, the approach could be developed to discriminate biotic from abiotic chemical signatures in small molecule data from planetary science missions. Our work shows how a combination of Van Krevelen fingerprinting and elemental scaling laws can provide a new class of ecological biosignatures for life detection leveraging mass spectrometric data from planetary missions, which could generalize beyond Earth's specific biochemistry.

While coding regions in the genome have a direct interpretation in terms of protein products, significant fractions are non-coding and yet control essential biological functions. Unlike the genetic code, there is no "lookup table" that identifies where regulatory proteins, known as transcription factors (TFs), bind. Here, we extract these binding sites by distilling sequences of nucleotide letters into collective coordinates (hyperletters) representing the binding sites that are active under specific environmental conditions. Going beyond local information footprints between individual bases and expression levels, our $\textit{information blueprint}$ algorithm compresses the global information by optimising filters that simultaneously scan an entire promoter sequence. Inspired by renormalisation-group techniques, we identify TF binding sites as coarse-grained variables combining groups of correlated mutations with the highest collective impact on gene expression. We validate our approach on experimental data for $\textit{E. coli}$ and discover novel regulatory elements illustrating its deployment at scale across growth conditions.

Generating stable molecular conformations typically forces a tradeoff between the physical realism of energy-based relaxation and the sampling efficiency of data-driven generative models. While machine learning force fields (MLFFs) can sample stable conformations by relaxing molecular geometries according to physical forces, they require costly ab-initio training data. Conversely, diffusion models (DMs) learn from equilibrium data alone but are dependent on noise schedules and time-step conditioning. In this work, we propose generative pseudo-force fields (GPFFs) to bridge these paradigms by training an MLFF on a quadratic pseudo-potential energy surface relative to reference equilibrium structures. Because no ab-initio calculations are required for the perturbed geometries, non-equilibrium training data can be generated on the fly by perturbing the equilibria with Gaussian noise. We show that GPFFs constitute a time-step-agnostic variant of variance exploding DMs: the score comes from the predicted pseudo-forces but because force magnitudes implicitly encode the noise level, no time-step conditioning is needed. Our GPFF can hence be used as a drop-in replacement in standard diffusion sampling (ancestral, Heun) but also facilitates more efficient, adaptive variants and an MLFF inspired direct denoising scheme. Our proposed sampling algorithms support arbitrary structural priors and geometric constraints. On QM9, GPFF has 100 % validity at 256 neural function evaluations (NFE) and over 50 % at just 6 NFE, outperforming diffusion baselines across all samplers. Combined with custom priors, we showcase the fast and accurate generation process of our method in a molecular editor for a drug design setting, where a molecule is generated in real time.

While intracortical Brain-Computer Interfaces (iBCIs) that decode imagined handwriting have achieved high communication rates for Latin scripts, they rely on observing every character in the alphabet during training. This poses a challenge in scaling to logographic languages (e.g., Chinese, Japanese), where the character set exceeds thousands of classes. The limitation highlights a fundamental question in motor neuroscience: does the motor cortex represent handwriting through the composition of shared kinematic primitives, that can be exploited by decoders? We introduce a computational framework for aligning neural activity to imagined kinematics in large datasets, enabling the training of a zero-shot capable machine learning algorithm for decoding unseen characters. Our model achieves 64% hits@3 retrieval on unseen letters, suggesting that neural representations of kinematic strokes are robustly conserved across different character contexts. This study provides a framework for dissecting conserved neural dynamics in large-scale intracortical datasets and offers strong evidence for a compositional basis of complex motor control. It also establishes a new paradigm for open-vocabulary iBCI communication with minimal recalibration burden on the user, crucial to increasing adoption of neuroprosthetics in logographic languages.

Human-generated randomness is constrained by cognitive, motor, and strategic biases. This study examines how these constraints appear in individual behavior and how they may be modified through interaction with another human. We analyzed repeated rock-paper-scissors data from 9 participants, yielding 108 human-human matches and 216 individual player sequences. Using Lempel-Ziv complexity (LZC), we compared human-human sequences with the RNG-opponent condition. In the RNG-opponent condition, the maximum human LZC value was 84, which we used as an empirical reference. In the human-human condition, most sequences remained below this value, but a small number exceeded it, producing a small high-complexity tail that was not present in the RNG-opponent condition. We introduced a sensitivity measure that captures whether a player responds to the opponent's recent frequency bias by choosing the move that beats the opponent's most frequent recent move. Partial regression showed that focal-player sensitivity positively predicted future entropy in the opponent's move sequence after controlling for the opponent's current entropy. Circular-shift surrogate analyses indicated that this relation was most clearly interaction-specific when the opponent was in a low-entropy state, where the recent move distribution contained a clear frequency bias. These results suggest that human randomness is not only an isolated individual capacity, but can be shaped by interaction in a state-dependent manner. The findings identify a local mechanism by which interaction may destabilize biased behavior and increase entropy, providing a concrete basis for future causal experiments and generative models of high-complexity human behavior.

Biomolecular generators are often adapted with reward feedback to improve task-specific utility, but pushing utility alone can concentrate generation on a narrow family of candidates. Maintaining diversity is difficult because sample diversity is a set-level property. We introduce Supergroup Relative Policy Optimization (SGRPO), a flexible GRPO-style framework that directly constructs rewards from set-level diversity. For each condition, SGRPO samples a supergroup of candidate sets, compares their diversity under the same condition, and redistributes the group diversity reward to individual rollouts through leave-one-out diversity contributions before combining it with rollout-level utility. This design decouples SGRPO from a particular generator, utility reward, or diversity metric, and allows instantiation with different GRPO-style approaches. We evaluate SGRPO on de novo small-molecule design, pocket-based small-molecule design, and de novo protein design, instantiating it with both GRPO and Coupled-GRPO across autoregressive and discrete diffusion generators. Across decoding sweeps, SGRPO expands the utility-diversity Pareto frontier and achieves the best frontier-level metrics relative to pretrained generators, GRPO, and memory-assisted GRPO when applicable. Our analyses further show that direct set-level diversity rewards remain effective with small groups and help preserve broader generation-distribution coverage during post-training. The code is available at https://github.com/IDEA-XL/SGRPO.

Protein language models (pLMs) have shown strong potential for zero-shot prediction of missense variant effects, yet systematic benchmarking on viral proteins remains limited, a critical gap given the need for proactive tools that can anticipate emerging mutations ahead of experimental validation. Here we introduce ViroGym, a comprehensive benchmark evaluating pLMs across three tasks: 79 deep mutational scanning (DMS) assays covering eukaryotic viruses with 552,065 mutated sequences across 7 phenotypic readouts, 21 influenza neutralisation tasks, and a real-world pandemic prediction task for SARS-CoV-2. We benchmark well-established pLMs on fitness landscapes, antigenic diversity, and pandemic forecasting, and find that the ProGen2 family consistently achieves the strongest performance across all three tasks. Crucially, DMS and neutralisation performance reliably identifies models that generalise to real-world emergence, even though the mutation sets they surface barely overlap, revealing that complementary in vitro benchmarks capture the evolutionary constraints needed for real-world mutation forecasting.

Understanding how humans and artificial intelligence systems process complex narrative videos is a fundamental challenge at the intersection of neuroscience and machine learning. This study investigates how the temporal context length of video clips (3--24 s clips) and the narrative-task prompting shape brain-model alignment during naturalistic movie watching. Using fMRI recordings from participants viewing full-length movies, we examine how brain regions sensitive to narrative context dynamically represent information over varying timescales and how these neural patterns align with model-derived features. We find that increasing clip duration substantially improves brain alignment for multimodal large language models (MLLMs), whereas unimodal video models show little to no gain. Further, shorter temporal windows align with perceptual and early language regions, while longer windows preferentially align higher-order integrative regions, mirrored by a layer-to-cortex hierarchy in MLLMs. Finally, experiments with four narrative-task prompts show that they elicit task-specific, region-dependent brain alignment patterns and context-dependent shifts in clip-level tuning in higher-order regions. Our work positions long-form narrative movies as a principled testbed for studying long-timescale temporal integration in long-context MLLMs and its relationship to cortical responses during narrative comprehension.

Differential gene expression (DGE) analysis is foundational to transcriptomic research, yet tool selection can substantially influence results. This study presents a comprehensive comparison of two widely used DGE tools, edgeR and DESeq2, using real and semi-simulated bulk RNA-Seq datasets spanning viral, bacterial, and fibrotic conditions. We evaluated tool performance across three key dimensions: (1) sensitivity to sample size and robustness to outliers; (2) classification performance of uniquely identified gene sets within the discovery dataset; and (3) generalizability of tool-specific gene sets across independent studies. First, both tools showed similar responses to simulated outliers, with Jaccard similarity between the DEG sets from perturbed and original (unperturbed) data decreasing as more outliers were added. Second, classification models trained on tool-specific genes showed that edgeR achieved higher F1 scores in 9 of 13 contrasts and more frequently reached perfect or near-perfect precision. Dolan-More performance profiles further indicated that edgeR maintained performance closer to optimal across a greater proportion of datasets. Third, in cross-study validation using four independent SARS-CoV-2 datasets, gene sets uniquely identified by edgeR yielded higher AUC, precision, and recall in classifying samples from held-out datasets. This pattern was consistent across folds, with some test cases achieving perfect separation using edgeR-specific genes. In contrast, DESeq2-specific genes showed lower and more variable performance across studies. Overall, our findings highlight that while DESeq2 may identify more DEGs even under stringent significance conditions, edgeR yields more robust and generalizable gene sets for downstream classification and cross-study replication, which underscores key trade-offs in tool selection for transcriptomic analyses.

RNA function is tied to secondary structure, operating through dynamic and heterogeneous structural ensembles. While current analysis tools typically output single static structures or averaged contact maps, chemical probing methods like DMS capture nucleotide-resolution signals representing the full structural ensemble, which remain difficult to interpret structurally. To address this, we present MERGE-RNA, a framework that describes and outputs RNA as a structural ensemble. By modeling the physics of the experimental pipeline, MERGE-RNA learns a small set of transferable and interpretable parameters, enabling the integration of measurements across different molecules, probe concentrations, and replicates in a single optimization to improve robustness. Our model employs a maximum-entropy principle to predict thermodynamic populations, with the minimal adjustments necessary to align the ensemble with experimental data. We validate MERGE-RNA on diverse RNAs, showing that it achieves structural accuracy surpassing standard pseudo-free-energy methods and yields ensembles better recapitulating measured DMS reactivity. Applied to the V. vulnificus adenine riboswitch, MERGE-RNA recovers the NMR-resolved conformations and their ligand-induced rearrangement, with population shifts matching the NMR-derived K_d. In a designed RNA construct for which we report new DMS data, MERGE-RNA deconvolves mixed states to reveal transient intermediate populations involved in strand displacement, dynamics invisible to traditional analysis methods.

Plants exhibit dynamic bioelectric properties that facilitate information transfer across tissues. This study investigates action potentials (APs) in Nicotiana tabacum recorded within a custom-designed growth chamber using a biosignal amplifier and environmental sensors. Consistent light- and dark-induced APs were observed during photoperiod transitions under controlled 12-hour artificial illumination cycles. To understand these bioelectric responses, a mathematical model based on the Hodgkin-Huxley framework is used. Electrophysiological measurements from Solanum lycopersicum revealed that under natural light conditions, only light-induced APs are observed, while light- and dark-induced APs coupled dynamics is exclusively elicited during rapid transitions in artificial photoperiods. These distinct phenomena are characterized as Prolonged Oscillatory Climatic Engagement (POCE) and Nimble Environmental Transition Oscillation (NETO), respectively. The model successfully reproduces the key features in both frameworks while maintaining computational efficiency through voltage-independent rate parameters.

Early detection of malignant lung nodules remains constrained by size and growth based screening criteria, often delaying diagnosis. We present an integrated AI system that jointly performs nodule detection and malignancy assessment directly at the nodule level from low dose CT scans, within a unified CADe/CADx framework. Unlike conventional pipelines separating detection and diagnosis, our approach targets malignant nodules directly, redefining evaluation at the point where clinical decisions are made. To address limitations in dataset scale and explainability, the system consists of a Large Ensemble Model (LEM) combining ensembles of shallow deep learning and feature based models. It was trained and evaluated on 25,709 scans with 69,449 annotated nodules, with external validation on an independent cohort. It achieved an AUC of 0.98 internally and 0.945 externally, outperforming all growth based metrics, Lung RADS size based triage, European volume and VDT based screening criteria, radiologists, and leading AI models. The model maintains high sensitivity at low false positive rates, excels for small and early stage cancers, and enables malignancy assessment up to one year earlier than radiologists for indeterminate and slow growing nodules. This approach has the potential to streamline lung cancer screening workflows and support earlier, more actionable clinical decision making.

Nearly all cell models explicitly or implicitly deal with the biophysical constraints that must be respected for life to persist. Despite this, there is almost no systematicity in how these constraints are implemented, and we lack a principled understanding of how cellular dynamics interact with them and how they originate in actual biology. Computational cell biology will only overcome these concerns once it treats the life-death boundary as a central concept, creating a theory of cellular viability. We lay the foundation for such a development by demonstrating how specific geometric structures can separate regions of qualitatively similar survival outcomes in our models, offering new global organizing principles for cell fate. We also argue that idealized models of emergent individuals offer a tractable way to begin understanding life's intrinsically generated limits.

Predicting the secondary structure of RNA is a core challenge in computational biology, essential for understanding molecular function and designing novel therapeutics. The field has evolved from foundational but accuracy-limited thermodynamic approaches to a new data-driven paradigm dominated by machine learning and deep learning. These models learn folding patterns directly from data, leading to significant performance gains. This review surveys the modern landscape of these methods, covering single-sequence, evolutionary-based, and hybrid models that blend machine learning with biophysics. A central theme is the field's "generalization crisis," where powerful models were found to fail on new RNA families, prompting a community-wide shift to stricter, homology-aware benchmarking. In response to the underlying challenge of data scarcity, RNA foundation models have emerged, learning from massive, unlabeled sequence corpora to improve generalization. Finally, we look ahead to the next set of major hurdles-including the accurate prediction of complex motifs like pseudoknots, scaling to kilobase-length transcripts, incorporating the chemical diversity of modified nucleotides, and shifting the prediction target from static structures to the dynamic ensembles that better capture biological function. We also highlight the need for a standardized, prospective benchmarking system to ensure unbiased validation and accelerate progress.

Recently, plenty research has been done on discovering the role of energy dissipation in biological networks, most of which focus on the relationship of dissipation and functionality. However, the development of networks science urged us to fathom the systematic architecture of biological networks and their evolutionary advantages. We found the dissipation of biological dissipative networks is highly related to their structure. By interrogating these well-adapted networks, we find that the energy producing module is relatively isolated in all situations. We applied evolutionary simulation and analysis on premature networks of classic dissipative networks, namely kinetic proofreading, activator-inhibitor oscillator and two typical adaptative response models. We found despite that selection was imposed merely on the network function, the networks tended to decouple high energy molecules as fuels from the functional module, to achieve higher overall dissipation during the course of evolution. Furthermore, we find that decoupled fuel modules can increase the robustness of the networks towards parameter or structure perturbations. We provide theoretical analysis on the kinetic proofreading networks and the general case of energy-driven networks. We find fuel decoupling can guarantee higher dissipation and, in most cases when considering dissipative networks, higher performance. We conclude that fuel decoupling is an evolutionary outcome and bears benefits during evolution.

Many living and physical systems such as cell aggregates, tissues or bacterial colonies behave as unconventional systems of particles that are strongly constrained by volume exclusion and shape interactions. Understanding how these constraints lead to macroscopic self-organized structures is a fundamental question in e.g. developmental biology. To this end, various types of computational models have been developed. Here, we introduce a new framework based on optimal transport theory to model particle systems with arbitrary dynamical shapes and deformability properties. Our method builds upon the pioneering work of Brenier on incompressible fluids and its recent applications to materials science. It lets us specify the shapes and volumes of individual cells and supports a wide range of interaction mechanisms, while automatically taking care of the volume exclusion constraint at an affordable numerical cost. We showcase the versatility of this approach by reproducing several classical systems in computational biology. Our Python code is freely available at https://iceshot.readthedocs.io/.

We introduce an interacting particle system that models the spread of an epidemic in terms of heterogeneous diffusive dynamics, rather than exogenous contact and transmission rates at the population level as in classical compartmental models. Each individual has a one-dimensional level of shielding that evolves according to a stochastic differential equation reflected at the advancing front of the epidemic. The front is driven by cumulative infections, and collisions with it represent at-risk situations which may lead to infection depending on a non-Markovian mechanism that involves the local time, the intrinsic transmissibility, and the current contagiousness within the population. We give a rigorous construction of the system and develop two key technical tools: a compensated martingale property for the infected proportion and a general result on how local time transforms under a random time-dependent bijection of the state space. The former yields a decomposition of the expected number of new infections that parallels a corresponding decomposition in the SIR model. The latter allows us to represent the law of each particle, after suitable conditioning, as a generalised elastic Brownian motion with drift.