Papers

Non-tuberculous mycobacterial (NTM) infections are a clinical challenge in cystic fibrosis (CF), where impaired mucociliary clearance and altered mucus rheology promote bacterial colonization despite host immune responses. Understanding how bacterial growth, immune cell dynamics, and mucus transport regulate infection progression is difficult because these processes interact across spatial and temporal scales. We develop a computational framework bridging a mechanistic agent-based model (ABM) of NTM infection with a spatially resolved partial differential equation (PDE) model. The PDE model couples bacterial proliferation, macrophage chemotaxis, immune-mediated clearance, mucus degradation, and viscoelastic transport in a two-compartment geometry representing mucus and lung tissue. Parameters are calibrated using data from the established ABM, yielding an efficient continuum representation while preserving cellular mechanisms. The PDE model reproduces bacterial and macrophage dynamics and enables analyses of mucus-related mechanisms and therapies. Sensitivity analysis identifies mucus viscosity, bacterial diffusivity, and macrophage mobility as key regulators of bacterial persistence through mucociliary clearance and tissue colonization. Simulations reveal nonlinear effects of mucolytic therapies: enhanced clearance reduces bacterial burden in mucus, whereas excessive viscosity reduction may promote migration into lung tissue, supporting combination with antibacterial treatment. This framework provides a quantitative platform for studying pulmonary infections, evaluating therapies, and developing patient-specific digital twins.

Large brains are metabolically costly, and associations with changing environments do not imply they evolved there, as the Cognitive Buffer Hypothesis (CBH) would suggest. They may instead evolve in stable conditions and later facilitate colonization of changing environments. Using neuro-evolution in an artificial seasonal foraging task, we compared agents evolving exclusively in changing environments to agents first evolved in static environments before transitioning. Results show that larger neural networks in dynamic environments arise mainly from prior static evolution, achieving superior performance under unpredictable changes. Our results challenge strict CBH predictions, provide agent-based (computational) support for a colonization-based account and highlight the role of evolutionary history in brain size evolution.

Co-folding models such as AlphaFold3, Protenix, ESMFold2, and OpenDDE have advanced rapidly, yet no single model consistently performs best across all biomolecular complexes. In this paper, we show that their pair representations encode complementary information that can be transferred across models to improve structure prediction. We introduce SoupFold, which combines pair representations from multiple co-folding models in a common representation space and generates structures from the combined representation. Importantly, SoupFold does not retrain the co-folding models and learns only simple mappings to transfer representations across models. We evaluate SoupFold on antibody-antigen, protein-protein, protein-ligand, molecular glue, GPCR, and oligomeric complex prediction using AlphaFold3, Protenix, ESMFold2, and OpenDDE. By combining representations across models, SoupFold improves over individual co-folding models across the considered benchmarks.

Traumatic brain injury (TBI) often leads to subtle white matter damage that remains undetected on conventional MRI. Diffusion kurtosis imaging (DKI), an extension of diffusion tensor imaging (DTI), provides complementary information on non-Gaussian water diffusion and is sensitive to complex white-matter microstructure. With the advent of ultra-high-field MRI, the spatial resolution and signal-to-noise ratios (SNR) have been significantly enhanced, enabling more precise visualization of subtle abnormalities. Building on these advances, we developed TractSpLearn, an individualized tract-based learning framework that jointly considers within-group variability and between-group differences. Unlike the original TractLearn framework, which learns a normative manifold exclusively from healthy controls, TractSpLearn incorporates both healthy controls and patients to learn a shared manifold with a healthy-anchored representation and an additional patient-related component. To assess the performance of the proposed method, we compared TractSpLearn with the original TractLearn in three cohorts: (i) healthy controls (HC), (ii) athletes with persistent post-concussive syndromes (PPCS), and (iii) athletes with repeated head injuries (RHI), with abnormalities particularly evident in axial kurtosis (AK) and mean diffusivity (MD). In RHI, TractSpLearn highlighted recurrent abnormalities across patients. In the PPCS cohort, the overall group-level differences were more modest, potentially reflecting both limited statistical power due to the small sample size and partial normalization of white-matter alterations during recovery. Still TractSpLearn identified abnormality evidence in more patients and across more affected tracts than TractLearn.

Protein-protein interaction databases record evidence without weighing it. In BioGRID, an interaction asserted once by a single high-throughput screen and one confirmed by twenty laboratories across a dozen assays are the same kind of row in the same file. Tools built on such databases inherit that flattening: they draw every reported interaction as an edge, and the resulting picture states that two proteins interact without stating how much anyone should believe it. We present ProLiVis 2.0, a rewrite of the literature-centric visualization system of arXiv:2111.12794. It contributes three things. First, a citation-trust model that scores each interaction from seven terms, including a term for the number of independent laboratories behind the supporting publications, obtained by clustering those publications over shared institutional affiliations; a plain count of publications cannot distinguish five confirmations from one group publishing five times. Second, a deterministic reformulation of the center layout, closed-form and $O(n \log n)$, which replaces the force-directed placement of the original and makes published figures regenerable from a session manifest. Third, an implementation that runs entirely in a web browser, with an embedded analytical database, requiring no installation and uploading no data. On BioGRID release 5.0.260 restricted to SARS-CoV-2, 24,344 of 34,540 reported interactions (70%) rest on a single publication, and raising the trust threshold to 0.2 leaves 11,320 of them. That the large majority of a curated interaction network is unreplicated is a fact no existing view of the database makes visible.

Animal activity often consists of intermittent bursts separated by prolonged periods of inactivity. Here, we describe this behavior using a two-state telegraph process with extrinsically fluctuating transition rates. We derived analytical expressions for the stationary behavior of the system and characterized how stationary fluctuations in the effective transition rates modified the activity and residence time statistics. In particular, we show that whereas fixed transition rates lead to exponential residence-time distributions, stationary rate fluctuations generate effective Lomax distributions with heavier tails. We also found that fluctuations can either increase or decrease the mean occupancy of the active state, and that when the fluctuations in the two transition rates are equal, their effect on the stationary occupancy becomes indistinguishable from the case without fluctuations. We assessed the parameter inference using synthetic data and applied the framework to observations of a domestic cat. For synthetic data, accounting for extrinsic fluctuations substantially improved the recovery of the kinetic parameters used to generate the data. In the experimental data, the inferred variability of the inactive-to-active transition rate was substantially larger than that of the active-to-inactive rate. These results establish a tractable framework for studying stochastic switching systems in which extrinsic variability reshapes burst and residence-time statistics.

Single-cell foundation models (scFMs) increasingly rely on large-scale transcriptomic pretraining, yet expanding pretraining data can yield diminishing gains while substantially increasing computational cost. Our data scaling analyses showed that incorporating biological knowledge, including cell-level text annotation and gene-level regulatory information, provided additional scaling dimension than simply increasing data size. Motivated by this observation, we present scKITE, a simple yet effective scFM that integrates cell-annotation and gene-regulatory supervision into a shared transcriptomic Transformer encoder through lightweight auxiliary decoders. These decoders are used only during pretraining and subsequently discarded, yielding a general-purpose encoder enriched with biological knowledge for downstream applications. With only 179,067 pretraining samples, i.e., less than 0.5% of those used by previous strong scFMs, scKITE outperformed these models across diverse downstream tasks, highlighting knowledge-enhanced pretraining as a promising paradigm for biologically grounded scFMs.

A small number of unusually high-gain parameters can exert disproportionate effects in transformer language models, but whether analogous structures recur in genomic foundation models and whether structural geometry determines functional importance remains unknown. We analyzed high-gain rows in gated feed-forward networks across text and genomic foundation models, including a frozen 22-model causal census. Computing an associated bilinear weight operator exactly, without a diagonal approximation, we tested whether structural extremeness is a transferable mechanism. Activation-derived candidates were functionally enriched relative to random and top-norm same-layer controls, yet neither spectral concentration nor operator magnitude predicted causal effect size, and these associations vanished within the endpoint-homogeneous text-decoder subset. A within-layer sweep of 36 rows in one genomic and one text decoder resolved this into two regimes: below the detector's acceptance threshold the ratio carried no positive information about causal damage, whereas above it the ratio ordered rows strongly but did not grade severity as a dose-response. The same sweep revealed a second individually catastrophic row invisible to a one-candidate-per-model census, and non-additive damage among co-located critical rows. Case studies showed divergent causal organizations: a robust super-additive pair interaction in DNABERT-2, and in GENERator a sharply position-localized dependence in which preserving or restoring the row's beginning-of-sequence contribution rescued essentially all native-loss damage. High-gain gated-FFN rows are therefore a recurrent architectural phenotype whose structural prominence acts as an enrichment signal, not a calibrated measure of functional criticality or a specification of causal organization. Enrichment is general, but the mechanism is model-specific.

Immune therapies act across cell-intrinsic programs, tissue ecosystems, and patient-specific immune states, yet most predictors address these scales separately. We used a governed evolutionary AI Scientist to construct the Immune World Model, an action-conditioned model that learns how interventions move immune states across cellular, tissue, and individual levels. The Immune World Model–building Scientist searched candidate architectures and workflows, and the resulting world model was frozen before independent confirmation. The frozen model generalized to unseen interventions and biological contexts, recovered intervention-specific cellular programs, integrated cell and tissue information to improve ecosystem and patient-response prediction, and forecast unseen perturbation combinations. Immune World Model–guided analysis then combined measured perturbations with cross-axis inference to nominate IL-36$\gamma$ plus SIRP$\alpha$ inhibition as a complementary-axis therapeutic hypothesis, whereas a governed self-correction audit rejected every screened cytokine pair. The Immune World Model provides a framework for multiscale immune simulation that connects AI Scientist-driven model construction, intervention forecasting, and the generation of prospectively testable therapeutic hypotheses.

We study the evolution of the speed of life history in populations competing for a single growth-limiting resource subject to demographic stochasticity and mass mortality events. We focus on a quasi-neutral regime in which competing types have equal resource-use efficiency but differ in life-history speed. In the large-carrying-capacity scaling limit, we reduce the model to a one-dimensional jump-diffusion supported on the manifold of ecological equilibria. The drift and diffusion components capture the joint effects of demographic stochasticity and density regulation, while the jump component is driven by the catastrophic mortality events. Using this limiting process, we derive a first-order approximation for the fixation probability of an invading type that differs slightly in life history speed from the resident population. Calculations show that small demographic events tend to favor slower life histories, whereas catastrophic mortality events create transient periods of resource abundance that benefit faster types. The interaction of these two evolutionary forces allows for the existence of a nontrivial evolutionarily attractive life-history speed, which is an increasing function of the frequency and intensity of the catastrophic mortality events. These results provide a rigorous mathematical framework for some classical r/K-selection arguments, and furthermore demonstrate how mass mortality events can maintain selection for faster life histories even in resource-constrained populations.

We determine statistics of allele-frequency trajectories across replicate populations. Defining $R = 2N_e|s|$ where $N_e$ is the effective population size and $s$ is the additive selection coefficient of a focal allele, we focus on strong selection which corresponds to $R \gg 1$. Strong selection does not require large selection coefficients: in populations of realistic size, it can readily arise from small selection coefficients. Our analysis concerns a biallelic locus over timescales on which mutation can be neglected. Every allele-frequency trajectory belongs to one of two absorbing classes: fixation or loss. When $R$ is large, individual allele-frequency trajectories can appear nearly deterministic. This does not imply that an approximation of allele-frequency statistics can be based on a single deterministic trajectory. For a beneficial allele, the deterministic trajectory approaches fixation, yet a non-negligible fraction of stochastic trajectories may be lost. Ignoring trajectories that achieve loss can produce severely erroneous statistics. We address this by conditioning separately on the eventual loss and eventual fixation of the focal allele. This yields an outcome-conditioned representation of a statistic. In the strong-selection regime, we apply a small-noise expansion that reasonably captures transient behaviours of statistics while recovering their exact long-time limits. We illustrate results with numerical examples for the mean allele frequency and its variance. The biological interpretation of this work is that, even under strong selection, both trajectory types are of importance. We provide a simple framework for calculating time-dependent allele-frequency statistics relevant to experimental evolution, longitudinal population-genomic data, and the dynamics of alleles driving selective sweeps.

Deep learning now underpins structure-based drug design, from complex and affinity prediction to ligand ranking and pose generation. Recent co-folding models reportedly approach free-energy-perturbation accuracy at far lower cost. Yet standard evaluation, a single held-out correlation or pooled pose-success rate, cannot separate transferable binding principles from repeated exposure to related protein families in public databases, and practical success depends on genuinely novel targets. We introduce MIRAGE (Measuring Interpolation and Redundancy in Affinity GEneralization), a plug-in benchmark treating historical public family support (through 2019) as an explicit variable, applying a family-support axis to affinity and pose prediction via matched strata, family-disjoint controls, ligand-only baselines, and temporal evaluation. Co-folder affinity accuracy rises sharply with family support, while shallow controls that cannot exploit the test family stay flat, large for co-folders and near zero for every family-disjoint or trivial control. For Nesso-1 it survives covariate, conditioning, balancing, and clustering checks; Boltz-2's endpoint is limited by coverage. It localizes to family support rather than ligand chemistry, approaching a level from family identity alone. Rankings reverse on novel families, where a family-disjoint random forest leads both co-folders, significantly vs Nesso-1. On one external low-support target, neither co-folder beats molecular weight, corroborative rather than population-level evidence. gnina shows significant support dependence in rescoring whereas smina does not; MSA-free pose engines show larger gaps than smina redocking. This redundancy-driven inflation differs from conventional leakage. We propose reporting performance across family support plus excess over a support-insensitive baseline, and release MIRAGE as an installable benchmark and dataset.

Classical theories of random neural networks typically assume independent connectivity, overlooking the local motif structures prevalent in biological circuits. Here, we investigate how four second-order synaptic motifs (chain, reciprocal, convergent, and divergent) shape the dynamics of nonlinear firing-rate networks. While previous studies have established that chain correlations generate outlier eigenvalues, we demonstrate that these motifs also jointly reshape the Jacobian eigenvalue bulk. Using the path-integral formalism, we derive a dynamic mean-field theory which reveals that the chain motif acts as a retarded feedback of the ensemble-mean activity through the response kernel, producing a rich repertoire of dynamical regimes, including ferromagnetic states and limit cycles. At sufficiently large magnitude, negative chain correlations produce a glassy, multistable regime that was previously mainly associated with partially symmetric networks. Our theory also distinguishes convergent from divergent motifs: divergent correlations primarily rescale temporal noise, while convergent correlations suppress temporal chaos by converting nonzero mean activity into quenched heterogeneity. Finally, analyses of the Lyapunov spectrum and participation-ratio dimension show that motif structure changes the geometry of chaotic activity, reducing entropy production and attractor dimensionality even when the effective spectral edge is held fixed. Together, these findings establish second-order motifs as a fundamental structural mechanism governing the dynamical regimes of local cortical circuits.

Physical Activity (PA) is consistently associated with lower risk of dementia, yet the mechanism linking PA to dementia prevention remain incomopletely understood. Here, we integrate large language model (LLM)-guided causal discovery with mediation analysis in 42,293 older adults aged 60 years or older from the UK Biobank to systematically identify pathways connecting objectively measured moderate-to-vigorous physical activity (MVPA) to dementia risk. Across behavioral, psychological, functional, and clinical domains, causal discovery consistently identified interconnected pathways linking higher MVPA to lower dementia risk through depression, functional capacity, smoking behavior, hypertension, cardiovascular disease, chronic kidney disease, and brain injury. Chain mediation analyses further identified depression as a central pathway, accounting for 15.1% of the overall association between MVPA and dementia risk. Sex-stratified analyses revealed distinct mechanistic patterns, with females exhibiting predominantly metabolic and functional pathways, while males showed behavioral and cardiometabolic cascades involving smoking and cardiovascular disease. Together, these findings suggest that the protective association between PA and dementia is mediated through interconnected behavioral, psychological, and cardiometabolic processes rather than a single pathway. Depression emerged as a prominent and potentially modifiable pathway, highlighting opportunities for integrating dementia prevention strategies that combine PA promotion with mental health and cardiovascular risk management.

Microstate analysis starts with clustering and the meta-criterion is a heuristic to find an optimum cluster number. We address the following questions: (i) what number is found for non-cluster-forming dynamical systems, (ii) do centroids fall in random attractor regions, (iii) do EEG topographies form clusters or a single connected structure in sensor space? We find that (i) the meta-criterion suggests spurious optimal cluster numbers (4-8) with high confidence on different attractor geometries, (ii) cluster centroids reliably fall in the same attractor regions, (iii) topological analysis of dynamical systems and resting-state EEG suggests that all form a single connected structure in their respective phase space, not clusters. We conclude that the meta-criterion should be used with caution and its results should not be taken as representing a ground truth. Cluster numbers deviating from the meta-criterion should not be discarded. A more far-reaching implication is that evidence for the existence of clusters in resting-state EEG data is still lacking. Microstate clustering may correspond to the partitioning of a single connected structure.

Single-cell foundation models (scFMs) are transforming computational biology by enabling generalizable, task-agnostic representations for versatile single-cell analysis. Despite their progress in facilitating rapid deployment for downstream tasks, off-the-shelf scFMs still have some overlooked concerns: (I) (Pretraining Cost.) Pretrain-based scFMs necessitate pretraining on a vast volume of cells, rendering it draining resources in applications. (II) (Heterogeneous Gap.) Large Language Models (LLM)-based scFMs ignore the tremendous heterogeneous gap between LLM textual and raw cellular spaces, leading to insufficient capability when facing downstream tasks. To this end, we introduce RAGCell, a versatile single-cell analysis framework that achieves a double-win in both cost-effectiveness and high performance. The success of RAGCell lies in two key aspects: Leveraging LLMs to construct cell-level and feature-level knowledge databases, which serve as supervision signals for training the cell model and significantly reduce the training cost ($>$pretrain-based scFMs). Aligning cell representations with text embeddings from the bi-level knowledge databases, enabling knowledge transfer from textual spaces to cellular spaces and effectively mitigating the heterogeneous gap ($>$LLM-based scFMs). Through extensive experiments on six downstream single-cell analysis tasks, we demonstrate that RAGCell achieves outstanding performance compared to state-of-the-art scFMs while operating at less than $\sim$1/10 the cost of pretrain-based scFMs.

Efferocytosis, the clearance of dying cells typically by macrophages, is essential for tissue homeostasis and the resolution of inflammation. Previous experiments by Ford et al. (Proc. R. Soc. B, 2019) showed that cannibalistic efferocytosis redistributes endogenous lipid from dying macrophages into the surviving population, but existing mathematical models do not reproduce the observed population dynamics and lipid distributions. Here, fifteen candidate models are compared, combining three mechanisms of apoptotic material uptake with five forms of the macrophage death rate. Model comparison is guided by the Akaike Information Criterion and qualitative agreement with the observed lipid distributions. Numerical solutions show that whole-cell uptake models predict internal maxima that are absent from the data, whereas nibbling uptake produces distributions that are too concentrated about their means. By contrast, intermediate "fragmented" uptake models provide substantially improved agreement when combined with either linear lipid-dependent or exponential time-dependent death rates. The fitted models predict that smaller fragments from dying cells are ingested at higher frequency than larger ones. This analysis provides new insight into how efferocytosis shapes the distribution of lipid within macrophage populations and highlights the importance of distribution-level data for distinguishing between mechanistic models that reproduce similar population-average dynamics.

The Interconnectedness Coefficient (IC) is a bounded semi-local graph-theoretic node measure designed to identify connector vertices between cohesive network regions. Such connector vertices, also referred to as bridging nodes, may mediate between locally cohesive regions even when they are neither hubs nor themselves highly clustered. The IC preferentially assigns high values to weakly clustered focal vertices whose adjacent vertices remain strongly clustered after exclusion of the focal connection. Candidate vertices are required to have degree at least two. The construction is partition-free, uses information within radius two, and requires no predefined community or module partition. The range and extremal properties of the score are derived analytically. Exact graph families isolate its maximal response to fully cohesive branches, its controlled response to a single cohesion defect, its invariance under a cohesion-free hub extension, and a sharp fragmentation threshold. A separate application to a Human Interactome Map reveals pronounced degree-dependent stabilization of IC values near the network's mean clustering level. This behavior follows directly from the multiplicative definition. If focal clustering tends to zero while mean leave-one-out cohesion in the neighborhood stabilizes, the IC converges to that neighborhood-cohesion level. Among the highly ranked IC vertices are proteins with established interface, scaffold, and adaptor roles in molecular complexes. The IC is therefore positioned as a semi-local connector measure for cohesive network regions.

The BabyLM challenge measures how much language a model can learn from developmentally-plausible, child-scale data rather than internet-scale corpora, yet prior language models forgo the biological constraints of the neural circuitry that acquires human language: spiking neurons separated into excitatory and inhibitory populations wired by a recurrent lateral connectome. This paper presents URCHIN (Unified Recurrent Connectome with Horizontal Integrate-and-fire Neurons), which applies the Parallelized Hierarchical Connectome Spiking State-space Model (PHCSSM) to language modeling: leaky integrate-and-fire neurons coupled by a Dale's-law lateral connectome resolve each token through a multi-transmission loop that recirculates activity to a fixed point. The instantiation is deliberately minimal: a single horizontal layer of 128 neurons, no attention, and 4.23M parameters. Two implementations share one set of weights and produce identical benchmark scores, so URCHIN is trained once and deployed either way with no conversion step: a parallel state-space model (SSM) scan that is GPU-efficient for training, or an event-driven recurrent spiking neural network (RSNN) with constant-cost inference for CPU or neuromorphic edge deployment. Across all three BabyLM tracks (Strict-100M, Strict-Small, and Multilingual), URCHIN offers a biologically plausible, efficient, and directly deployable reference point.

How can a neural circuit rhythmically burst when none of its constituent neurons can endogenously do so? We address this question through a bottom-up reconstruction of a 4-cell neural circuit modeled after the swim central pattern generator (CPG) of the sea slug Dendronotus iris. We first map the intrinsic regimes of a swim interneuron (SiN) model neuron and show that slow mutual inhibition can generate anti-phase bursting in a half-center oscillator (HCO) assembled from tonic-spiking or quiescent cells. A slow–fast phase-space deconstruction explains this pairwise rhythm as a release mechanism. We then move on to CPG parametrization, in which cells 1 and 2 are quiescent, while cells 3 and 4 are tonic spikers but their isolated HCO can only exhibit tonic spiking or suppression. Bursting therefore does not arise at either the cellular or HCO level. It appears only after the two modules are assembled into the complete 4-cell network, where cross excitation, cross inhibition, and rectified electrical coupling act together to support a robust network rhythm-generation. Event-based symbolic encoding and GPU-parallel parameter sweeps show that this higher-order collective state occupies extended parameter domains rather than a single tuned point, and they quantify how the network interactions reshape those domains and the spike counts per burst. Symbolic sweeps identify the healthy range of activity regimes (periodic sequences) and transition boundaries; Lempel–Ziv complexity is used as a descriptor of aperiodic symbolic output rather than as proof of chaos or dynamical instability. Our results establish a hierarchy of rhythm generation—from intrinsic cell dynamics, through conditional HCO bursting, to bursting that emerges only in the fully assembled 4-cell CPG—and provide experimentally accessible predictions for perturbing its chemical and electrical couplings.

The basic reproduction number $R_0$ is the central dimensionless quantity in mathematical epidemiology, characterizing the threshold for disease outbreak and the early growth rate of an epidemic. The algebraic form of $R_0$ varies widely across models of distinct transmission mechanisms, and its interpretation can yield further biological insight into transmission dynamics and disease intervention. We present a structural taxonomy of $R_0$ for compartmental ordinary differential equation models spanning a range of disease transmission features, including staged progression, differential infectivity, competing strains, vector-borne transmission, sexually transmitted infection, recurrent infection, maternal transmission, and gene drive inheritance. For each structural class, we provide a worked example, deriving $R_0$ via the next-generation matrix approach and interpreting the resulting algebraic expression in terms of the underlying transmission pathway. By unifying disparate derivations under a single structural framework, we clarify when and why particular algebraic forms of $R_0$ arise. This review serves both as a research synthesis and as a self-contained pedagogical reference for students and researchers entering the field.

Purpose: To develop and validate a deep learning-based method for the automated identification and volumetric segmentation of microaneurysms (MAs) in diabetic retinopathy (DR) using OCT. Participants: A total of 125 participants were enrolled, including 20 healthy eyes, 27 with mild NPDR, 30 with moderate NPDR, 30 with severe NPDR, and 18 with PDR. Methods: We obtained multiple repeated 3x3-mm scans from each participant using a commercial 120-kHz spectral-domain OCT system (Solix; Visionix/Optovue, Inc., California, USA), which were registered and averaged to generate high-definition volumes. We developed a 3D deep learning network to segment MAs volumetrically. The input to the network consists of the original OCT volume concatenated with its reflectance-inverted counterpart. Expert graders manually delineated MAs to generate annotations. We evaluated model performance at multiple levels, including voxel-level segmentation, lesion-level detection, and eye-level diagnosis. Results: In the test dataset (20 healthy, 20 DR eyes), the algorithm demonstrated high voxel-level accuracy, with F1 scores of 79.2% on single volumes and 86.1% on averaged volumes. Lesion-level detection reached an F1 score of 96.0% (single) and 97.1% (averaged), while scan-level diagnostic accuracy for MA presence was 97.5% (single and averaged). Conclusions: A deep learning-based method can accurately identify and segment MAs volumetrically on OCT, enabling quantification and characterization, and potentially aiding in the diagnosis, monitoring, and management of DR.

Brain-computer interfaces (BCIs) decode neural activity to restore lost function. Typically, training a high-performance neural decoder requires a large labeled dataset to be collected from every new subject. One way to reduce the labeled data cost is self-supervised pretraining, which learns general neural representations from unlabeled recordings that accumulate across subjects. However, for intracranial electroencephalography (iEEG) recordings, self-supervised learning has been challenging due to differences in contact placement and neuroanatomy between subjects. We propose MAPA, an otherwise vanilla masked autoencoder with two spatial encodings, an anatomical region embedding and a relative positional encoding, which together enable it to learn neural representations that transfer to unseen subjects and across various tasks. MAPA sets a new state of the art across all three regimes of the Neuroprobe benchmark without fine-tuning: within-session, cross-session, and cross-subject. In the cross-subject regime, a linear probe on MAPA's features needs only ${\sim}164$ labeled trials to reach the accuracy that takes 3,500 without pretraining. Our results show that self-supervised pretraining can scale across heterogeneous iEEG recordings and reduce the labeled data needed for accurate decoding in new subjects.

Scientific research is a continuous process that emphasizes inheritance. Methods developed by predecessors are often expanded upon by new researchers to explore more novel and in-depth scientific questions. However, the change of lab staff, such as student graduation, leads to a lack of personnel capable of replicating methods. Methods that have been developed with significant effort and resources cannot be continued. To address these limitations, we propose LabAgent, a reproduce and discovery harness tailored for a lab's continuous work. LabAgent employs two mechanisms to guarantee that all skills can be executed and verified and to record the corrective methods and experiences, allowing for direct correction or avoidance of similar errors. We applied LabAgent to drug property prediction, biomedical problem analysis, protein variant effect prediction, and statistical genetics in life science domains. LabAgent ranks first over commercial generalist agents in every domain, and demonstrates accurate reproduction of a published figure. Overall, these results demonstrate that LabAgent can effectively integrate and reasonably expand laboratory knowledge.

In this paper, we study a stochastic Susceptible-Infected-Removed (SIR) model where the infection and the recovery rates depend on individual covariates for susceptibility and infectiousness of the infector and the infectee. Such models allow explicit nonlinearity in the incidence term. They are also important from a practical perspective, as they allow for the incorporation of individual heterogeneity into the epidemic process. Statistical estimates for crucial epidemiological parameters, such as the basic reproduction number, herd immunity threshold, could be vastly different, and even biased, when the population heterogeneity is ignored in the mathematical model. We describe our epidemic model as an Interacting Particle System (IPS) of Stochastic Differential Equations (SDEs) driven by Poisson Random Measures. Our main mathematical contributions are a Functional Law of Large Numbers (FLLN), which approximates the empirical random measure of the IPS by means of a deterministic measure-valued function, and the propagation of chaos phenomenon, which establishes asymptotic independence of the particles as the population size goes to infinity with an explicit construction of McKean–Vlasov type Kac's “nonlinear process”. We also briefly mention how the propagation of chaos phenomenon leads to a product-form likelihood function, which forms the basis of the so-called Dynamic Survival Analysis (DSA) method for parameter inference based on sparse data.

We study the evolution of sexually reproducing populations subjected to sudden environmental changes. Using an individual based model we consider scenarios where abrupt changes can affect the carrying capacity, the mating range or the strength of assortativity, that controls the minimum similarity between individuals that allows mating to occur. We show that a boost in carrying capacity can either lead to new speciation events, thereby increasing biodiversity, or to widespread extinctions, causing the system to become dominated by a single species. A similar effect is observed with respect to the mating range. We show that the key factor determining the outcome of the process is genome length, i.e., the number of genes controlling reproduction and assortativity. We also show that when mating becomes more restrictive, increasing the degree of assortativity, a burst of speciation occurs. The explosion lasts only for a few generations, converging to values larger than before the change, but not as high as at the peak.

We introduce GrassTop, a genome representation that integrates Grassmann manifolds and algebraic topology for viral classification and phylogenetic analysis. The framework begins by constructing multiscale topological and spectral descriptors of (k)-mer positional patterns. It then extracts a low-rank subspace that summarizes variation across the filtration and compares genomes using a Grassmannian distance. Although the reported implementation uses the chordal distance, the framework is not restricted to this particular choice. We evaluate GrassTop on four families of viral classification datasets, four phylogenetic clustering datasets, and a sequence perturbation experiment. Under the reported 5-nearest-neighbor protocol, GrassTop achieves higher scores than five published alignment-free reference methods across all reported classification metrics and datasets. Its UPGMA (unweighted pair-group method using arithmetic averages) trees achieve an average label purity of 1.0 on every phylogenetic dataset. The perturbation experiment provides a more nuanced result: the subspace representation differs most clearly from direct comparison of the unprojected feature matrices for SARS-CoV-2, whereas the differences are smaller or non-monotonic for the other datasets. Overall, these results support GrassTop as an effective topological-geometric representation for viral classification and phylogenetic analysis.

Clustering systems provide a natural way to encode structural information contained in phylogenetic networks. In this note, we study the clustering systems of normal and tree-child networks through an overlap-based property of set systems, called not-overlap-covered (NOC). We show that the NOC property is equivalent to inclusion-visibility, a memberwise formulation of the strict-compatibility condition previously used for tree-child clustering systems. We characterize normal networks as precisely the semi-regular networks whose clustering systems satisfy NOC. Consequently, a clustering system is realized by a normal network if and only if it satisfies NOC, or equivalently, if every one of its clusters is inclusion-visible. In this case, the Hasse diagram provides a canonical normal realization. These are exactly the clustering systems realized by tree-child networks. The NOC formulation yields a sharp quadratic upper bound on the number of distinct clusters of tree-child and normal networks and a direct polynomial-time recognition algorithm. Finally, we explore several consequences of the NOC perspective beyond the phylogenetic setting. These include connections to the enumeration of normal networks, an order-theoretic interpretation of inclusion-visibility, structural properties of NOC set systems, and a tractable special case of Minimum Set Cover, which is NP-hard in general.

Statistical models of ecological and evolutionary dynamics often include latent variables that are either continuous (e.g., average body size) or discrete (e.g., numerical abundance). Mixed-type hierarchical models containing both are typically fitted using Markov chain Monte Carlo (MCMC), which can be prohibitively slow for large models. Here, we introduce an alternative in the R package RTMB that automates the sequential reduction of small groups of related discrete variables, allowing them to be efficiently marginalized. Sequential reduction is combined with automatic differentiation and the Laplace approximation to estimate parameters and predict both continuous and discrete variables. We demonstrate speed and flexibility using demographic examples (occupancy, dynamic occupancy, N-mixture, and open dynamic N-mixture models), benchmarking RTMB against JAGS and unmarked. We then develop two novel applications. The first is a multi-site open N-mixture model with a spatial latent variable governing site-specific initial abundance and recruitment, which shows that continuous Gaussian Markov random fields can be estimated jointly with discrete abundance dynamics in under a minute. The second is phylogenetic trait imputation for a published data set of female Liolaemus lizards, where we jointly impute a binary trait (viviparity), estimate its state-switching rates, and estimate its effect on a continuous trait (body size) during ancestral state reconstruction. This indicates that phylogenetic comparative methods can estimate linkages among discrete and continuous traits. We envision that intuitive and efficient specification of mixed-type models will allow more expressive representation of ecological and evolutionary dynamics.

Computational models supporting mechanistic understanding of (complex) biological systems, systems behaviour prediction, and experimental design are becoming more and more embedded in research on complex biological systems. Reuse and refinement of models, rather than continuous reinvention, is becoming increasingly important as models' demands on computational infrastructure increase. However published models - despite the variety of efforts taken so far - are frequently difficult to reproduce or reuse, substantially limiting their scientific value. Here we address the requirements for model reusability in the light of the field-specific CURE framework (Credible, Understandable, Reproducible, Extensible) and the more general FAIR principles (Findable, Accessible, Interoperable, Reusable). Considering published guidance we identify broad agreement on requirements for findability, accessibility, and interoperability, but continued lack of clarity and consensus around reusability. Focusing on the scientific quality and usability of computational models we discuss six key practices underpinning model sharing and re-use. Mapping the FAIR and CURE principles onto the model lifecycle we propose ten recommendations for building and sharing systems biology models that are both FAIR- and CURE-compliant.