High-resolution brain imaging can now capture not just synapse locations but their molecular composition, with the cost of such mapping falling exponentially. Yet such ultrastructural data has so far told us little about local neuronal physiology - specifically, the parameters (e.g., synaptic efficacies, local conductances) that govern neural dynamics. We propose to translate molecularly annotated ultrastructure into physiology, introducing the concept of an ultrastructure-to-dynamics compiler: a learned mapping from molecularly annotated ultrastructure to simulator-ready, uncertainty-aware physiological parameters. The requirement is paired training data, with jointly acquired ultrastructure from imaging, and dynamical responses to perturbations from physiological experiments. With this data we can train models that predict local physiology directly from structure. Such a compiler would support biophysical simulations by turning anatomical maps into models of circuit dynamics, shifting structure-to-function from a descriptive program to a predictive one and opening routes to understanding neural computation and forecasting intervention effects.

Short tandem repeats (STRs) are low-entropy regions in the genome, consisting of a short (1-6 bp) unit that is consecutively repeated multiple times. They are known for high mutational instability, due to so-called stutter-mutations, in which the number of units in the run increases or descreases. In particular, STRs with repeat unit length of 1-2 bp are prone to mutate even within several cell divisions. The extremely rapid accumulation of variation makes them interesting phylogenetic markers for retrospective single-cell lineage reconstruction. Here we model their mutational dynamics at the level of individual repeat unit type and then aggregate length variations over many STR loci with the aim of obtaining a very fast ``molecular clock''. We calibrate our model based on several datasets with known lineage structure prepared from cultured cells. We find that the mutational dynamics of STRs are reasonably consistent for a given cell line, but vary among different ones. This suggests that the dynamics are not entirely explained by mutations in caretaker genes, rather, various other factors play a role -- possibly tissue origin and differentiation state. Further data and research is necessary to asses their relative effects.

Robust oscillations play crucial roles in a wide variety of biological processes and are often generated by deterministic mechanisms. However, stochastic fluctuations often generate complex perturbations of these deterministic oscillations, potentially strengthening or weakening their robustness. In this paper, we study bistable phosphorylation as a mechanism for robust oscillation. We present a simple nucleocytoplasmic transport and cell growth model where cargo proteins undergo bistable phosphorylation prior to nuclear import. We perform a detailed bifurcation analysis to examine the system's dynamical behavior. We then introduce additive noise into the model and study the stochastic resonance behavior and robustness of oscillations under noise. Our results show that, depending on the phosphorylation threshold, time-scale parameters, and nucleocytoplasmic transport rate, bistable phosphorylation may generate oscillations via Hopf bifurcations; moreover, stochastic resonance and Bautin bifurcations enhance the robustness of the oscillations.

In a dataset of 423 patients who had had radical prostatectomy for localised prostate cancer we estimated the apparent Shannon information (ASI) about time to biochemical recurrence in various subsets of the available pre-op variables using a Bayesian Gamma-power-mixture survival regression model. In all the subsets examined the ASI was positive with posterior probability greater than 0.975 . Using only age and results of pre-operative blood tests (PSA and biomarkers) we achieved 0.232 (0.180 to 0.290) nats ASI (0.335 (0.260 to 0.419) bits) (posterior mean and equitailed 95% posterior confidence intervals). This is more than double the mean posterior ASI previously achieved on the same dataset by a subset of the current authors using a log-skew-Student-mixture model, and is greater than that previous value with posterior probability greater than 0.99 . Additionally using pre- or post-operative Gleason grades, operative findings, clinical stage, and presence or absence of extraprostatic extension or seminal vesicle invasion did not increase the ASI extracted. However removing the blood-based biomarkers and replacing them with either pre-operative Gleason grades or findings available from MRI scanning greatly reduced the available ASI to respectively 0.077 (0.038 to 0.120) and 0.088 (0.045 to 0.132) nats (both less than the values using blood-based biomarkers with posterior probability greater than 0.995). A greedy approach to selection of the best biomarkers gave TGFbeta1, VCAM1, IL6sR, and uPA in descending order of importance from those examined.

Biomolecular condensates organize biochemical processes by spatially concentrating molecules while allowing for dynamic exchange with their surroundings. However, transport across their interface can be strongly attenuated, leading to enhanced retention and preferential internal mixing. Two key mechanisms have been proposed to describe this behavior: biased interfacial reflectivity, which compares how strongly particles are reflected at the interface when attempting to enter or leave the condensate, and interfacial resistance, which sets the kinetic rate at which particles can cross the interface. Quantifying these parameters experimentally has remained challenging. Here, we present a theoretical and experimental framework to address this issue, extending our previously developed half-FRAP approach. We solve the spherical diffusion problem with a semipermeable interface by spectral decomposition. By evaluating the information content of the integrated recovery curves, we show that they encode sufficient information to recover interfacial parameters over extended regions of parameter space. Applying our framework to tunable coacervates composed of poly-lysine and hyaluronic acid, we find that their interfaces exhibit strongly biased reflectivity and substantial resistance, both driving preferential internal mixing. These parameters depend on salt concentration, linking interfacial transport to intermolecular interaction strength and position in the phase diagram. Our results establish a quantitative connection between interfacial properties and condensate dynamics, revealing how their interplay gives rise to distinct transport regimes.

If the universe follows a specific design, then a central question is which cost function is optimized by the observed forces. This is the problem of inverse optimal control, or inverse reinforcement learning, in which a reward function is inferred from the dynamics of the observed system. We first establish the {\em least cost principle}, whereby the laws of motion can be derived from minimization of a time-discounted integral of the acceleration cost minus a state-dependent reward function. After determining the functional form of the acceleration cost from basic principles, we infer the reward function from the laws of motion governing classical gravitation and Coulomb forces. The inferred reward function is high when pairs of particles have high relative velocities and when their relative motion is orthogonal to their distance vectors. All in all, our work suggests that relative motion and quasi-circular orbits are the dynamical and static features optimized by central forces in nature.

Gait is increasingly recognized as a vital sign, yet current approaches treat it as a symptom of specific pathologies rather than a systemic biomarker. We developed a gait foundation model for 3D skeletal motion from 3,414 deeply phenotyped adults, recorded via a depth camera during five motor tasks. Learned embeddings outperformed engineered features, predicting age (Pearson r = 0.69), BMI (r = 0.90), and visceral adipose tissue area (r = 0.82). Embeddings significantly predicted 1,980 of 3,210 phenotypic targets; after adjustment for age, BMI, VAT, and height, gait provided independent gains in all 18 body systems in males and 17 of 18 in females, and improved prediction of clinical diagnoses and medication use. Anatomical ablation revealed that legs dominated metabolic and frailty predictions while torso encoded sleep and lifestyle phenotypes. These findings establish gait as an independent multi-system biosignal, motivating translation to consumer-grade video and its integration as a scalable, passive vital sign.

In this paper we study the stability properties of the equilibrium point for an age-structured chemostat model with renewal boundary condition and coupled substrate dynamics under constant dilution rate. This is a complex infinite-dimensional feedback system. It has two feedback loops, both nonlinear. A positive static loop due to reproduction at the age-zero boundary of the PDE, counteracted and dominated by a negative dynamic loop with the substrate dynamics. The derivation of explicit sufficient conditions that guarantee global stability estimates is carried out by using an appropriate Lyapunov functional. The constructed Lyapunov functional guarantees global exponential decay estimates and uniform global asymptotic stability with respect to a measure related to the Lyapunov functional. From a biological perspective, stability arises because reproduction is constrained by substrate availability, while dilution, mortality, and substrate depletion suppress transient increases in biomass before age-structure effects can amplify them. The obtained results are applied to a chemostat model from the literature, where the derived stability condition is compared with existing results that are based on (necessarily local) linearization methods.

What substrate features allow life? We exhaustively classify all 262,144 outer-totalistic binary cellular automata rules with Moore neighbourhood for self-replication and produce phase diagrams in the $(λ, F)$ plane, where $λ$ is Langton's rule density and $F$ is a background-stability parameter. Of these rules, 20,152 (7.69%) support pattern proliferation, concentrated at low rule density ($λ\approx 0.15$--$0.25$) and low-to-moderate background stability ($F \approx 0.2$--$0.3$), in the weakly supercritical regime (Derrida coefficient $μ= 1.81$ for replicators vs. $1.39$ for non-replicators). Self-replicating rules are more approximately mass-conserving (mass-balance 0.21 vs. 0.34), and this generalises to $k{=}3$ Moore rules. A three-tier detection hierarchy (pattern proliferation, extended-length confirmation, and causal perturbation) yields an estimated 1.56% causal self-replication rate. Self-replication rate increases monotonically with neighbourhood size under equalised detection: von Neumann 4.79%, Moore 7.69%, extended Moore 16.69%. These results identify background stability and approximate mass conservation as the primary axes of the self-replication phase boundary.

Biological AI models increasingly predict complex cellular responses, yet their learned representations remain disconnected from the molecular processes they aim to capture. We present CDT-III, which extends mechanism-oriented AI across the full central dogma: DNA, RNA, and protein. Its two-stage Virtual Cell Embedder architecture mirrors the spatial compartmentalization of the cell: VCE-N models transcription in the nucleus and VCE-C models translation in the cytosol. On five held-out genes, CDT-III achieves per-gene RNA r=0.843 and protein r=0.969. Adding protein prediction improves RNA performance (r=0.804 to 0.843), demonstrating that downstream tasks regularize upstream representations. Protein supervision sharpens DNA-level interpretability, increasing CTCF enrichment by 30%. Analysis of experimentally measured mRNA and protein responses reveals that the majority of genes with observable mRNA changes show opposite protein-level changes (66.7% at |log2FC|>0.01, rising to 87.5% at |log2FC|>0.02), exposing a fundamental limitation of RNA-only perturbation models. Despite this pervasive direction discordance, CDT-III correctly predicts both mRNA and protein responses. Applied to in silico CD52 knockdown approximating Alemtuzumab, the model predicts 29/29 protein changes correctly and rediscovers 5 of 7 known clinical side effects without clinical data. Gradient-based side effect profiling requires only unperturbed baseline data (r=0.939), enabling screening of all 2,361 genes without new experiments.

Accurate prediction of protein function is essential for elucidating molecular mechanisms and advancing biological and therapeutic discovery. Yet experimental annotation lags far behind the rapid growth of protein sequence data. Computational approaches address this gap by associating proteins with Gene Ontology (GO) terms, which encode functional knowledge through hierarchical relations and textual definitions. However, existing models often emphasize one modality over the other, limiting their ability to generalize, particularly to unseen or newly introduced GO terms that frequently arise as the ontology evolves, and making the previously trained models outdated. We present STAR-GO, a Transformer-based framework that jointly models the semantic and structural characteristics of GO terms to enhance zero-shot protein function prediction. STAR-GO integrates textual definitions with ontology graph structure to learn unified GO representations, which are processed in hierarchical order to propagate information from general to specific terms. These representations are then aligned with protein sequence embeddings to capture sequence-function relationships. STAR-GO achieves state-of-the-art performance and superior zero-shot generalization, demonstrating the utility of integrating semantics and structure for robust and adaptable protein function prediction. Code is available at https://github.com/boun-tabi-lifelu/stargo.

We consider the problem of fitting a reinforcement learning (RL) model to some given behavioral data under a multi-armed bandit environment. These models have received much attention in recent years for characterizing human and animal decision making behavior. We provide a generic mathematical optimization problem formulation for the fitting problem of a wide range of RL models that appear frequently in scientific research applications. We then provide a detailed theoretical analysis of its convexity properties. Based on the theoretical results, we introduce a novel solution method for the fitting problem of RL models based on convex relaxation and optimization. Our method is then evaluated in several simulated and real-world bandit environments to compare with some benchmark methods that appear in the literature. Numerical results indicate that our method achieves comparable performance to the state-of-the-art, while significantly reducing computation time. We also provide an open-source Python package for our proposed method to empower researchers to apply it in the analysis of their datasets directly, without prior knowledge of convex optimization.

Patients with rare types of melanoma such as acral, mucosal, or uveal melanoma, have lower survival rates than patients with cutaneous melanoma; these lower survival rates reflect the lower objective response rates to immunotherapy compared to cutaneous melanoma. Understanding tumor-immune dynamics in rare melanomas is critical for the development of new therapies and for improving response rates to current cancer therapies. Progress has been hindered by the lack of clinical data and the need for better preclinical models of rare melanomas. Canine melanoma provides a valuable comparative oncology model for rare types of human melanomas. We analyzed RNA sequencing data from canine melanoma patients and combined this with literature information to create a novel mechanistic mathematical model of melanoma-immune dynamics. Sensitivity analysis of the mathematical model indicated influential pathways in the dynamics, providing support for potential new therapeutic targets and future combinations of therapies. We share our learnings from this work, to help enable the application of this proof-of-concept workflow to other rare disease settings with sparse available data.

Transcriptomic foundation models pretrained with masked language modeling can achieve low pretraining loss yet produce poor cell representations for downstream tasks. We introduce whole-cell expression decoding (WCED), where models reconstruct the entire gene vocabulary from a single CLS token embedding, even with limited inputs, creating a maximally informative bottleneck. WCED consistently outperforms MLM on all downstream metrics despite higher reconstruction error during training. Gene-level error tracking reveals that both methods preferentially learn genes whose expression co-varies with stable transcriptional programs rather than those driven by transient factors. We further add hierarchical cross-entropy loss that exploits Cell Ontology structure for zero-shot annotation at multiple granularity levels. Models trained with these objectives achieve best overall performance across CZI benchmarks, on zero-shot batch integration and linear probing cell-type annotation. Methods are implemented in biomed-multi-omic ( https://github.com/BiomedSciAI/biomed-multi-omic ), an open-source framework for transcriptomic foundation model development.

In drug discovery, predicting the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of small-molecule drugs is critical for ensuring safety and efficacy. However, the process of accurately predicting these properties is often resource-intensive and requires extensive experimental data. To address this challenge, we propose SMILES-Mamba, a two-stage model that leverages both unlabeled and labeled data through a combination of self-supervised pretraining and fine-tuning strategies. The model first pre-trains on a large corpus of unlabeled SMILES strings to capture the underlying chemical structure and relationships, before being fine-tuned on smaller, labeled datasets specific to ADMET tasks. Our results demonstrate that SMILES-Mamba exhibits competitive performance across 22 ADMET datasets, achieving the highest score in 14 tasks, highlighting the potential of self-supervised learning in improving molecular property prediction. This approach not only enhances prediction accuracy but also reduces the dependence on large, labeled datasets, offering a promising direction for future research in drug discovery.

The backpropagation algorithm has experienced remarkable success in training large-scale artificial neural networks; however, its biological plausibility has been strongly criticized, and it remains an open question whether the brain employs supervised learning mechanisms akin to it. Here, we propose correlative information maximization between layer activations as an alternative normative approach to describe the signal propagation in biological neural networks in both forward and backward directions. This new framework addresses many concerns about the biological-plausibility of conventional artificial neural networks and the backpropagation algorithm. The coordinate descent-based optimization of the corresponding objective, combined with the mean square error loss function for fitting labeled supervision data, gives rise to a neural network structure that emulates a more biologically realistic network of multi-compartment pyramidal neurons with dendritic processing and lateral inhibitory neurons. Furthermore, our approach provides a natural resolution to the weight symmetry problem between forward and backward signal propagation paths, a significant critique against the plausibility of the conventional backpropagation algorithm. This is achieved by leveraging two alternative, yet equivalent forms of the correlative mutual information objective. These alternatives intrinsically lead to forward and backward prediction networks without weight symmetry issues, providing a compelling solution to this long-standing challenge.

We propose a new microscopy simulation system that can depict atomistic models in a micrograph visual style, similar to results of physical electron microscopy imaging. This system is scalable, able to represent simulation of electron microscopy of tens of viral particles and synthesizes the image faster than previous methods. On top of that, the simulator is differentiable, both its deterministic as well as stochastic stages that form signal and noise representations in the micrograph. This notable property has the capability for solving inverse problems by means of optimization and thus allows for generation of microscopy simulations using the parameter settings estimated from real data. We demonstrate this learning capability through two applications: (1) estimating the parameters of the modulation transfer function defining the detector properties of the simulated and real micrographs, and (2) denoising the real data based on parameters trained from the simulated examples. While current simulators do not support any parameter estimation due to their forward design, we show that the results obtained using estimated parameters are very similar to the results of real micrographs. Additionally, we evaluate the denoising capabilities of our approach and show that the results showed an improvement over state-of-the-art methods. Denoised micrographs exhibit less noise in the tilt-series tomography reconstructions, ultimately reducing the visual dominance of noise in direct volume rendering of microscopy tomograms.

Cryo-Electron Tomography (cryo-ET) is a new 3D imaging technique with unprecedented potential for resolving submicron structural detail. Existing volume visualization methods, however, cannot cope with its very low signal-to-noise ratio. In order to design more powerful transfer functions, we propose to leverage soft segmentation as an explicit component of visualization for noisy volumes. Our technical realization is based on semi-supervised learning where we combine the advantages of two segmentation algorithms. A first weak segmentation algorithm provides good results for propagating sparse user provided labels to other voxels in the same volume. This weak segmentation algorithm is used to generate dense pseudo labels. A second powerful deep-learning based segmentation algorithm can learn from these pseudo labels to generalize the segmentation to other unseen volumes, a task that the weak segmentation algorithm fails at completely. The proposed volume visualization uses the deep-learning based segmentation as a component for segmentation-aware transfer function design. Appropriate ramp parameters can be suggested automatically through histogram analysis. Finally, our visualization uses gradient-free ambient occlusion shading to further suppress visual presence of noise, and to give structural detail desired prominence. The cryo-ET data studied throughout our technical experiments is based on the highest-quality tilted series of intact SARS-CoV-2 virions. Our technique shows the high impact in target sciences for visual data analysis of very noisy volumes that cannot be visualized with existing techniques.

Causal discovery aims to infer causal relationships among variables from observational data, typically represented by a directed acyclic graph (DAG). Most existing methods assume independent and identically distributed observations, an assumption often violated in modern applications. In addition, many datasets contain a mixture of continuous and discrete variables, which further complicates causal modeling when dependence across samples is present. To address these challenges, we propose a de-correlation framework for causal discovery from dependent mixed data. Our approach formulates a structural equation model with latent variables that accommodates both continuous and discrete variables while allowing correlated Gaussian errors across units. We estimate the dependence structure among samples via a pairwise maximum likelihood estimator for the covariance matrix and develop an EM algorithm to impute latent variables underlying discrete observations. A de-correlation transformation of the recovered latent data enables the use of standard causal discovery algorithms to learn the underlying causal graph. Simulation studies demonstrate that the proposed method substantially improves causal graph recovery compared with applying standard methods directly to the original dependent data. We apply our approach to single-cell RNA sequencing data to infer gene regulatory networks governing embryonic stem cell differentiation. The inferred regulatory networks show significantly improved predictive likelihood on test data, and many high-confidence edges are supported by known regulatory interactions reported in the literature.

When designing control strategies for an infectious disease it is critical to identify the key pathways of transmission. Data on infected hosts - when they were born, where they lived and with whom they interacted - can help infer sources of infection and transmission clusters. However such data are generally not powerful enough to identify infector-infectee pairs with any certainty. Whole-genome sequencing data of the underlying pathogen, on the other hand, can serve as a powerful adjoint to these data as they can be used to estimate a time to a most recent common ancestor between two infected hosts. and in turn their relative proximity in the transmission tree. A statistical model that explains the genetic distance between different host pathogens and associated risk factors can therefore inform key risk factors for transmission itself. We show how graph neural networks (GNNs) are a powerful and natural modelling architecture for such a problem. By treating the epidemiological dataset as a graph where infected hosts are nodes and edges are weighted by the genetic distance between different host pairs, we show how a GNN can be fit to predict the genetic distance between known hosts and new, unsequenced hosts. Comparisons with other established approaches show that GNNs have useful performance advantages albeit with greater computational cost.

Quantifying human movement (kinematics) and musculoskeletal forces (kinetics) at scale, such as estimating quadriceps force during a sit-to-stand movement, could transform prediction, treatment, and monitoring of mobility-related conditions. However, quantifying kinematics and kinetics traditionally requires costly, time-intensive analysis in specialized laboratories, limiting clinical translation. Scalable, accurate tools for biomechanical assessment are needed. We introduce OpenCap Monocular, an algorithm that estimates 3D skeletal kinematics and kinetics from a single smartphone video. The method refines 3D human pose estimates from a monocular pose estimation model (WHAM) via optimization, computes kinematics of a biomechanically constrained skeletal model, and estimates kinetics via physics-based simulation and machine learning. We validated OpenCap Monocular against marker-based motion capture and force plate data for walking, squatting, and sit-to-stand tasks. OpenCap Monocular achieved low kinematic error (4.8° mean absolute error for rotational degrees of freedom; 3.4 cm for pelvis translations), outperforming a regression-only computer vision baseline by 48% in rotational accuracy (p = 0.036) and 69% in translational accuracy (p < 0.001). OpenCap Monocular also estimated ground reaction forces during walking with accuracy comparable to, or better than, our prior two-camera OpenCap system. We demonstrate that the algorithm estimates important kinetic outcomes with clinically meaningful accuracy in applications related to frailty and knee osteoarthritis, including estimating knee extension moment during sit-to-stand transitions and knee adduction moment during walking. OpenCap Monocular is deployed via a smartphone app, web app, and secure cloud computing (https://opencap.ai), enabling free, accessible single-smartphone biomechanical assessments.

Diffusion models offer a powerful means of capturing the manifold of realistic protein structures, enabling rapid design for protein engineering tasks. However, existing approaches observe critical failure modes when precise constraints are necessary for functional design. To this end, we present a constrained diffusion framework for structure-guided protein design, ensuring strict adherence to functional requirements while maintaining precise stereochemical and geometric feasibility. The approach integrates proximal feasibility updates with ADMM decomposition into the generative process, scaling effectively to the complex constraint sets of this domain. We evaluate on challenging protein design tasks, including motif scaffolding and vacancy-constrained pocket design, while introducing a novel curated benchmark dataset for motif scaffolding in the PDZ domain. Our approach achieves state-of-the-art, providing perfect satisfaction of bonding and geometric constraints with no degradation in structural diversity.

In attitude theory, formal theoretical predictions come largely from the simulation of computational models. We argue that to push attitude theory further, we should employ mathematical analysis/analytic methods alongside of computational simulation, something that other sciences and engineering consider standard practice. Our work first attempts to portray the complementary nature of mathematical analysis along side of computational simulation using as an example the Causal Attitude Network model of attitudes (Dalege et al., 2016). We then introduce a mathematical theory, Graph Dynamical Systems (GDS), as a broad theoretical framework for network models of attitudes. We illustrate the use of GDS, in the context of the Attitudes as Constraint Satistfaction (ACS) theory of attitude dynamics (Monroe & Read, 2008), as a generator of precise, quantitative theoretical predictions. We conclude by pointing out the value of improved attitude theory for the so-called replication crisis in psychology. KEYWORDS: attitudes, neural networks, dynamical systems, psychological networks

One of the fundamental questions in population dynamics is how biological populations respond to environmental perturbations. In population dynamics, the mean fitness and the fraction of a trait in the steady state are important because they indicate how well the trait and the population adapt to the environment. In this study, we examine the parallel mutation-reproduction model, which is one of the simplest models of an evolvable population. As an extension of the Markov chain tree theorem, we derive diagrammatic expressions for the static responses of mean fitness and the steady-state distribution of the population. For the parallel mutation-reproduction model, we consider self-loops, which represent trait reproduction and are excluded from the Markov chain tree theorem for the linear master equation. To generalize the theorem, we introduce the concept of rooted $0$/$1$ loop forests, which generalize spanning trees with loops. We demonstrate that the weights of rooted $0$/$1$ loop forests yield the static responses of mean fitness and the steady-state distribution. Our results provide exact expressions for the static responses and the steady-state distribution. Additionally, we discuss approximations of these expressions in cases where reproduction or mutation is dominant. We provide numerical examples to illustrate these approximations and exact expressions.