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Ventrolateral prefrontal-amygdala repetitive transcranial magnetic stimulation (rTMS) modulation of impulsivity in borderline personality disorder: a proof-of-concept study
That author's affiliation: California Institute of Technology First author institution: California Institute of Technology Last author institution: West Los Angeles College
Ventrolateral prefrontal-amygdala repetitive transcranial magnetic stimulation (rTMS) modulation of impulsivity in borderline personality disorder: a proof-of-concept study
Depression detection from multimodalities based on LeNet with hunter-geese optimization
Depression detection from multimodalities based on LeNet with hunter-geese optimization
Stage-dependent role of NEK7 in the inactive-to-active conformational transition of NLRP3 monomer
by Jin Peng, Wenjian Li, Hao Wang, Xiaohui Chen, Manjie Zhang, Bin Sun
The NLRP3 inflammasome is a multiprotein complex that primes cytokine production in the innate immune system. The inflammasome activation involves the cage-to-disk transition of NLRP3 oligomers, facilitated by the co-factor NEK7 protein. While NEK7’s role in promoting cage disassembly has been reported, its involvement in the large conformational changes of the NLRP3 monomer during activation remains elusive. Here, by using multi-scale simulations, we uncovered a stage-dependent role of NEK7 in the inactive-to-active transition. In the early stage, NEK7 reshapes the dynamics of the highly unstable inactive NLRP3 monomer to resemble active state, priming the conformational transition. In the middle stage, NEK7 impedes progression by populating an intermediate state farther from the active conformation than the NEK7-free counterpart, and structures in this state exhibit reduced allosteric potential toward activation. In the late stage, NEK7 has negligible impact, as the active conformation remains inherently isolated by a high energy barrier regardless of NEK7 presence. This highlights the critical role of oligomeric assembly in enabling monomeric NLRP3 to complete its conformational transition, in agreement with experiment observations. Our work suggests a multilayered activation mechanism where oligomer-level assembly and monomeric conformational changes are coupled, providing new mechanistic insights into this physiologically essential macromolecular process.A new method for augmenting short time series, with application to pain events in sickle cell disease
by Kumar Utkarsh, Nirmish R. Shah, Tanvi Banerjee, Daniel M. Abrams
Researchers across different fields, including but not limited to ecology, biology, and healthcare, often face the challenge of sparse data. Such sparsity can lead to uncertainties, estimation difficulties, and potential biases in modeling. Here we introduce a novel data augmentation method that combines multiple sparse time series datasets when they share similar statistical properties, thereby improving parameter estimation and model selection reliability. We demonstrate the effectiveness of this approach through validation studies comparing Hawkes and Poisson processes, followed by application to subjective pain dynamics in patients with sickle cell disease (SCD), a condition affecting millions worldwide, particularly those of African, Mediterranean, Middle Eastern, and Indian descent.Ten simple rules for executing an inherited research plan in computational biology
by Sahar Javaheri Tehrani, Toni Ingolf Gossmann
Trainees in computational biology frequently inherit research plans whose aims, datasets, analytical strategies, and technical constraints were defined before their arrival. These plans often emerge from grants, collaborations, legacy codebases, shared high-performance computing environments, or partially completed analyses. While such plans provide a useful scaffold, they rarely specify all implementation details, prior assumptions, evaluation criteria, or dependencies needed for reliable execution. The transition from inheriting a partially articulated plan to producing reproducible results therefore creates an execution gap: a phase in which trainees must reconstruct what the project is, which elements are fixed, which remain negotiable, and which technical or organizational assumptions need to be tested before full-scale analysis begins. In this Ten Simple Rules article, we provide a practice-oriented framework for stabilizing inherited computational biology projects before workflows, benchmarks, and decision paths become entrenched. We do not claim that the individual practices described here are novel in isolation. Rather, our contribution is to organize familiar practices into a sequenced framework for a recurrent but under-articulated phase of computational research: inherited-plan execution. Computational biology makes this phase especially important because projects often combine heterogeneous datasets, fragile software environments, undocumented preprocessing choices, benchmarking assumptions, distributed collaborators, and asymmetrical access to contextual knowledge. By making this transition visible and operational, the rules aim to help trainees, supervisors, and collaborators reduce ambiguity, test feasibility, document decisions, and support reproducible and equitable project execution under real-world constraints.DRP1 and MID49 co-diffusion scans mitochondria for fission
That author's affiliation: Goethe University Frankfurt First author institution: University of Cologne Last author institution: Goethe University Frankfurt
Zollo et al. examine DRP1 behaviour at mitochondria: DRP1 diffuses along mitochondria in helical-like patterns influenced by MID49/MID51, scanning the organelle surface and stalling at preconstricted fission sites.
Proteomics-based insights into mammalian oocyte and early embryo development
This Perspective highlights the use of current proteomics technologies in defining stage-specific reprogramming events to understand reproductive ageing, improve oocyte quality, and refine the outcomes of assisted reproductive technology (ART).
Interpreting higher-order dependence in multimorbidity using cohort data: A partial information decomposition approach
by Cillian Hourican, Geeske Peeters, René J. F. Melis, Almar Kok, Natasja M. van Schoor, Sandra Wezeman, Mike Lees, Marcel G. M. Olde Rikkert, Rick Quax
In the context of multimorbidity, clinical features seldom act in isolation: symptoms, signs and behaviours form interdependent systems in which joint effects on function can be demonstrated only when features are considered together. We introduce an open, reusable workflow that detects and interprets these “together-only” interactions using bivariate Partial Information Decomposition (PID; two sources to one target), linking synergy-based dependence to the broader network of clinical variables rather than to a single target. The workflow estimates synergy with small-sample bias correction and summarises each pair in a Breadth–Uniformity–Synergy–Total (BUST) map: breadth of synergy across target variables (broad “generalist” vs narrow “specialist” patterns), cross-stratum uniformity across age, sex and multimorbidity (uniform vs subgroup-specific), synergy strength, and total shared information. Simple diagnostics contrast observed targets with additive expectations, revealing the specific joint configurations through which non-additive effects arise. Applied to data from the Longitudinal Ageing Study Amsterdam, we treated all health-related variables—covering symptoms, clinical signs, behaviours, lifestyle factors, and self-rated health indicators—as both sources and targets in the PID framework. This symmetric design permits synergy to be quantified for every pair of variables with respect to every other variable. The workflow identifies synergistic constellations that additive models miss. Multidomain cliques involving subjective health, pain, cognition and grip strength showed multiple non-additive configurations, whereas pairs such as alcohol use with grip strength exhibited focused, narrow but uniform synergy. Notably, the pairs with the strongest synergistic contributions were largely distinct from those with the highest total mutual information, indicating that synergy captures dependency structure overlooked by conventional association measures. Rather than a new measure, this work provides a bias-aware workflow that makes higher-order dependence visible and transferable. Our results support synergy-aware mapping as a practical complement to conventional multimorbidity analyses: it highlights specific combinations of routinely assessed features whose joint states may be especially informative across multiple health targets and therefore candidates for prioritised joint assessment and future multi-domain intervention studies.A mean-field model of neural networks with PV and SOM interneurons reveals connectivity-based mechanisms of gamma oscillations
by Farzin Tahvili, Martin Vinck, Matteo Di Volo
Classic theoretical models of cortical oscillations are based on the interactions between two populations of excitatory and inhibitory neurons. Nevertheless, experimental studies and network simulations suggest that interneuron subclasses such as parvalbumin (PV) and somatostatin (SOM) exert distinct control over oscillatory dynamics. Yet, we lack a theoretical understanding of the mechanisms underlying oscillations in E-PV-SOM circuits and of the differences with respect to the classical mechanisms for oscillations in simpler E–I networks. Here, we derive a biologically realistic mean-field model of a canonical three-population E-PV-SOM circuit. This model robustly generates oscillations whose features are consistent with experimental observations, including the relative timing of PV and SOM activity and the effects of optogenetic perturbations. By reducing the model to a linear analytical form, we demonstrate that gamma oscillations emerge directly from the cell-specific connectivity of the three-population circuit. This connectivity motif alone accounts for experimentally observed phase relationships, with PV activity consistently leading that of SOM neurons. Together, this mean field model identifies a distinct structural mechanism giving rise to oscillations in canonical E–PV–SOM circuits and provides theoretical primitives for constructing large-scale, cell-type-specific models of cortical dynamics.Long-range mutual activation establishes Rho and Rac polarity during cell migration
De Belly et al. show Rac induces membrane-tension-mediated mTORC2 activation to stimulate long-range Rho activation. Meanwhile, Rho-mediated contractility and blebbing at the opposite side of the cell may lead to PI3K-dependent Rac activation.
Machine learning–enabled ECG arrhythmia classification: a systematic and educational study from signal processing to decision support
Machine learning–enabled ECG arrhythmia classification: a systematic and educational study from signal processing to decision support
Collagen IV outperforms alternative ECM coatings to preserve human neural progenitor properties on electrically conductive neural interfaces
Collagen IV outperforms alternative ECM coatings to preserve human neural progenitor properties on electrically conductive neural interfaces
Statistics of cortical representational drift can enable robust readout
That author's affiliation: University of Cambridge
Institution (first & last author): University of Cambridge
by Charles Micou, Timothy O’Leary
Representational drift of fixed stimuli, learned tasks and familiar environments is observed in many brain areas, leading to reconfiguration of population codes over days to weeks. This raises the question of whether downstream brain regions employ mechanisms to track changes in population activity and thus preserve the fidelity of the information they extract. We show that the statistical properties of drift have a significant impact on such mechanisms. Over an extended period, a net change in population tuning due to drift can arise from an accumulation of small changes distributed across the population, or via abrupt jumps that affect smaller subsets of cells at each time point. We demonstrate that an adaptive readout can exploit the heavy-tailed statistics of abrupt jumps to maintain a more stable readout using a simple inference mechanism. Using experimental data, we investigate the extent to which heavy-tailed drift statistics are observed during representational drift in the posterior parietal cortex and visual cortex. We find that experimentally measured drift does not conform to a Gaussian random walk. Instead, we find sudden jumps in neural tuning that would be advantageous for a downstream observer adapting to changes in representation. These observations motivate future study to determine whether adaptive decoding mechanisms exist in the brain and to determine the physiological mechanisms that shape the statistics of representational drift.SSDLabeler: realistic semi-synthetic data generation for multi-label artifact classification in EEG
SSDLabeler: realistic semi-synthetic data generation for multi-label artifact classification in EEG
Knowledge distillation for named entity recognition in traditional chinese medicine
Knowledge distillation for named entity recognition in traditional chinese medicine
Predictive modeling in biology and medicine: Digital twins and multi-scale modeling
by Mark Alber, Amber Smith, Reinhard Laubenbacher, Roeland M. H. Merks
Federated MobileNetV2 with ensemble meta-learning for privacy-preserving brain tumor classification
Federated MobileNetV2 with ensemble meta-learning for privacy-preserving brain tumor classification
PepAnno: A structure-aware deep learning framework for bioactive peptide prediction, structural visualization, and physicochemical profiling
by Enyan Liu, Yueming Hu, Liya Liu, Yifan Chen, Shilong Zhang, Sida Li, Haoyu Chao, Luyao Xie, Yi Shen, Liangwei Wu, Julio Raúl Fernández Massó, Ming Chen
Peptides are gaining prominence as therapeutic candidates due to their diverse physiological functions and structural simplicity. Although multiple computational tools exist for bioactive peptide prediction, many suffer from limitations such as non-intuitive interfaces, sequence-only representations, insufficient structural awareness, restricted interpretability, or fragmented analysis workflows, leading to reduced research efficiency and higher costs. To address these challenges, we present PepAnno (https://bis.zju.edu.cn/pepanno/), a comprehensive and user-friendly web server for multi-functional peptide annotation. PepAnno is powered by a novel structure-aware, multi-view geometric deep learning framework that integrates pre-trained sequence embeddings with predicted 3D structural graphs through a dual-stream architecture combining a Transformer and a GATv2 network. A cross-modal attention mechanism is employed to effectively fuse semantic and geometric representations, enabling accurate multi-task prediction across 7 key bioactivities, including antimicrobial and anticancer properties. Comprehensive evaluation on seven curated bioactivity datasets demonstrates that PepAnno achieves robust and competitive predictive performance across tasks, consistently outperforming or matching existing methods in terms of discrimination and stability. Beyond functional prediction, PepAnno provides automated calculation of physicochemical properties, structure visualization, and access to an integrated repository of peptide-related databases and tools. By enabling one-click peptide annotation, PepAnno offers an efficient and interpretable solution for large-scale peptide analysis and facilitates downstream experimental design and peptide-based drug discovery.A comparative study of simulation-based inference methods for epidemic models with identifiability considerations
by Geunsoo Jang, K. Selçuk Candan, Gerardo Chowell
Epidemic models play a critical role in understanding transmission dynamics, generating forecasts, and informing public health interventions when they are properly calibrated to epidemiological data. Traditional Bayesian inference methods rely on the likelihood function to update prior knowledge using observed data. However, for realistic epidemic models, likelihood functions are often analytically intractable or computationally prohibitive, which can limit the applicability of these methods. Simulation-based inference provides a promising alternative by approximating posterior distributions through forward simulations rather than an explicit likelihood evaluation. In this study, we present a systematic comparison of four approaches: Approximate Bayesian Computation (ABC), Neural Posterior Estimation (NPE), a neural method with temporal embedding, and Preconditioned Neural Posterior Estimation (PNPE), which integrates elements of both classical and neural techniques. These methods are evaluated across epidemic models of increasing complexity under fixed simulation budgets and varying levels of observational noise, with explicit attention to both structural and practical identifiability. Our results show that neural methods generally improve posterior fidelity and predictive accuracy compared with ABC under constrained simulation budgets. PNPE achieved strong performance in several simulation settings, whereas temporal embeddings improved inference in models with complex epidemic dynamics by capturing sequential dependencies. These gains come with important trade-offs: PNPE required substantially greater computational resources and, unlike fully amortized NPE-based methods, may require reconditioning for each new observation. In contrast, ABC remained computationally efficient and provided reasonable, though often more conservative, posterior estimates. Overall, our findings highlight trade-offs among computational efficiency, posterior accuracy, uncertainty calibration, and inference reusability, suggesting that method selection should depend on model complexity, data quality, identifiability, and available computational resources.Data-driven model reveals increased stability of CAG-expanded <i>huntingtin</i> RNA due to MID1 binding
That author's affiliation: Life & Brain (Germany)
First author institution: Life & Brain (Germany)
Last author institution: University of Bonn
by Yuhong Liu, Annika Reisbitzer, Domagoj Dorešić, Jan Hasenauer, Sybille Krauß, Tatjana Tchumatchenko
RNA-binding proteins (RBP) are important regulators of RNA metabolism. In neurodegenerative disorders such as Huntington’s Disease (HD), disrupted RBP-RNA interactions contribute to neuronal dysfunction. One such RBP, Midline 1 (MID1), has been shown to aberrantly associate with mutant huntingtin (Htt) RNA, enhancing its translation, yet the mechanism driving this effect remains unknown. Here, we develop a computational model to understand the role of MID1. Based on previously published data, our model predicts that MID1 increases the stability of the Htt RNA. We experimentally validate this prediction, showing that overexpression of MID1 significantly prolongs the half-life of mutant Htt RNA. Furthermore, we evaluate model refinements, including clustering of MID1-bound RNA, which allow capturing all key observations in the data. Together, we provide a data-driven framework that underlines the importance of RBP-RNA interaction in post-transcriptional regulation. This framework also shows how individual molecular reactions jointly determine RNA stability and protein levels in HD.Assessing the importance of sex and disease-specific anatomy in electrophysiology and mechanical simulations with a newly developed public virtual cohort of four-chamber heart models
by José Alonso Solís-Lemus, Rosie K. Barrows, Cristobal Rodero, Marina Strocchi, Natalie Montarello, Nishant Lahoti, Cesare Corrado, Abdul Qayyum, Shahrokh Rahmani, Caroline Roney, Gernot Plank, Christoph Augustin, Hao Xu, Alistair Young, Pras Pathmanathan, Ronak Rajani, Steven A. Niederer
This work presents a study on how differences in cardiac anatomy attributed to sex and disease can influence cardiac electrophysiology and mechanics using a virtual cohort of four-chamber heart models. Patient anatomy varies across sex and disease. However, capturing this variation in in-silico studies remains poorly accounted for, with studies often using either single representative cases or imbalanced virtual cohorts. Whole-heart electromechanics models incorporate the patient’s anatomy, electrophysiology and mechanics across different scales, from molecular, tissue and whole-heart and circulatory system levels. However, cardiac models are typically built from one or a small number of anatomies, with sex rarely reported and the effects of anatomical variability, which include those due to sex or disease, largely unexplored. This limits clinical translation and reduces regulatory credibility. We developed fifty patient-specific anatomical models of 25 male and 25 female hearts in heart failure and control cases. We ran benchmark passive inflation and paced activation simulations with consistent parameters and boundary conditions across cases to isolate the impact of anatomical variations with sex and disease. Heart failure models exhibited increased chamber volumes, larger volume changes during inflation, and delayed activation times relative to controls. These trends were consistent across sexes, although right ventricular activation showed a significant sex-based difference. Variations in anatomy with sex and disease have a significant impact on cardiac simulations, which support the inclusion of multiple heart anatomical models in in-silico trials. The resulting virtual cohort captures key anatomical variability and is publicly available, along with the underlying code (see Data Availability statement).Linking reduced prefrontal microcircuit inhibition in schizophrenia to EEG biomarkers in silico
That author's affiliation: Centre for Addiction and Mental Health
Institution (first & last author): Centre for Addiction and Mental Health
by Sana Rosanally, Frank Mazza, Heng Kang Yao, Faraz Moghbel, Hannah Seo, Etay Hay
Reduced cortical inhibition by parvalbumin-expressing (PV) interneurons in schizophrenia is thought to be associated with impaired processing in the prefrontal cortex and altered EEG signals such as oddball mismatch negativity (MMN). Recent studies also suggest loss of somatostatin (SST) interneuron inhibition. However, establishing the link between reduced interneuron inhibition and reduced MMN experimentally in humans is currently not possible. To overcome these challenges, we simulated spiking activity and EEG during baseline and oddball response in detailed models of human prefrontal microcircuits in health and schizophrenia, with reduced PV and SST interneuron inhibition as constrained by postmortem patient data. We showed that reduced PV interneuron inhibition can account for the decreased MMN amplitude seen in schizophrenia, with a threshold below which the amplitude effect was low as seen in at-risk patients. In contrast, reduced SST interneuron inhibition did not affect the MMN amplitude. We further showed that both types of inhibition loss were necessary to account for changes in resting EEG in schizophrenia, with reduced SST interneuron inhibition increasing broadband power, and reduced PV and SST interneuron inhibition both leading to a right shift from alpha to beta frequencies. Our study thus links reduced PV and SST interneuron inhibition in schizophrenia to distinct EEG biomarkers that can serve to improve stratification and early detection using non-invasive brain signals.The nuclear shredder behind PARPi resistance
PARP inhibitors kill cancer cells by trapping poly(ADP-ribose) polymerase 1 (PARP1) on DNA. A study now shows that cancer cells use a specialized form of autophagy to extract and degrade trapped PARP1, limiting the efficacy of PARP-trapping drugs. Blocking this escape route can re-sensitize resistant tumours.
PromptSE: drug side effect prediction with LLM-derived pharmacological representations
PromptSE: drug side effect prediction with LLM-derived pharmacological representations
Comparison of endurance and electromyographic activity of core muscles in overhead athletes with and without scapular dyskinesis
Comparison of endurance and electromyographic activity of core muscles in overhead athletes with and without scapular dyskinesis
Accurate computation of ionic concentrations in the synaptic cleft requires the full Poisson–Nernst–Planck (PNP) equations
That author's affiliation: Simula Research Laboratory
Institution (first & last author): Simula Research Laboratory
by Karoline Horgmo Jæger, Aslak Tveito
The synaptic cleft between neighboring neurons is the site of neurotransmitter-mediated communication that underlies normal brain function, including learning and memory. When an action potential reaches the presynaptic terminal, released neurotransmitters cross the cleft under the combined influence of diffusion and electrical forces to activate postsynaptic receptors. Despite this, synaptic-cleft transport is commonly modeled using a pure diffusion model, neglecting electrical drift. Here, we quantify the relative contributions of diffusion and electrical terms in the Poisson–Nernst–Planck (PNP) framework and assess whether the pure diffusion approximation is adequate. We solve the full PNP system in a three-dimensional computational model of the synaptic cleft at nanometer-scale resolution, tracking five ionic species (Na+, K+, Ca2+, Cl−, Glu−) with full spatial and temporal detail. Solutions are compared directly with those of the pure diffusion (D) model. The D and PNP models produce markedly different ionic concentration fields. Analysis of ionic fluxes confirms that diffusive and electrical contributions are of comparable magnitude across all species. These discrepancies are robust across parameter variations, including the number of AMPA receptors, the amount of released glutamate, the cleft height, and the cleft diffusion coefficient, and are amplified as the number of AMPA receptors or released glutamate ions increases, when the cleft becomes narrower or when diffusion becomes more restricted. However, because of competing effects, the resulting difference in the associated AMPA current is modest. The quantitative and qualitative differences between the pure D model and the full PNP model demonstrate that neglecting electrical forces in the synaptic cleft has consequences. These discrepancies are large enough to alter the predicted dynamics and biological interpretation of synaptic transmission, establishing that accurate computation of ionic concentrations in the synaptic cleft requires the full PNP equations.UNified FramewOrk for reguLatory Dynamics (UNFOLD): Dissecting robustness, plasticity, evolvability and canalisation of biological function
by Debomita Chakraborty, Raghunathan Rengaswamy, Karthik Raman
A unique balance of seemingly contradictory properties like robustness and plasticity, or evolvability and functional canalisation, characterises biological systems. To understand the basis of these properties, we investigate gene regulation, which is at the core of biological function. We simulate dynamical models of over 190 million genetic circuits covering all possible three-gene circuit structures. Our computational pipeline classifies these circuits into functional clusters by matching their temporal response shapes. Thus, we generate a dataset linking circuit structure, parameters and a corresponding functional label. Our key finding is a finite list of 20 functions that three-node genetic circuits can perform under step input and within the explored parameter space. Moreover, the structure-parameter space for these circuits tends to be primed for responses that stabilise over time following a perturbation. Every structure exhibits potential for multifunctionality with a range of 2–17 functions contingent upon parameters. We quantify network degeneracy, showing that many structural changes can be made to circuits without altering function. We define three quantities: structural, parametric, and functional diversities. Using these diversities, we construct a UNified FramewOrk for reguLatory Dynamics (UNFOLD) to analyse four key biological properties—robustness, plasticity, evolvability, and functional canalisation. Using UNFOLD, and within the explored parameter space, we identify that only 6.5% of network structures are non-plastic, while parameter sets enabling parametric robustness exist for every three-node network. We identify functionally canalised circuits from structure pairs that can be interchanged for a large number of parameter sets without a change in function. Overall, our framework offers insights into the fundamental organisation of biological networks by thorough analysis of three-node networks.Hierarchical recurrent temporal prediction as a model of the mammalian dorsal visual pathway
by Sebastian Klavinskis-Whiting, Andrew J. King, Nicol S. Harper
A major goal of neuroscience is to identify general principles that can explain the diverse structures and functions of the brain. The principle of temporal prediction provides one approach, arguing that the sensory brain is optimized to represent stimulus features that efficiently predict the immediate future input. Previous work has demonstrated that feedforward hierarchical temporal prediction models can capture the tuning properties of neurons along the visual pathway, and that recurrent temporal prediction models can explain local functional connectivity within primary visual cortex. However, the visual system is also characterized by extensive inter-areal feedback recurrency, which existing models lack. We aimed to better account for the dynamic features of neurons in the visual cortex by incorporating both local recurrency and inter-areal feedback connectivity into a hierarchical temporal prediction model. The resulting model captured tuning properties along the dorsal visual pathway, including pattern motion selectivity and surround suppression, and the contribution of inter-areal connectivity to these properties. Moreover, compared with several alternative normative models, the hierarchical recurrent temporal prediction model provided the closest fit to these tuning properties and was best able to explain neuronal responses to natural stimuli. Accordingly, temporal prediction accounts well for information processing along the visual pathway.Transcription-independent induction of rapid-onset senescence is integral to healing
That author's affiliation: WinnMed Institution (first & last author): Ludwig Boltzmann Gesellschaft
Valdivieso, Rozmaric et al. show that wounding rapidly induces a senescent state in skin cells involving p21 protein induction, without the need for new transcription. These senescent cells are beneficial to early stages of healing.
The interplay between ecological networks drives host-plasmid community dynamics
by Ying-Jie Wang, Kaitlin A. Schaal, Johannes Nauta, Armun Liaghat, Manlio De Domenico, James P. J. Hall, Shai Pilosof
Plasmids drive evolution by transferring traits across microbial hosts. Transmission depends on both host–plasmid (infection) and plasmid–plasmid (compatibility) interactions, yet how the structure of these networks shapes transmission remains poorly understood. We hypothesized that these two ecological networks interact in non-additive ways to influence community outcomes. To test this, we developed a stochastic agent-based model that embeds both network structures and simulates coupled host–plasmid dynamics. We systematically varied the structure of each network, both individually and in combination, to isolate the effect of structure on host-plasmid dynamics. A modular (interactions organized into clusters) and hub (interactions concentrated on the highly connected) plasmid-plasmid compatibility network promoted transient host coexistence, while a modular host-plasmid infection network promoted plasmid diversity and stable host coexistence. Importantly, structured networks interacted non-additively, and their impact was most apparent when plasmid carriage imposed a moderate fitness cost on hosts. For example, combining a modular infection network with a hub compatibility network reversed the expected plasmid prevalence patterns, demonstrating that the structure of one network can counteract the effects of the other. We further re-parameterized our model to recapitulate empirical host-plasmid community dynamics, showing that infection network structure can strongly shape plasmid prevalence even in the presence of substantial biological heterogeneity. Our results highlight the necessity of jointly considering host–plasmid infection and plasmid–plasmid compatibility networks to understand host–plasmid community dynamics and their eco-evolutionary potential. More broadly, this work provides an initial mechanistic framework for generating testable hypotheses and underscores that systems involving multiple hosts and infectious agents require explicit consideration of how different ecological networks interact to shape community dynamics.Utilizing virus genomic surveillance to predict vaccine effectiveness
That author's affiliation: Yale University
Institution (first & last author): Yale University
by Jiye Kwon, Ke Li, Joshua L. Warren, Sameer Pandya, Anne M. Hahn, Yale SARS-CoV-2 Genomic Surveillance Initiative , Virginia E. Pitzer, Daniel M. Weinberger, Nathan D. Grubaugh
BackgroundSince the development of the first vaccines targeting the original SARS-CoV-2 virus sequence in 2020, mRNA-based vaccines have been updated three times: targeting Omicron BA.4/BA.5 in 2022, the XBB lineage in 2023, and the KP.2 variant in 2024. While genomic surveillance has advanced our understanding of pathogen diversity, gaps remain in incorporating genomic information to evaluate vaccine effectiveness (VE) against emerging variants. This study aims to characterize the relationship between VE and sequence-based genetic distance, to establish a framework for predicting near real-time changes in the level of vaccine protection from virus surveillance data.
MethodsWe analyzed 10,156 whole genome sequences of SARS-CoV-2 cases from Connecticut, USA, between April 2021 to July 2024. We first assessed how genetic distance, specifically the number of amino acid substitutions in the spike gene between COVID-19 case sequences and the mRNA vaccine formulation sequence(s), correlates with vaccine protection levels. Incorporating data from over 1 million test-negative controls, we developed a Bayesian time-varying model with autoregressive terms to assess VE at a weekly level. The analysis was adjusted for ZIP-code-level income, age, sex, and prior vaccine doses received. We then employed a random effects meta-regression to explore the relationship between VE and amino acid distance over time. Finally, we used the meta-regression model to estimate potential vaccine protection against emerging variants.
FindingsWe found that spike gene amino acid distance showed a negative correlation with VE over time. Stepwise increases in amino acid distance aligned with sharp VE declines during variant emergence, while accumulation of within-variant changes was also associated with gradual VE decline. Each 10 amino acid increase in distance in the spike gene corresponds to a predicted 15.4% (95% credible intervals (CrI): –2.0%, 34.6%) reduction in VE. For the 2023/24 updated vaccine, spike distance rose from 12.25 to 30.23, predicting a 43.4% (95% CrI: –5.7%, 90.1%) drop in VE using sequence information alone.
ConclusionOur framework quantifies how the emergence of new variants is expected to affect VE for SARS-CoV-2. By quantifying the relationship between amino acid substitutions and time-varying VE, we leverage intrinsic pathogen features, such as spike amino acid distance, to inform future vaccine updates using genomic sequences. As genomic surveillance data becomes more widely available across pathogens, this framework can serve as a near-real time surveillance tool to infer population-level protection and offers valuable insights for vaccine update decisions.
Multilabel prediction of virus target proteins via multimodal graph representation learning
by Kuang Ma, Kaiyu Liu, Yuhui Xin, Rong Liu
Identification of virus target proteins (VTPs) is crucial for understanding viral pathogenesis. Existing computational studies have addressed this issue by predicting host-virus protein interactions, typically framed as a single-label problem. However, targets can be identified using only intrinsic information of host proteins. Moreover, a host protein may participate in the infection processes of multiple viruses, a scenario that can be treated as a multilabel prediction problem. Herein, we present MultiVTP, a multilabel framework for VTP prediction that employs graph learning with multimodal information. This algorithm samples subgraphs centered on query proteins to capture topological properties, while multimodal features are extracted to represent proteins from complementary perspectives. A graph transformer integrates and upgrades these attributes, followed by a progressive layered extraction module that captures both shared and virus-specific binding patterns to predict VTPs. Ablation experiments reveal that graph-based attributes and modules are the key contributors to performance, with additional components leading to further improvements in accuracy. Comprehensive evaluations demonstrate that MultiVTP not only surpasses various baseline models but also remains robust under limited training data. Applying our approach to the human proteome enables the systematic identification of novel VTPs for both individual and multiple viruses.Cooperative molecular interaction networks govern PARP1 inhibitor selectivity and binding affinity
That author's affiliation: Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Institution (first & last author): Universidad Complutense de Madrid
by Alejandro Feito, Natàlia DeMoya‐Valenzuela, Cristian Privat, Andrés R. Tejedor, Lucía Paniagua-Herranz, Adiran Garaizar, Alberto Ocana, Jorge R. Espinosa
Selective inhibition of PARP1 represents a promising strategy to improve the therapeutic index of PARP inhibitors, a class of anticancer agents that exploit defects in DNA repair pathways. While PARP inhibitors have shown remarkable clinical benefit, particularly in BRCA-mutated tumors, the lack of discrimination between PARP1 and its close homolog PARP2, often leads to hematological toxicity and limits treatment efficacy. Thus, achieving molecular selectivity for PARP1 remains a central challenge in the rational design of safer and more potent inhibitors. To explore the molecular determinants of ligand selectivity, we focus on four clinically relevant PARP inhibitors—two PARP1-selective (saruparib and NMS-P118) and two non-selective (veliparib and olaparib) inhibitors—and perform atomistic potential-of-mean-force calculations of the PARP1 catalytic binding domain in the presence of these molecules. Our simulations near-quantitatively capture the experimental relative binding preferences, demonstrating that our approach reliably reflects selectivity patterns. Based on these findings, we analyze protein–ligand contact frequencies to identify the stabilizing interaction network and contact connectivity inducing protein selectivity. The most frequent protein–inhibitor contacts are primarily mediated by tyrosine triads and electrostatic interactions, showing a cooperative complex network of intermolecular contacts which strongly relies on protein multivalency. To dissect the decisive role of individual residues across the binding site, we also perform targeted mutagenesis of the PARP1 catalytic pocket in complex with saruparib, replacing several active-site amino acids by glycines. Progressively increasing the number of mutations markedly reduces binding stability, with distinct residue combinations exerting two primary effects: destabilization of the final bound state and the emergence of energetic barriers along the ligand association pathway. Together, our results provide a coherent mechanistic framework for understanding PARP1 selectivity and informs the rational design of next-generation inhibitors with improved efficacy and safety.MIAAIM: Multi-omics image integration with dimensional reduction for tissue state mapping
by Joshua M. Hess, Richard K. Dzeng, Iulian Ilieş, Denis Schapiro, John J. Iskra, Divya Mirgh, John Nam, Erin H. Seeley, David E. Verrill, Walid M. Abdelmoula, Michael S. Regan, Georgios Theocharidis, Chin Lee Wu, Aristidis Veves, Nathalie Y. R. Agar, Ann E. Sluder, Mark C. Poznansky, Ruxandra F. Sîrbulescu, Patrick M. Reeves
High-parameter tissue imaging enables detailed molecular analysis of single cells within their spatial environment. A current challenge to more complete tissue and single-cell spatial profiling is in situ data alignment across imaging platforms that quantify multiple types of biomolecules at differing resolutions. Here, we describe MIAAIM (Multi-omics Image Alignment and Analysis by Information Manifolds), a modular framework to align and process data from separate imaging technologies with distinct imaging resolutions and data complexity. MIAAIM is designed to be applied to align and analyze images of clinical biopsies from histological staining, imaging mass cytometry, and mass spectrometry imaging. A key advantage of the MIAAIM approach is its capacity to identify unbiased molecular phenotypes that correlate with cell identities and states determined using high-resolution targeted immunodetection. In a large diabetic foot ulcer (DFU) biopsy, this strategy allowed the identification of unique molecular characteristics of infiltrating immune cells as a function of local tissue health. In multi-core tissue microarrays (TMAs) of prostate cancer, MIAAIM allowed the classification of adjacent tumor grades with high accuracy, with over 90% of classification signal sourced from spatial features, generated from segmented cells across multiple imaging modalities while revealing novel cell/ immune signatures of the disease state. MIAAIM provides a disease and cell type agnostic general framework to construct multimodal tissue imaging datasets, yielding novel insights into the association of molecular analytes with cell subsets and their activation states for the analysis of complex tissue states.Agent-based modeling demonstrates how target-independent processes supplement killing by antibody-drug conjugates in cancer therapy
That author's affiliation: University of Michigan
Institution (first & last author): University of Michigan
by Melissa C. Calopiz, Jennifer J. Linderman, Greg M. Thurber
Antibody-drug conjugates (ADCs) have had remarkable clinical success in recent years with multiple new approvals. However, for some ADCs, the response rates don’t closely correlate with clinical target expression. One particular ADC targeting HER2, trastuzumab deruxtecan or T-DXd, is notable due to its success at expression levels ranging from high to low and ultralow. This raises the question of the relative contributions of target-independent mechanisms on ADC efficacy in the clinic, and several such mechanisms have been proposed. However, in vitro and preclinical data have different doses and exposures, making it challenging to quantitatively extrapolate preclinical data to the clinic. In this work, we use our computational hybrid agent-based model, SimADC, to simulate target-dependent and -independent mechanisms, scaling from mice to humans. We first demonstrate that CD8 + T cells can significantly contribute to tumor regression, especially when the ADC further activates the immune cells. Next, we test target-independent payload-driven mechanisms including: 1) Fc-mediated internalization of ADC by intratumoral macrophages and payload release to neighboring cancer cells, 2) free payload circulating in the blood and re-entering the tumor, and 3) extracellular linker cleavage and payload release due to an abundance of proteases in the tumor. We find that free payload in the blood and extracellular linker cleavage had low and moderate impacts, respectively, while macrophage uptake and payload release resulted in high levels of efficacy. This is due to the macrophages’ ability to sustain free payload in the tumor. Moderate and high HER2 expression were more efficacious than target-independent mechanisms. Overall, our simulations demonstrate that moderate to high HER2 expression, immune activation, or macrophage uptake and payload release are sufficient for T-DXd tumor regression. Additionally, SimADC provides a robust framework for modeling both target-dependent and target-independent mechanisms for any ADC, providing the opportunity to engineer more effective therapeutic agents.DREAMER-S: Deep leaRning-Enabled Attention-based Multiple-instance approaches with Explainable Representations for Spatial biology
That author's affiliation: Royal College of Surgeons in Ireland
Institution (first & last author): Technological University Dublin
by M. Rifqi Rafsanjani, Alison Dooney, Rahul Suresh, Alice C. O’Farrell, Monika A. Jarzabek, Liam Shiels, Annette T. Byrne, Jochen H. M. Prehn, Aidan D. Meade
Identifying image features that associate strongly with diagnostic or prognostic classes in large-scale, multi-channel spatial imaging is challenging without pixel-level annotations. We present DREAMER-S, an attention-based multiple-instance learning (MIL) framework that, using only image- or slide-level labels, learns spatial features within 3D imaging hypercubes that are most informative for downstream classification. We demonstrate DREAMER-S on Quantum Cascade Laser infrared (QCL-IR) tissue imaging, where attention weights are rendered spatially to highlight class-relevant spectral instances without manual annotation. Because the MIL attention layer assigns interpretable importances to spatial instances, the method is broadly transferable to spatial-biology applications that require instance-level filtering to focus towards salient regions of interest in high-content datasets. We further evaluate DREAMER-S on a chemotherapy-response task in a colorectal cancer patient-derived xenograft (PDX) model. After tuning, DREAMER-S separated spectral instances from a chemo-sensitive PDX (CRC0344) and a less responsive PDX (CRC0076) with an F1 score of ~0.95. To validate explainability, we linked model saliency to cellular physiology, observing that, (i) unsupervised UMAP embeddings of high-attention spectra stratified samples by treatment (chemotherapy, apoptosis sensitizer, combination, vehicle), and (ii) selected spectral markers correlated with pro-apoptotic proteins measured independently in the same PDX system. Together, these results support a mechanistic link between spectral signals and apoptosis pathways and position DREAMER-S as an efficient, interpretable approach for analysing high-content spatial-biology imaging datasets.Evaluating place cell detection methods in Rats and Humans: Implications for cross-species spatial coding
by Weijia Zhang, Thomas Donoghue, Salman E. Qasim, Joshua Jacobs
Place cells, first identified in the rat hippocampus as neurons that fire selectively at specific locations, are central to investigations of the neural underpinnings of spatial navigation. Recent spatial studies in human patients with drug-resistant epilepsy have made identifying and characterizing place cells across species increasingly important for understanding the extent to which decades of rodent research generalize to humans and for uncovering fundamental principles of spatial cognition. One challenge, however, is that detection methods differ: rodent studies often rely on spatial information (SI) in conjunction with place field stability measures, whereas human studies employ analysis of variance (ANOVA) based approaches. These methodological differences may affect the identified place cell populations, which complicates how their properties are interpreted and cross-species comparisons. To address this, we systematically applied multiple detection pipelines to human and rat datasets, supported by simulations that vary place-field properties. Our analyses and simulations demonstrate that spatial information and ANOVA-based approaches are responsive to distinct place field properties: spatial information primarily reflects the contrast between peak and average firing rates, while ANOVA emphasizes consistency across trials. Across species, rodent place cells revealed a broad spectrum of spatial tuning, including strongly tuned neurons with high spatial information and high ANOVA values. In contrast, human place cells lacked this strongly tuned population and exhibited a narrower distribution of tuning scores, concentrated at the lower end of both spatial tuning metrics. Despite these differences, both species had an overlapping population of neurons with weaker yet consistent spatial tuning, which may support important functional roles such as generalization and mixed selectivity. Addressing these analytical differences allows for more direct comparisons between species, though differences in spatial tuning may still relate to variations in experimental paradigms that warrant further investigation. Together, our study provides a roadmap showing how spatial tuning metrics shape place cell detection and interpretation.When one race is not enough: A relay model explains multisensory response times
That author's affiliation: University of St Andrews
Institution (first & last author): University of St Andrews
by Kalvin Roberts, Thomas U. Otto
Humans typically respond faster to multisensory signals than to their unisensory components, a phenomenon known as the redundant signal effect (RSE). One of the earliest and most influential accounts, the race model, attributes the RSE to statistical facilitation, which arises from parallel, independent processing across sensory modalities. While this model captures some key features of the RSE, it frequently underestimates the observed speed-up leading to violations of the race model inequality (RMI), a benchmark used to test the model’s validity. To reconcile this discrepancy, we introduce the relay model, a minimal extension of the race architecture that incorporates cross-modal initiation. In this model, responses result from two sequential race processes, allowing a signal in one modality to initiate the onset of perceptual decision processing in another. This structure retains statistical facilitation as a core principle while introducing a single free model parameter that partitions unisensory processing into gating and decision stages. Through simulations and fits to foundational empirical datasets, we show that the relay model captures both the magnitude and distributional shape of the RSE, including RMI violations. It also accounts for changes in the RSE under asynchronous stimulus onsets and manipulations of signal intensity, which are critical tests in multisensory research. By extending the classical race model with minimal added complexity, the relay model offers a mechanistically explicit and biologically plausible framework for explaining the dynamics of multisensory decision-making.Predictive metacognition: a neuro-computational framework for self-monitoring in large language models
Predictive metacognition: a neuro-computational framework for self-monitoring in large language models
Discrimination stability and calibration of cardiovascular risk prediction models in the Framingham baseline cohort
Discrimination stability and calibration of cardiovascular risk prediction models in the Framingham baseline cohort
Integrated computational and experimental analysis explores FOLH1 expression patterns across cancers and nominates melatonin as a potential modulator in prostate cancer models
by Rui Zhang, Junyu Zhou, Sihan Dong, Guoquan Liu, Xunbin Wei
BackgroundGrowing evidence indicates that Folate Hydrolase 1 (FOLH1, also known as prostate-specific membrane antigen, PSMA) is aberrantly expressed across multiple malignancies, particularly showing significant upregulation in prostate cancer. However, systematic investigations into its pan-cancer expression patterns, immunomodulatory roles, and immune cell infiltration remain limited. The potential role of FOLH1 in prostate cancer is also not fully elucidated.
MethodsWe analyzed FOLH1 mRNA expression, prognostic relevance, and immune infiltration across multiple malignancies, with a particular focus on prostate cancer. A machine learning (ML) workflow incorporating a deep learning model was developed to screen the therapeutic potential of drugs targeting FOLH1. The therapeutic potential of these candidates was validated through in vitro cellular assays and nude mouse xenograft models.
ResultsFOLH1 expression was significantly altered in 27 cancer types and showed cancer-specific immune correlations. Our AI platform identified melatonin as a computationally predicted FOLH1-interacting candidate. In vitro and in vivo experiments demonstrated that melatonin suppresses FOLH1 expression in a concentration-dependent manner, inhibits invasive and migratory capacities, and restricts tumor growth under physiological circadian melatonin levels.
ConclusionThis study highlights FOLH1’s pan-cancer expression patterns and nominates melatonin as an exploratory therapeutic candidate for prostate cancer requiring further mechanistic validation. Our integrated computational-experimental framework highlights the promise of AI-driven drug discovery in oncology, while emphasizing the need for further mechanistic validation.
Spatial richness of neural magnetic fields
That author's affiliation: Stanford University
Institution (first & last author): Stanford University
by Ziad Ali, Ada S. Y. Poon
Brain implants that measure neural magnetic fields, rather than electrical potentials, are expected to confer significant clinical advantages related to implant longevity and signal fidelity due to the elimination of the electrode-tissue interface. However, the informational differences between neural electrical potentials and magnetic fields remain poorly understood. Using a mathematical formalism based on neuronal current sources, we directly establish the complementary informational content of extracellular magnetic fields and electrical potentials. This formalism also reveals that extracellular magnetic fields generated by spiking neurons inherently exhibit one order lower spatial polarity than electric fields, resulting in more favorable distance-scaling characteristics. We then use computational modeling to illustrate how dense networks of neurons are easier to distinguish and spike sort on the basis of their magnetic, rather than electrical, spike templates. Lastly, we show how the solenoidal nature of neural magnetic fields facilitates approximate morphological reconstruction, even with sparse sensor arrays. Our findings highlight the unique experimental advantages of neural magnetic field sensing, motivating the development of compact, low-noise devices capable of meeting the stringent sensitivity requirements for cortical recordings.A simple model captures key characteristics of biological non-deterministic genotype-phenotype maps
That author's affiliation: Barcelona Biomedical Research Park
Institution (first & last author): Barcelona Biomedical Research Park
by Nora S. Martin
By connecting genotypic mutations to the higher-level phenotypes relevant for selection, genotype-phenotype (GP) maps play a key role in evolution. GP maps are typically investigated using computational models of biophysical phenotypes (for example, RNA secondary structures and simplified models of protein tertiary and quaternary structures), but GP map concepts are relevant beyond these specific models. While there has been significant progress in quantifying GP map properties and their evolutionary implications, this is largely limited to the simplest case, where each genotype corresponds to a single, categorical phenotype. Here, I turn to a more realistic, but also more complex, non-deterministic (ND) treatment, meaning that each genotype generates an ensemble of phenotypes. To provide a tool for tackling the additional complexity of ND GP maps, this paper identifies a tuneable synthetic model that produces an ND GP map reproducing central features of biophysical ND GP maps: phenotypic bias, genetic correlations, a tradeoff between genotypic robustness and evolvability and a non-negative trend between phenotypic robustness and evolvability. These features are reproduced for several alternative models combining additive genotype dependencies with non-linearities, suggesting that few ingredients are needed for these shared features to appear. Moreover, the synthetic ND GP map may be useful as a conceptually and computationally simpler model for addressing open questions about ND GP maps: for simulations linking GP map properties to evolutionary implications, for the development of sampling methods for ND GP maps and for extrapolations.MIRAGE: Robust multi-modal architectures translate fMRI-to-image models from vision to mental imagery
by Reese Kneeland, Cesar Kadir Torrico Villanueva, Tong Chen, Jordyn Ojeda, Shubh Khanna, Jonathan Xu, Paul S. Scotti, Thomas Naselaris
To be useful for downstream applications, vision decoding models that are trained to reconstruct seen images from human brain activity must be able to generalize to internally generated visual representations, i.e., mental images. In an analysis of the recently released NSD-Imagery dataset, we demonstrated that while some modern vision decoders can perform quite well on mental image reconstruction, some fail, and that state-of-the-art (SOTA) performance on seen image reconstruction is no guarantee of SOTA performance on mental image reconstruction. Motivated by these findings, we developed MIRAGE, a method explicitly designed to train on vision datasets and cross-decode mental images from brain activity. MIRAGE employs a linear backbone and multi-modal text and image features as input to a diffusion model. Feature metrics and human raters establish MIRAGE as SOTA for mental image reconstruction on the NSD-Imagery benchmark. With ablation analysis we show that mental image reconstruction works best when decoders use image features with relatively few dimensions and include guidance from text-based and both high- and low-level image-based features. Our work indicates that–given the right architecture–existing large-scale datasets using external stimuli are viable training data for decoding mental images, and warrant optimism about the future success and utility of mental image reconstruction.Association between mucus phenotypes, histopathological features, and ultra-high magnification endoscopic findings in ulcerative colitis
Association between mucus phenotypes, histopathological features, and ultra-high magnification endoscopic findings in ulcerative colitis
Gender disparities in random blood glucose levels among Pakistani adults with type 2 diabetes: a cross-sectional analysis
That author's affiliation: Lady Reading Hospital First author institution: Silesian University of Technology Last author institution: Sarhad University of Science and Information Technology
Gender disparities in random blood glucose levels among Pakistani adults with type 2 diabetes: a cross-sectional analysis
DENcode: A model for haplotype-informed transmission probability of dengue virus
That author's affiliation: New South Wales Institute of Psychiatry
Institution (first & last author): UNSW Sydney
by Sachith Maduranga, Braulio Mark Valencia, Chathurani Sigera, Praveen Weeratunga, Deepika Fernando, Senaka Rajapakse, Andrew R. Lloyd, Rowena A. Bull, Haley Stone, Chaturaka Rodrigo
Dengue virus transmission networks are often only partially resolved, due to gaps in sampling, unobserved mosquito-mediated transmission, and using methods (phylogenetics) that describe evolutionary relatedness but not explicit, probabilistic transmission links between individual infections. We developed DENcode, a framework to estimate the relative likelihood of vector-mediated transmission between pairs of dengue cases by combining a temperature- and time-modulated epidemiological kernel, which captures the extrinsic incubation period and human infectiousness, with a phylogenetically informed genetic similarity kernel derived from patristic distances between viral haplotypes or consensus sequences. Validation with a real-life dataset of 90 dengue infections sampled from Colombo, Sri Lanka between 2017 – 2020 and sequenced to resolve within-host haplotypes, DENcode estimates were stable across 100 Monte Carlo iterations, yielding narrow credible intervals (median width <0.001) and consistent top-ranked transmission pairs. Sensitivity analyses using ablation experiments showed that removing either the genetic or epidemiological component substantially altered the distribution of linkage probabilities, indicating that both contribute meaningfully to the inferred transmission structure. Serotype-specific transmission networks constructed from pairwise linkage probabilities from DENcode were analysed using degree- and path-based centrality measures at probability thresholds of 0.1 and 0.5, revealing relative importance of cases to disease transmission within the community. Haplotype-derived networks were more informative than consensus-based networks (x 3.6 and x 1.6 times more edges for DENV2 and 3 respectively). DENcode is a robust framework to explore dengue transmission within a community that provides an output of network of transmission probabilities informed by pathogen genetic similarity and clinical epidemiological parameters.Dynamics of trachoma infection in West Africa revealed by a hidden state model
by Jake Carson, Thomas Crellen, Anna Borlase, Joaquin M. Prada, Robin Bailey, T. Déirdre Hollingsworth, Simon E. F. Spencer
Trachoma is estimated to be the leading infectious cause of blindness globally, predominantly affecting low-income populations with poor sanitation and hygiene. Over a decade of mass drug administration with antibiotics has led to substantial progress in control and elimination, but hotspots remain where infection persists or rebounds following mass drug administration for reasons that remain unclear. Transmission modelling is a key component of understanding these dynamics, but the complex dynamics of infection and reinfection with Chlamydia trachomatis are challenging to infer from cross–sectional surveys. Here, we analyze longitudinal data collected over six months in 1991 using multiple diagnostics from two villages in The Gambia by developing and fitting a Bayesian epidemiological model that classifies individuals into disease states at each time point using a forward-filtering backward-sampling algorithm. We find that infection risk is clustered within households and the weekly probability of transmission within a shared room is 40–fold higher than in a shared village. Infected children are estimated to contribute disproportionately to transmission, accounting for 70–90% of the force of infection within the observed period. We estimate the basic reproduction number, R0, to be 2.2 by simulation and find that the distribution of secondary cases per individual is less aggregated than for other directly-transmitted pathogens. We further quantify heterogeneity in predisposition to becoming infected and estimate the sensitivity and specificity for PCR, antigen detection tests, and clinical examinations. Our study uncovers the natural history of trachoma infection, with implications for simulating pathogen dynamics and designing interventions to halt transmission and prevent avoidable cases of blindness.Trial-level sequence modeling reveals hidden dynamics of dual-task interference
That author's affiliation: Utrecht University
Institution (first & last author): Utrecht University
by Rick den Otter, Anna Dame, Sjoerd Stuit, Leendert van Maanen
Theories of dual-task interference assume that the same cognitive operations underlie multitasking regardless of stimulus timing, yet this core assumption has remained untested due to methodological limitations of behavioral averaging. Here, we combine hidden multivariate pattern (HMP) analysis with deep spatiotemporal sequence modeling of single-trial EEG to uncover the neural dynamics of multitasking in the psychological refractory period (PRP) paradigm. Using a deep spatiotemporal sequence model trained on Long stimulus-onset asynchrony (SOA) trials, we identify Encoding, Central, and Response operations and show that these same operations occur in the Short SOA condition, demonstrating shared cognitive processes across interference conditions. Additionally, trial-level decoding reveals multiple distinct sequences of cognitive operations across both tasks during interference, varying both within and across individuals. These sequences predict behavioral differences in reaction time and accuracy, revealing how interference timing within the cognitive operation sequence influences performance. In other words, we found trial-by-trial variability related to individual strategies directly affecting accuracy and reaction time (RT). Our findings challenge static bottleneck accounts and establish trial-level sequence modeling as a powerful tool to investigate the hidden dynamics of multitasking.Coevolutionary dynamics of viruses and their defective interfering particles
That author's affiliation: University of Wisconsin–Madison
Institution (first & last author): University of Wisconsin–Madison
by Shiv Muthupandiyan, John Yin
Defective interfering particles (DIPs) are viral mutants that arise naturally during infection. Because they lack one or more essential functions, DIPs cannot replicate on their own, but they can parasitize intact viruses during coinfection by competing for growth resources, thereby interfering with viral replication. The evolutionary interplay between viruses and their DIPs involves growth, mutation, interference, and resource trade-offs, but the mechanisms shaping population-level outcomes remain poorly understood. To address this, we developed a phenotype-space model across continuous traits (e.g., replicase binding affinity or packaging signal strength) using coupled partial differential equations that incorporate mutation, phenotype-dependent interference, intrinsic fitness costs, and de novo DIP generation. Unlike traditional strong-selection models, this framework captures strong-mutation regimes in which both virus and DIP populations evolve by diffusion through trait space and interact based on phenotypic similarity. Our analysis reveals two levels of dynamics. At the population level, viruses and DIPs undergo oscillations, consistent with predator–prey–like cycles (the von Magnus effect) observed experimentally. At the trait level, evolution drives shifts in resistance and interference, producing coevolutionary chases in which viruses temporarily escape and DIPs attempt to follow, as observed in serial-passage evolution studies. Systematic variation of parameters reveals four qualitative regimes: viral–DIP coexistence, sustained coevolutionary (Red Queen) chase dynamics, DIP extinction, and mutual extinction. Chase dynamics are most strongly promoted by intermediate interference strength and low decay rates, while higher levels drive collapse of one or both populations. The model further predicts thresholds where viral escape is either constrained by intrinsic fitness penalties or enabled through phenotypic separation from DIPs. These findings establish a general framework for virus–DIP coevolution, showing how both population dynamics and trait evolution shape outcomes, with implications for designing DIP-based therapeutics that better resist viral escape.Multimodal data integration to determine viral and innate immune kinetics in human airway epithelium
by Pascal Lukas, Aurélien Gibeaud, Clarisse Schumer, Jonas Arruda, Jeremie Guedj, Olivier Terrier, Frederik Graw
Understanding the mechanisms that govern viral spread in human airway epithelium (HAE) remains a major challenge, particularly with regard to identifying and quantifying key factors such as cell-type-specific infectivity, viral transmission paths, and the innate immune dynamics. Although mathematical models and experimental advances have provided valuable insights into respiratory infections, revealing the complex spatio-temporal interactions of infection and immune processes on a tissue-level have remained elusive. Here, we present a novel workflow that combines time-resolved bulk measurements and spatially-explicit image information to allow the inference of viral and immune kinetics within HAE for respiratory viruses. While standard inference methods typically require custom summary statistics and resourceful fitting procedures for each individual data set, our workflow relies on the combination of different, simulation-based trained neural networks using BayesFlow, a framework for neural posterior estimation that allows for amortized inference and the integrative analysis of multimodal data. We validated our approach by simulating viral infection dynamics in HAE using systems of increasing complexity that account for tissue heterogeneity, cell-type specific kinetics and interferon-mediated immune responses, mirroring experimental measurements. Thereby, we could show that integrating spatial information is essential to reliably infer viral transmission kinetics and innate immune interactions on a tissue-level. Applying our approach to experimental data on SARS-CoV-2 infection dynamics within HAE culture systems, we estimated that 84% [58%,100%] of all infections were due to cell-associated transmission, pointing towards local transmission as the dominant mode of SARS-CoV-2 spread within HAE. Our workflow can be readily applied to HAE culture systems for inference of viral and innate immune kinetics of different respiratory viruses, allowing multimodal data integration without the need for frequent resourceful re-fitting approaches.Dual-channel graph learning reveals similarity and complementarity in protein-protein interaction networks
That author's affiliation: Hunan University
First author institution: Nanjing University of Posts and Telecommunications
Last author institution: Hunan University
by Tao Tang, Taiguang Shen, Weizhuo Li, Yangyang Chen, Sisi Yuan, Yuansheng Liu, Xinyu Yang, Xiao Luo
Protein-protein interactions (PPIs) are governed by two fundamental interfacial mechanisms: similarity-driven, often involving symmetric structural motifs, and complementarity-driven, arising from geometric and physicochemical matching between binding surfaces. Despite their biological significance, computational models have largely overlooked the coexistence and interplay of these twofold interaction modes. Here, we introduce DMG-PPI, a dual-channel graph neural network framework that jointly models similarity and complementarity in PPI networks, extending prior heterophilous GNN concepts to explicitly disentangle these dual interaction modes. The core of the model consists of two parallel processing pathways: Alignment Message Passing (AMP), which aggregates information from proteins with similar features to capture interactions driven by shared structural patterns, and Divergence Message Passing (DMP), which emphasizes differences between proteins and identifies complementary features that may indicate physicochemical compatibility. The signals captured by AMP and DMP are integrated via an adaptive fusion strategy within each block, and the outputs of blocks are aggregated using the MixHop framework to encode higher-order interaction patterns. DMG-PPI substantially outperforms state-of-the-art methods on classical benchmark datasets, achieving a 7.19% improvement in Micro-F1 over the second-best method. Additionally, the dual-channel framework provides interpretable insights into key binding residues by identifying interfacial mechanisms. Overall, DMG-PPI serves as a powerful tool that reveals the mechanisms behind accurate PPI predictions and facilitates downstream biological analysis.Soft microfingers with flexible tactile sensor using liquid metal for in situ evaluation of cellular spheroid stiffness
Soft microfingers with flexible tactile sensor using liquid metal for in situ evaluation of cellular spheroid stiffness
Energy transfer leaves fingerprints in cyanine photoswitching behavior
by Vincent Ebert, Markus Sauer, Sören Doose
Super-resolution microscopy resolves molecular structures in biological systems but is limited by properties of the fluorescent labels. dSTORM experiments with multiple Cy5 fluorophores in sub-10 nm spaced labelling positions have shown distinct cumulative localization counts over time, depending on the distances between the fluorophores, that suggest Förster resonance energy transfer between ON states and long living OFF states. This photophysical effect hinders precise localization of the individual emitters but produces a photoswitching fingerprint that can be used to draw conclusions about sub-10 nm spatial conformations in molecular structures that are not spatially resolvable. Here we present a theoretical framework for analysing the photophysical systems that yield distinct fingerprint signatures. We developed a Python-based continuous-time Markov chain simulation software package that reproduces the photophysical processes of organic fluorophores. We show that the established photophysical models of Cy5 extended by Förster resonance energy transfer between the excited singlet state and the long living OFF state explain experimental fingerprint signatures as seen in dSTORM experiments. Matching experimental signatures including fluorescence lifetimes provides evidence for an additional energy transfer to the radical anion of cyanine dyes like Cy5. This work contributes to the understanding of proximity-based photophysical processes and paves the way for future development of sub-10 nm dSTORM imaging.A three-dimensional shear dependent continuum model of platelet aggregation under flow
by David Montgomery, Eric S. Barrientos, Jake M. Grdadolnik, Kelli Henderickson, Aaron L. Fogelson, Keith B. Neeves, Karin Leiderman
Platelet aggregation under flow is a key component of hemostasis, strongly influenced by shear-dependent interactions mediated by von Willebrand factor (vWF). We present a three-dimensional continuum model that incorporates shear-dependent platelet adhesion, cohesion, and activation. The model tracks seven platelet species and integrates shear-dependent kinetics for vWF-mediated binding and activation. Parameterization was guided by microfluidic experiments under controlled shear rates (300/s and 1500/s) with platelet activation pathways inhibited. Simulations reproduce experimental aggregate growth and occlusion dynamics in both straight channels and physiologically relevant extravascular geometries, where shear rates exceed 8000/s. Functional forms for shear-dependent on- and off-rates were implemented using piecewise and nonlinear scaling: on-rates exhibit double-threshold behavior with saturation at high shear, while off-rates combine linear and exponential terms to capture bond lifetime changes under extreme shear. Simulations using these rate forms reproduced occlusion times within the experimentally observed range. Qualitative comparisons with microfluidic imaging further demonstrated that the model reproduces intrathrombus heterogeneity, including the core–shell architecture with activated platelets concentrated near the collagen surface and unactivated platelets forming an outer shell. These results provide mechanistic insight into how shear-dependent vWF-mediated interactions regulate thrombus growth and occlusion. By linking microfluidic data with continuum-scale modeling, this framework provides a computationally efficient platform to study shear-regulated platelet aggregation and its contribution to hemostatic occlusion under physiologic and pathologic flow conditions.Multiscale modeling of blood circulation with cerebral autoregulation and network pathway analysis for hemodynamic redistribution in the vascular network with anatomical variations and stenosis conditions
That author's affiliation: Tohoku University
Institution (first & last author): Tohoku University
by Jiawei Liu, Atsushi Kanoke, Hidenori Endo, Kuniyasu Niizuma, Hiroshi Suito
Cerebral hemodynamics is fundamentally regulated through the Circle of Willis (CoW), which redistribute flow via communicating arteries to stabilize perfusion under anatomical variations and vascular stenosis. In this study, a multiscale circulation model was developed by coupling a multiscale systemic hemodynamic framework with cerebral arterial network reconstructed from medical imaging. The model integrates a cerebral autoregulation mechanism (CAM) and enables quantitative simulation of flow redistribution across the CoW under normal, anatomically varied, and pathologically narrowing (stenosis) conditions. Baseline simulations at normal states reproduced physiological flow distributions in which the communicating arteries remained nearly inactive, showing negligible across-flow and agreement with clinical measurements, while two anatomical variations revealed distinct collateral activation patterns: the anterior communicating artery (ACoA) acted as the earliest and most sensitive functional collateral pathway, whereas the posterior communicating arteries (PCoAs) exhibited structure-dependent engagement. Progressive stenosis modeling further demonstrated the transition from a complete CoW to a fetal-type posterior cerebral artery (PCA) configuration, with early ACoA flow reversal followed by the ipsilateral PCoA activation, in agreement with experimental and transcranial Doppler observations. We further present a path-based quantitative analysis of source-to-sink flow contributions to quantitatively illustrates how the cerebral vascular network dynamically reconfigures collateral pathways in response to structural changes. Overall, the proposed framework provides a physiologically interpretable and image-informed tool for investigating cerebral flow regulations through the functional collaterals within the CoW, offering potential for clinical applications in the diagnosis, prognosis, and treatment planning of cerebrovascular diseases.The speed limit of visual perception: Bidirectional influence of image memorability and processing speed on perceived duration and recognition
by Martin Wiener, Chloe Mondok, Alex Ma, Chetan Desai, April Joyner, Giuliana Macedo
Visual stimuli are known to vary in their perceived duration, with some stimuli engendering so-called “time dilation” and others “time compression” effects, in which stimuli appear to last for relatively longer or shorter durations, respectively. Extant theories have suggested these effects rely on the level of attention devoted to stimuli, the magnitude of the stimulus, or the intensity of the neural response, yet none of these can fully account for the observed effects. Recently, we demonstrated that perceived time is dilated by the memorability of an image (Ma, et al. 2024). To explain the memorability effect, we found that a recurrent convolutional neural network (rCNN) could recapitulate the time dilation effect by indexing the rate of entropy decline, or “speed”, across successive timesteps, with more memorable images associated with faster speeds. Here, we replicate and extend these findings by applying this model to a wider array of images and testing three groups of subjects (n = 20ea.) on images sampled according to their speed, memorability, or both. We found that images that increased in speed, but with constant memorability, or images that increased in memorability, but with constant speed, both dilated perceived time, and further found that speed alone could induce a shift in 24h memory recognition performance of ~17%. However, we also found that images with very fast speeds exhibited an opposite, time compression effect. These findings can be explained by a simple inverted-U model between speed and perceived duration that scales with the memorability of the image. Overall, our findings provide the boundaries of speed and memorability effects on time perception, suggesting the visual system dilates time when presented with informative stimuli but compresses it when these stimuli become overwhelmingly complex.A miniature bio-inspired antenna for sub-6 GHz consumer wireless and biomedical diagnostic applications
A miniature bio-inspired antenna for sub-6 GHz consumer wireless and biomedical diagnostic applications
Quantum-enhanced federated blockchain for privacy-preserving cardiovascular intelligence
Quantum-enhanced federated blockchain for privacy-preserving cardiovascular intelligence
Mechanisms and functions of large extracellular vesicle biogenesis
This Review presents the formation of large extracellular vesicle (L-EV) subsets, highlighting that their contents and physiological relevance, for example, in intercellular communication, are driven by the different mechanisms underlying their biogenesis.
CASPULE: A computational tool to study sticker spacer polymer condensates
That author's affiliation: Harvard University
Institution (first & last author): Harvard University
by Aniruddha Chattaraj, David S. Kanovich, Srivastav Ranganathan, Eugene I. Shakhnovich
Phase separated condensates are recognized as a ubiquitous mechanism of spatial organization in cell biology. Biophysical modeling of condensates provides critical insights into the dynamics and functions of these subcellular structures that are difficult to extract via experiments. Here we present an efficient computational pipeline, CASPULE (Condensate Analysis of Sticker Spacer Polymers Using the LAMMPS Engine), to simulate and analyze the biological condensates made of sticker-spacer polymers. CASPULE implements a unique force field that combines traditional Langevin dynamics with a “detailed-balance proof” protocol for single-valent bond formation between stickers. This framework allows us to study the non‑trivial biophysics that emerge from single‑valent sticker interactions, coupled with the effect of separating the energetic contributions of stickers and spacers. We provide detailed documentation on how to setup the simulation environment, perform simulations and analyze the results. Through case studies, we highlight the utility and efficacy of our pipeline. Importantly, we provide statistical parameters to characterize the cluster size distribution often observed in biological systems. We envision this tool to be broadly useful in decoding the interplay of kinetics and thermodynamics underlying the formation and function of biological condensates.Multiplex networks-based directed graph neural network for cancer driver gene identification
by Pingting Li, Minzhu Xie
Identifying cancer driver genes is crucial in precision oncology. Most existing methods rely on a single interaction network to capture gene relationships. However, with the increasing availability of multi-omics and biological network data, integrating multiplex networks offers a more comprehensive representation of the complex and directional regulatory interactions among genes. Moreover, the number of validated cancer driver genes remains small compared with the vast number of unlabeled genes, leading to label scarcity and class imbalance. To address these limitations, we propose a multiplex networks-based directed graph neural network (MNDGNN). The model learns gene representations on multiplex networks with multi-omics data through directed graph convolution, which integrates neighbor diversity and degree diversity. We also incorporate data augmentation combining positive-sample augmentation with negative-sample inference to mitigate label scarcity. Experimental results show that the proposed method achieves better predictive performance and robustness than existing state-of-the-art methods. The predicted cancer driver genes are significantly enriched in cancer-related pathways and exhibit extensive interactions with known cancer driver genes, offering a new perspective for cancer driver gene discovery and the design of therapeutic strategies.Art’s hidden topology: A window into human perception
That author's affiliation: Jagiellonian University
First author institution: University of Hertfordshire
Last author institution: University of Warsaw
by Emil Dmitruk, Beata Bajno, Lidia Kot, Joanna Dreszer, Bibianna Bałaj, Ewa Ratajczak, Marcin Hajnowski, Romuald A. Janik, Marek Kuś, Shabnam N. Kadir, Jacek Rogala
Generations of researchers have sought a link between features of an artistic image and the audience’s experience. However, a direct link between the properties of an image and the responses evoked has still not been established. Given the importance of shape to human perception and artistic creation, it can be assumed that one of the most important aspects of an artistic image is the use of different visual structures. We show that a method from the field of computational topology, persistent homology, can be used to analyse properties of image structures and composition at multiple scales. In order to determine the reliability of this method as a tool for analysing visual artworks, we analysed two different sets of abstract paintings that revealed significant discrepancies in the eye tracking, electrical brain activity and the subjective experience of viewers. Our research showed that our newly developed method not only clearly distinguished between two sets of images but also allowed us to map topological features onto gaze fixation heat maps. Furthermore, the extent to which various artistic images violate a topological duality (Alexander duality) is significantly different from that of pseudo-art. It is intriguing that a diverse group of eminent abstract artists seem to favour a special rate of violation close to a specific value.VesiclePy: A machine learning vesicle analysis toolbox for volume electron microscopy
That author's affiliation: Columbia University
Institution (first & last author): Boston College
by Jason Ken Adhinarta, Yutian Fan, Adam Gohain, Michael Lin, Paige Nurkin, Richard Ren, Micaela Roth, Shulin Zhang, Ayal Yakobe, Rafael Yuste, Donglai Wei
Vesicles are critical components of neurons that package neurotransmitters and neuropeptides for their release, in order to communicate with other neurons and cells. However, due to their small size, the reconstruction of the full vesicle endowment across an entire neuronal morphology remains challenging. To achieve this, we have used, as a tool to identify and visualize vesicles, Volume Electron Microscopy (vEM), a method that has the nanoscale resolution to detect individual vesicle boundaries, content, and 3D locations. However, the large volume of vEM datasets poses a challenge in the segmentation, classification, and spatial analysis of tens of thousands of vesicles and their target cell in 3D. Here we report the development of VesiclePy, an integrated pipeline for automated segmentation, classification, proofreading, and spatial analysis of vesicles, relative to neuron masks in large-volume electron microscopy data. Our package integrates the efficiency of deep learning and the accuracy of human proofreading and provides a streamlined package in chunked processing and accurate indexing, localization, and visualization of single vesicle resolution in large vEM data. We demonstrate the viability of VesiclePy using high-pressure frozen serial EM data of Hydra vulgaris and quantify the performance of the package using ground truth manual annotations. We show that VesiclePy can process a multiterabyte serial EM dataset, efficiently annotate 53,851 vesicles from 20 complete neurons, and classify vesicles into 5 types. Each vesicle has a unique ID and 3D location for further spatial analysis in relation to neuron or non-neuronal targets nearby. Finally, by combining vesicle data and morphological information of each neuron, we can quantitatively cluster neurons into subtypes. VesiclePy is available at https://github.com/PytorchConnectomics/VesiclePy under an MIT license.High-throughput generation of patient-derived cancer stem cells for precision medicine using a microwell-chip platform
That author's affiliation: Soochow University Institution (first & last author): Chinese Academy of Sciences
Zhao et al. develop a microwell cell-chip-based culture platform that enables high-throughput generation of micro-tumourspheres and enrichment of functional cancer stem cells from biopsies obtained from patients with breast cancer, facilitating personalized drug testing.
RNA imbalance as a hallmark of cellular ageing
This Perspective highlights the failures of an ageing cell in properly maintaining mRNA health at the various steps of the mRNA life cycle that result in vulnerability to disease, pointing to RNA imbalance as an emerging hallmark of cellular ageing.
NerveAI- a machine learning algorithm for detection of nerve pain in the head and neck
NerveAI- a machine learning algorithm for detection of nerve pain in the head and neck
Hybrid vision–IMU deep learning framework with graph convolutional networks and attention for personalized yoga posture identification
Hybrid vision–IMU deep learning framework with graph convolutional networks and attention for personalized yoga posture identification
Role of artificial intelligence in analyzing human behavior and predicting personality traits and personality disorders
Role of artificial intelligence in analyzing human behavior and predicting personality traits and personality disorders
Inflammation starves antitumour immunity
That author's affiliation: Discovery Institute Institution (first & last author): Discovery Institute
When cells sense amino acids, they activate a kinase complex known as mTORC1 in a process that can regulate cancer metabolism and growth. Work now shows that in nutrient-limiting conditions, inflammatory cytokines aberrantly activate mTORC1 in cancer cells, thereby depriving cancer-screening CD8+ T cells of amino acids and causing their death.
Graph neural networks can predict ketosynthase substrate specificity
That author's affiliation: Department of Chemistry First author institution: Department of Chemistry Last author institution: Chemical Biology and Biological Chemistry
Graph neural networks can predict ketosynthase substrate specificity
Combination of dysfunctional beliefs about sleep and excessive daytime sleepiness as a psychobehavioral characteristic of comorbid insomnia and sleep apnea
That author's affiliation: National Center of Neurology and Psychiatry Institution (first & last author): National Center of Neurology and Psychiatry
Combination of dysfunctional beliefs about sleep and excessive daytime sleepiness as a psychobehavioral characteristic of comorbid insomnia and sleep apnea
lncRNA in EGFR‑driven glioblastoma
That author's affiliation: Cleveland Clinic Lerner Research Institute First author institution: Cleveland Clinic Last author institution: Cleveland Clinic Lerner Research Institute
EGFR amplification is common in glioblastoma and represents a therapeutic challenge, conferring resistance to targeted treatment. A new study reveals that the same locus hides the HELDR lncRNA, which epigenetically activates KAT7 to drive growth independently of EGFR. Targeting HELDR or KAT7 may improve anti-EGFR therapies in glioblastoma.
Predicting protein cascade expression from H&E images
That author's affiliation: The Ohio State University
Institution (first & last author): The Ohio State University
by Alejandro Leyva, Abdul Rehman Akbar, Muhammad Khalid Khan Niazi
Protein expression within oncogenic or suppressive pathways is a hallmark indicator of oncogenesis. While traditional AI models in digital pathology attempt to predict singular proteins, there is a need to predict the downstream expression of proteins to indicate the propagation of signals. RNA expression provides novel information, but does not provide information about the downstream propagation of protein signals or whether those signals are functional. Using Reverse Phase Protein Array (RPPA) data with whole-slide images (WSIs) from the publicly available Cancer Genome Atlas Breast Adenocarcinoma dataset (TCGA-BRCA), we predict the expression of five key proteins identified from the apoptosis cascade, using DNA damage and repair (DDR) cascades as a biological control. Furthermore, we examine the performance of patch- level Vision Transformers (ViT) on the regression task, which was tested against the designed cellular-level ViT, CellRPPA. Our results demonstrate that patch-level vision transformers were unable to obtain statistically significant predictive results, achieving R-squared values < 0.1 for all folds. In addition, CellViT obtained R-squared values >0.1 in all five test folds. We also show that morphologically indicative cascades, such as the apoptosis cascade, provide significantly higher performance compared to the DDR cascade.Co-morbid biomarkers for sarcopenic obesity associated with gut microbiota metabolites: From burden to treatment
by Juehan Wang, Haijun Li, Weiyi Shi, Xiaoxu Ren, Yingying Liu, Lin Mao, Daming Wang, Tianfang Zhang, Ziwei Zhang, Huiqin Zheng, Xiaofeng Yang, Mingfei Yao, Zuobing Chen
BackgroundThe detrimental cycle of sarcopenic obesity (SO) significantly reduces quality of life in older adults, while the mechanisms are still unclear.
Materials and methodsWe first analyzed the incidence of SO using the CHARLS database. We identified key genes by integrating differentially expressed genes, weighted gene co-expression network analysis, and targets of gut microbiota metabolites, refining the selection through machine learning methods (LASSO, XGBoost, SVM-REF, Random Forest). These genes were validated through single-cell sequencing, receiver operating characteristic analysis, and Muscle immunohistochemistry in a high-fat-diet (HFD) induced mouse model. Further analyses comprised immune infiltration profiling, pathway enrichment, and transcriptional regulation analysis. Additionally, we explored the relationships between key genes and autophagy, ferroptosis, and immunity responses. Finally, we predicted and evaluated potential therapeutic compounds via the CMap database and molecular docking.
ResultsSO incidence in China increased significantly from 16.1% (2011) to 20.4% (2018). Machine learning identified ALDH1A3, CSF1R, and PHGDH as key genes. These genes were validated in external muscle single-cell datasets, demonstrating robust diagnostic performance with AUC values exceeding 0.72 across four independent GEO cohorts. Following an HFD intervention in mice, ALDH1A3 and CSF1R expression in muscle tissue was significantly upregulated, while PHGDH showed a consistent upward trend that did not reach statistical significance. Immune infiltration analysis revealed a significant increase in resting NK cells in both obesity and sarcopenia states. Functional enrichment analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes linked the genes to transcriptional regulation pathways. The Cisbp_M4923 motif was identified as the most relevant transcription factor binding site. Finally, molecular docking simulations indicated stable binding of the top candidate compound, Birinapant, to the key gene targets.
ConclusionALDH1A3, CSF1R, and PHGDH serve as potential co-morbid biomarkers for SO.
VUStruct: A compute pipeline for high throughput and personalized structural biology
That author's affiliation: Vanderbilt University
Institution (first & last author): Vanderbilt University
by Christopher W. Moth, Jonathan H. Sheehan, Abdullah Al Mamun, R. Michael Sivley, Alican Gulsevin, David C. Rinker, Zenab F. Mchaourab, Undiagnosed Diseases Network , John A. Capra, Jens Meiler
Effective diagnosis and treatment of rare genetic disorders requires the interpretation of a patient’s genetic variants of unknown significance (VUSs). Today, clinical decision-making is primarily guided by gene-phenotype association databases and DNA-based scoring methods. Our web-accessible variant analysis pipeline, VUStruct, supplements these established approaches by deeply analyzing the downstream molecular impact of variation in context of 3D protein structure. VUStruct’s growing impact is fueled by the co-proliferation of protein 3D structural models, gene sequencing, compute power, and artificial intelligence. Contextualizing VUSs in protein 3D structural models also illuminates longitudinal genomics studies and biochemical bench research focused on VUS, and we created VUStruct for clinicians and researchers alike. We now introduce VUStruct to the broad scientific community as a mature, web-facing, extensible, High-Performance Computing (HPC) software pipeline. VUStruct maps missense variants onto automatically selected protein structures and launches a broad range of analyses. These include energy-based assessments of protein folding and stability, pathogenicity prediction through spatial clustering analysis, and machine learning (ML) predictors of binding surface disruptions and nearby post-translational modification sites. The pipeline also considers the entire input set of VUS and identifies genes potentially involved in digenic disease. VUStruct’s utility in clinical rare disease genome interpretation has been demonstrated through its analysis of over 175 Undiagnosed Disease Network (UDN) Patient cases. VUStruct-leveraged hypotheses have often informed clinicians in their consideration of additional patient testing, and we report here details from two cases where VUStruct was key to their solution. We also note successes with academic research collaborators, for whom VUStruct has informed research directions in both computational genomics and wet lab studies.Explainable AI-driven diagnosis model for early glaucoma detection using grey-wolf optimized extreme learning machine approach
That author's affiliation: Harvard University
First author institution: Dr. C. V. Raman University
Last author institution: Harvard University
by Debendra Muduli, Santosh Kumar Sharma, Sujata Dash, Bernardo Lemos, Saurav Mallik
Glaucoma is a leading global cause of blindness, making early detection essential. This paper introduces GlaucoXAI (Glaucoma Explainable AI), an advanced computer-aided diagnosis (CAD) model that integrates machine learning and explainable AI for glaucoma detection using retinal fundus images. The proposed model consists of four stages, including preprocessing, feature extraction, dimensionality reduction, and classification. Initially, features are extracted using the fast discrete curvelet transform with wrapping (FDCT-WRP) to obtain curve-type features. During the next stage, principal component analysis (PCA) and linear discriminant analysis (LDA) are combined to reduce the dimensionality of the feature matrix, followed by a classification stage employing an improved grey wolf optimization (IMGWO) with an extreme learning machine (ELM) to optimize the weight and bias to reduce the overfitting of the model. The model has been experimented with two publicly available datasets named G1020 and ORIGA. The model has achieved 93.87% accuracy on G1020 and 95.38% on ORIGA, outperforming existing methods. The 10 × 5-fold stratified cross-validation (SCV) with explainable AI enhances the interpretability of models and improves clinician trust. Overall, the proposed approach offers accurate, efficient, and explainable glaucoma diagnosis, potentially supporting ophthalmologists in early disease detection.NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac<sup>4</sup>C-independent mechanism
Li, Huo, Zhang, Liu and colleagues report that the transcripts of genes involved in haematopoietic stem cell function share a protective mechanism against RNA decay through a non-canonical function of NAT10, independent of its N4-acetylcytidine catalytic activity.
SARS-CoV-2 spike protein exerts an anti-cancer effect in A549 cells in association with MEG3 and BCYRN1 regulation
SARS-CoV-2 spike protein exerts an anti-cancer effect in A549 cells in association with MEG3 and BCYRN1 regulation
Learning the bistable cortical dynamics of the sleep-onset period
That author's affiliation: University of Washington
Institution (first & last author): Centre National de la Recherche Scientifique
by Zhenxing Hu, Manaoj Aravind, Xu Lei, J. Nathan Kutz, Jean-Julien Aucouturier
Humans just don’t fall asleep like a log – or step-function. Rather, the sleep-onset period (SOP) exhibits dynamic and non-monotonous changes of electroencephalogram (EEG) with high, and so far poorly understood, intra- and inter-individual variability. Computational models of the sleep regulation network have suggested that the transition to sleep can be viewed as a noisy bifurcation at a saddle node which is determined by an underlying control signal or “sleep drive”. However, such models do not describe how internal control signals in the SOP can produce rapid switches between stable wake and sleep states, nor how these state-space changes are translated in the macroscopic EEG. Here, we propose a minimally-parameterized stochastic dynamical model, in which one slowly-varying control parameter drives the wake-to-sleep transition while exhibiting noise-driven bistability. We provide a procedure for estimating the parameters of the model given single observations of experimental sleep EEG data, and show that it can reproduce a wide variety of SOP phenomenology. Using the model to analyze a pre-existing sleep EEG dataset, we find that the estimated model parameters correlate with subjective sleepiness reports. These results suggest that the bistable characteristics of the SOP can serve as biomarkers for tracking intra- and inter-individual variability of sleep-onset disorders.Evolutionary Kuramoto dynamics unravels origins of chimera states in neural populations
That author's affiliation: City St George's, University of London
Institution (first & last author): Dartmouth College
by Thomas Zdyrski, Scott Pauls, Feng Fu
Neural synchronization is central to cognition. However, incomplete synchronization often produces chimera states, where coherent and incoherent dynamics coexist. Recent studies have suggested that these chimera states could be important in human cognitive organization. In particular, chimera states have been suggested as a regulator of cognitive integration and regulation with varying quality as humans age. While previous studies have explored such chimera states using networks of coupled oscillators, it remains unclear why neurons commit to communication or how chimera states persist. Here, we investigate the coevolution of neuronal phases and communication strategies on directed, weighted networks where interaction payoffs depend on phase alignment and may be asymmetric due to unilateral communication. The graph structure enables us to apply a game-theoretic model of Kuramoto-like oscillators to brain connectomes, and the asymmetry captures biochemical differences between communicative and non-communicative neurons. Combined, these two generalizations enable us to apply the computationally-tractable game-theoretic model of Kuramoto models to realistic brain networks and analyze the role of connectome structure on neuron communication. We find that both connection weights and directionality influence the stability of communicative strategies—and, consequently, full synchronization—as well as the strategic nature of neuronal interactions. Applying our framework to the C. elegans connectome, we show that emergent payoff structures, such as the staghunt game, control population dynamics. We demonstrate that weighted, directed connectivity in the Caenorhabditis elegans (C. elegans) connectome is sufficient to generate robust chimera states modulated by payoff asymmetries. Our computational results demonstrate a promising neurogame-theoretic perspective, leveraging evolutionary graph theory to shed light on mechanisms of neuronal coordination beyond classical synchronization models.Evaluating the utility of amino acid similarity-aware kmers to represent TCR repertoires for classification
That author's affiliation: University of Liverpool
Institution (first & last author): University of Liverpool
by Hannah Kockelbergh, Shelley C. Evans, Liam Brierley, Peter L. Green, Andrea L. Jorgensen, Elizabeth J. Soilleux, Anna Fowler
Insights gained through interpretation of models trained on the T-cell receptor (TCR) repertoire contribute to advances in understanding of immune-mediated disease. This has the potential to improve diagnostic tests and treatments, particularly for autoimmune diseases. However, TCR repertoire datasets with samples from donors of known autoimmune disease status generally include orders of magnitude fewer samples than TCR sequences. Promising TCR repertoire classification approaches consider relationships between non-identical TCR sequences. In particular, kmer methods demonstrate strong and stable performance for small datasets. We propose a TCR repertoire representation that considers the relationships between amino acids within kmers flexibly and efficiently. XGBoost and logistic regression models are trained and tested on kmer representations of TCR repertoire datasets including samples from patients with coeliac disease as well as donors with previous cytomegalovirus infection. XGBoost models outperform logistic regression, indicating that interactions may be crucial for discriminative ability. We find that a reduced alphabet based on BLOSUM62 can lead to a model with slightly stronger XGBoost testing performance than other kmer features. Though it remains unclear whether there is an amino acid encoding that can substantially improve TCR repertoire classification with reduced alphabet kmers, evidence that this representation enables faster training of XGBoost models in comparison to kmer clusters suggests that our reduced alphabet approach permits wider exploration of amino acid similarity in practice. Finally, we detail motifs which are important in each top-performing XGBoost model and compare them to TCR sequences previously associated with each immune status. We highlight the challenge of interpreting non-linear TCR repertoire classification models trained on kmers which, if overcome, could lead to biomarker discovery for autoimmune diseases.Complexity of resting cortical activity predicts neurophysiological responses to theta-burst stimulation but fails to generalize: A rigorous machine-learning approach
That author's affiliation: Harvard Medical School, Beth Israel Deaconess Medical Center
First author institution: University of Texas MD Anderson Cancer Center
Last author institution: Harvard Medical School, Beth Israel Deaconess Medical Center
by Matthew Herbert Ning, Haoqi Sun, Brice Passera, Duygu Bagci Das, Brandon Westover, Alvaro Pascual-Leone, Emiliano Santarnecchi, Mouhsin M. Shafi, Recep A. Ozdemir
BackgroundSubstantial variability in individual responses to intermittent theta-burst stimulation (iTBS) limits its clinical efficacy, yet neurophysiological mechanisms underlying this variability remain unclear. While most machine-learning studies have focused on modeling behavioral or clinical effects of repetitive transcranial magnetic stimulation (rTMS), the few studies examining neurophysiological outcomes utilized limited feature sets in single-visit settings, which captured only inter-subject variability and most importantly lacked independent validation sets.
MethodsTo address these gaps, we employed supervised machine learning models that integrated baseline resting-state EEG (rsEEG) features and baseline transcranial magnetic stimulation (TMS)-evoked measures, including motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs), to predict neurophysiological responses to a single iTBS session applied over the primary motor cortex in two independent test-retest studies of healthy adults. We also employed statistical and reliability analysis to understand the statistical relationship between resting state EEG and responses to iTBS.
ResultsInternal cross-validation within the training cohort yielded promising binary classification performance (accuracy: 81%), identifying coarse-grained multiscale distribution entropy of rsEEG as the most robust predictor of local cortical excitability changes indexed by the 100–131ms window of TEPs. However, predictive performance markedly declined upon external validation (accuracy: 69%), reflecting unstable relationships between predictors and outcomes likely driven by substantial intra- and inter-individual variability of iTBS-induced changes in neurophysiological outcomes.
ConclusionsThese findings emphasize that while EEG complexity measures can capture baseline brain states relevant for neuromodulation to a certain degree, the inherent instability of single-session iTBS effects significantly constrains model generalizability and underscores the necessity of test-retest paradigm to avoid overly optimistic performance estimates. Future studies with multi-session and individualized stimulation protocols are urgently needed to better characterize neurophysiological mechanisms underlying rTMS effects and ultimately enhance its therapeutic potential.
Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer’s brains
That author's affiliation: University of Texas Southwestern Medical Center First author institution: Shanghai Jiao Tong University Last author institution: University of Texas Southwestern Medical Center
Yu, Li and colleagues explore the metabolome of neurons, microglia and astrocytes under normal, ageing and Alzheimer’s disease conditions. They find enrichment of glutathione and polyamine metabolism in microglia, which decreased with ageing and in Alzheimer’s disease.
CASER: A semi-supervised model with multi-omics data integration prioritizes cancer-associated epigenetic regulator genes
That author's affiliation: Salk Institution for Biological Studies
First author institution: Unknown
Last author institution: Wenzhou Medical University
by Hao Li, Chaohuan Lin, Liyu Liu, Jie Lyu, Zhen Feng
Prioritizing a reliable list of cancer-associated epigenetic regulators (cERs) is critical for cancer diagnosis and discovery of drug targets. While various cERs have been proposed to play important roles as cancer drivers, we anticipate that further cERs can be identified through computational analyses. In this study, we introduce a semi-supervised machine-learning approach based on tri-training model, termed Cancer-ASsociated Epigenetic Regulator identification (CASER). CASER integrates a wide range of multi-omics-derived features, including mutational, genomic, epigenetic, and transcriptomic data, to prioritize cERs as well as the four functional subtypes of cERs. When evaluated against an independent gene set, CASER demonstrates superior predictive performance compared to various other supervised machine-learning and deep semi-supervised models. CASER identified novel cERs that demonstrated cancer-driving potential and essentiality for cell survival. These novel cERs were comparable to established cancer driver genes and outperformed existing approaches for cER prediction. CASER identified dozens of novel cERs, of which six candidate cERs were shown to have roles in altering cell proliferation in four cancer cell lines. Furthermore, the prioritized cERs, particularly dual-role cERs, are more associated with anti-cancer medicines, underscoring their potential as therapeutic targets in cancer. Our study can offer valuable insights of cERs for future functional studies, advancing the understanding of their role in cancer biology.Bifurcation of neural firing patterns driven by potassium dynamics and neuron–electrode geometry during high-frequency stimulation
That author's affiliation: Johns Hopkins School of Medicine
First author institution: Johns Hopkins School of Medicine
Last author institution: Unknown
by Yue Yuan, Junyang Zhang, Chen Wang, Hao Yan, Ning Zhang, Kun Zhang, Zheshan Guo, Zhaoxiang Wang
High-frequency stimulation (HFS), the basis of deep brain stimulation, elicits diverse neuronal responses, yet the mechanisms remain unclear. Classical conduction block theories cite sodium channel inactivation and axonal failure but cannot explain the abrupt, reproducible firing transitions observed in vivo. Here, we combine single-unit recordings from rat CA1 neurons with a biophysically detailed multi-compartment model to examine how HFS shapes axonal excitability. The results show that neuronal responses are governed by two coupled factors: the electrode–axon geometry and peri-axonal extracellular potassium ([K⁺]o) dynamics. Small changes in either parameter reliably triggered bifurcation-like transitions between tonic, clustered, and low-rate regular firing. Conduction block preceded initiation failure with increasing electrode-axon distance, whereas elevated [K⁺]o shifted membranes between excitable and non-excitable states. This unified bifurcation framework extends the conduction block hypothesis, recasts axons as nonlinear elements, and provides mechanistic insights to optimize electrode placement, stimulation tuning, and closed-loop neuromodulation strategies.Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing
That author's affiliation: University of Bergen Institution (first & last author): Beth Israel Deaconess Medical Center
Kozlova et al. report a functional role for NDRG1 in regulating R-loops and DNA repair, thereby linking cancer-associated fibroblast-derived extracellular matrix to chemotherapy responses in pancreatic cancer.
Nine quick tips for software containerization
That author's affiliation: University of Auckland
Institution (first & last author): University of Auckland
by David Moreau, Kristina Wiebels
Software containerization has become a cornerstone of modern computational biology, enabling researchers to package code, dependencies, and execution environments in portable and reusable units. Containers support reproducibility, facilitate collaboration, and lower barriers to deploying complex computational workflows across heterogeneous systems. At the same time, inappropriate or superficial use of containers can undermine these benefits, leading to brittle environments, security risks, or false confidence in reproducibility. In this article, we present nine practical and actionable tips for using software containers effectively in computational biology research. Rather than focusing narrowly on container syntax or tooling, we address conceptual decisions that arise throughout the research lifecycle: when containerization is appropriate, how to balance reproducibility with flexibility, how to manage dependencies and data, and how to share containers responsibly. These tips are intended for researchers with varying levels of experience, from those adopting containers for the first time to those maintaining mature, containerized workflows.Automating population construction and parallel simulation of biophysical models for neuromuscular cells: An inverse approach
That author's affiliation: Korea Institute of Science and Technology
Institution (first & last author): Korea Institute of Science and Technology
by Hojeong Kim
Biophysical modeling and simulation help to promote a comprehensive understanding of the neuromuscular mechanisms underlying muscle force generation and control in normal and pathological states. However, this process is labor intensive and limited to special conditions due to the heterogeneity of neuromuscular cells and the variability in their organization across body parts and ages. We present a methodology to resolve this issue. First, we formulate a building-block approach with an inverse modeling framework for automated population construction and tractable hierarchical analysis under various physiological conditions. Second, we devise a network folder-based approach with a virtual environment technique for efficient parallel simulation that can operate on a multicore computer, a supercomputing system, or a computer network through the internet. Third, we implement the methodology by developing open-source command-line software called pNMS. Finally, we demonstrate that pNMS can replicate experimental and simulation results from different environments and predict the population behaviors of neuromuscular cells depending on their organization and muscle length. With an intuitive, flexible application programming interface, this software tool may offer a solution for promoting efficient investigation and an in-depth understanding of neuromuscular function at cellular resolution under realistic scenarios.Structural mechanisms underlying distinct binding and activities of 18:0 and 18:1 lysophosphatidic acids at LPA1 receptor
That author's affiliation: Washington State University
Institution (first & last author): Washington State University
by Ayobami Diyaolu, Peter Obi, Pravita Balijepalli, Kathryn E. Meier, Senthil Natesan
Lysophosphatidic acids (LPAs) are bioactive lipids that regulate numerous physiological functions in humans. Cell signaling by LPAs is mediated mainly via six LPA receptors (LPA1-6), class A G protein-coupled receptors (GPCRs). Among these, LPA1 is recognized to play an essential role in cell proliferation, survival, migration, and tumorigenesis. Despite the structural similarity, 18:0-LPA and 18:1-LPA exhibit distinct functional responses in cell lines overexpressing LPA1. Specifically, our in vitro studies show that 18:1-LPA induces greater Erk activation than 18:0-LPA in PC-3 human prostate cancer cells. The structural basis underlying this differential receptor activation has not been previously studied. Using classical molecular dynamics and enhanced sampling techniques, we examined the access and binding mechanisms of the two LPA species to the active state LPA1 receptor. The results show that 18:0-LPA and 18:1-LPA adopt distinct and dynamic poses in the orthosteric pocket despite their similar starting configurations. Mainly, the alkyl chains of the ligands exhibit distinct orientations and residue interactions, leading to differential conformational changes in key activation switches on the conserved CWxP and PIF structural motifs of the receptor. Also, there are significant differences in interhelical interactions at the intracellular end of the transmembrane helices 1, 3, 6, and 7. These distinct arrangements lead to striking differences in LPA1 interactions with the Gα-helix of the heterotrimeric Gi-protein. Notably, 18:0-LPA and 18:1-LPA exhibit similar membrane partitioning characteristics and receptor entry processes through aqueous paths. Our comprehensive in-silico studies offer valuable structural insights into the observed differences in functional responses by 18:0- and 18:1-LPA.Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability
D’Ambrosio et al. screen 10,480 electrophilic compounds for senolytic effects and show that senolytic chloroacetamides or GPX4 inhibitors selectively kill senescent cells by ferroptosis.
Using experimental results of protein design to guide biomolecular energy-function development
by Hugh K. Haddox, Gabriel J. Rocklin, Francis C. Motta, Devin Strickland, Samer F. Halabiya, Cameron Cordray, Hahnbeom Park, Eric Klavins, David Baker, Frank DiMaio
Computational models of macromolecules have many applications in biochemistry, but physical inaccuracies limit their utility. One class of models uses energy functions rooted in classical mechanics. The standard datasets used to train these models are limited in diversity, pointing to a need for new training data. Here, we sought to explore a new paradigm for training an energy function, where the Rosetta energy function was used to design de novo proteins. Experimental results on these designs were then used to identify failure modes of design, which were subsequently used as a “guiding principle” to retrain the energy function. Specifically, we examined a diverse set of de novo protein designs experimentally tested for their ability to stably fold, identifying unstable designs that were predicted to be stable by the Rosetta energy function. Using deep mutational scanning, we identified single amino-acid mutations that rescued the stability of these designs, providing insight into common failure modes of the energy function. We identified one key failure mode, involving steric clashing in protein cores. We identified similar overpacking when using Rosetta to refine high-resolution protein crystal structures, quantified the degree of overpacking, and refit a small set of energy-function parameters to better recapitulate native-like packing. Following fitting, we largely eliminated the failure mode in the refinement task, while retaining performance on other benchmarks, resulting in an updated version of the Rosetta energy function. This work shows how learning from protein designs can guide energy-function development.Spatio–temporal modelling of <i>in vitro</i> influenza A virus infection: The impact of defective interfering particles on the type I interferon response
by Yimei Li, Bjarke Frost Nielsen, Simon A. Levin, Aartjan J.W. te Velthuis, Bryan T. Grenfell
Defective interfering particles (DIPs) are incomplete viral genomes that modulate infection by competing with wild–type viruses and activating the innate immune response. Activation of the immune response leads to the production of cytokines and chemokines, including type I interferon (IFN), which restricts viral growth and may cause cell death. How DIPs interact with type I interferon (IFN) in spatially structured environments remains unclear. Focusing here on influenza A viruses, we developed a spatially explicit, stochastic model of in vitro viral infection that integrates virus and DIP replication, IFN signalling, and alternative dispersal modes. We find that: (1) our model captures the ring–like and patchy plaque morphologies observed experimentally; (2) IFN production peaks at an intermediate DIP ratio, reflecting a trade–off between early immune activation and sufficient co–infection; and (3) even a small fraction of long–range spread by virus and DIPs enables escape from the immune-based containment despite long-range IFN diffusion; this causes stronger antiviral responses but earlier peaks in virus egress at similar levels of cell loss. The model is available as an interactive platform: https://shiny-spatial-infection-app-production.up.railway.app/.DMAPLM: A multimodal pretrained framework for computational drug repositioning
by Hailin Chen, Zhongling Li
Drug repositioning offers an efficient route to discover new therapeutic indications for existing drugs. However, current computational drug repositioning models often face challenges related to data scarcity, heterogeneity, and therefore limited generalizability. To address these limitations, this study introduces DMAPLM, a multimodal pretrained framework for predicting drug-disease associations for further drug repositioning screening. DMAPLM leverages a lightweight dual-encoder architecture, utilizing ChemBERTa-2 for molecular encoding of drug SMILES strings and BioBERT for semantic encoding of multi-field disease texts. The framework explicitly aligns drug and disease representations through contrastive learning and employs attention-weighted pooling to emphasize informative molecular substructures. A Random Forest classifier is finally used for association prediction based on the enhanced multimodal features. We compile a new and comprehensive benchmark dataset for performance evaluation. Extensive experiments demonstrate that DMAPLM significantly outperforms six state-of-the-art baseline models, achieving an AUROC of 0.8919 and AUPR of 0.9116 under five-fold cross-validation, representing an improvement of up to 9%. Furthermore, DMAPLM exhibits robust performance in challenging cold-start scenarios, highlighting its practical utility for identifying novel drug-disease relationships. Case studies along with molecular docking analysis confirm the interpretability and biological meaningfulness of our predictions. Our study provides a powerful and interpretable approach for computational drug repositioning.Sharing the spotlight: Uncovering common attentional dynamics across species
That author's affiliation: Society for Neuroscience
Institution (first & last author): Society for Neuroscience
by Mina Glukhova, Alejandro Tlaie, Robert Taylor, Pierre-Antoine Ferracci, Katharine Shapcott, Berkutay Mert, Olga Arne, Andrei Ciuparu, Raul C. Muresan, Martha N. Havenith, Marieke L. Schölvinck
Sustained attention is a key underlying process to many natural behaviours that are shared across species. Yet the way attention is commonly studied in a lab context precludes meaningful cross-species comparisons. Here, we engaged mice, monkeys, and humans in the same, naturalistic perceptual decision task in a virtual reality environment. We captured their behaviour in several parameters along the speed/accuracy axes along which sustained attention is classically defined, and used Hidden Markov Models (HMMs) to infer four attentional states. We show that the dynamics of these states, both in terms of their durations and transitions, are more similar across species than might have been expected. Moreover, attentional state fluctuations seem to be internally generated and are not predicted by task attributes. The task and analyses developed here represent a new approach to infer the dynamics of sustained attention from naturalistic behaviours, in a way that is generalizable across species.Phase-field modeling of border cell cluster migration in <i>Drosophila</i>
by Naghmeh Akhavan, Alexander George, Michelle Starz-Gaiano, Bradford E. Peercy
Collective cell migration is a fundamental biological process that drives events such as embryonic development, wound healing, and cancer metastasis. In this study, we develop a biophysically informed phase-field model to investigate the collective migration of the border cell cluster in the Drosophila melanogaster egg chamber. Our model captures key aspects of the egg chamber architecture, including the oocyte, nurse cells, and surrounding epithelium, and incorporates both mechanical forces and biochemical cues that guide cell migration. We introduce the Tangential Interface Migration (TIM) force which captures contact-mediated propulsion generated along interfaces between the border cell cluster and surrounding nurse cells. Our simulations reveal three key features of TIM-driven migration that distinguish it from previous forms of chemotaxis: (1) the explicit nature of border cell–nurse cell overlap to initiate movement (i.e., border cells cannot move without a nurse cell substrate), (2) motion is tangential to border cell-nurse cell interfaces, and (3) persistent migration occurs even in regions where the spatial slope of chemoattractant is decreasing. Additionally, we demonstrate that with or without geometry-mediated alterations in chemoattractant distribution such as at intercellular junctions, we can vary induced migration pauses, independent of mechanical confinement. We capture an experimentally observed transition to dorsal migration at the oocyte with a sustained medio-lateral chemical cue of small amplitude. The results show how spatial constraints and interfacial forces shape collective cell movement and highlight the utility of phase-field models in capturing the interplay between tissue geometry, contact forces, and chemical signaling.Enhancing generalizability of model discovery across parameter space with multi-experiment equation learning for biological systems
by Maria-Veronica Ciocanel, John T. Nardini, Kevin B. Flores, Erica M. Rutter, Suzanne S. Sindi, Alexandria Volkening
Agent-based modeling (ABM) is a powerful tool for understanding self-organizing biological systems, but it is computationally intensive and often not analytically tractable. Equation learning (EQL) methods can derive continuum models from ABM data, but they typically require extensive simulations for each parameter set, raising concerns about generalizability. In this work, we extend EQL to Multi-experiment equation learning (ME-EQL) by introducing two methods: (i) one-at-a-time ME-EQL (OAT ME-EQL), which learns individual models for each parameter set and connects them via interpolation, and (ii) embedded structure ME-EQL (ES ME-EQL), which builds a unified model library across parameters. We demonstrate these methods by learning continuum models from a noisy birth–death mean-field model and from an on-lattice agent-based model of birth, death, and migration with spatial structure, often used to investigate cell biology experiments. We show that both methods significantly reduce the relative error in recovering parameters from agent-based simulations, with OAT ME-EQL offering better generalizability across parameter space. Our findings highlight the potential of equation learning from multiple experiments to enhance the generalizability and interpretability of learned models for complex biological systems.Monotherapy cancer drug-blind response prediction is limited to intraclass generalization
That author's affiliation: 3Argonne National Laboratory, Lamont, IL
Institution (first & last author): Mayo Clinic in Arizona
by William G. Herbert, Nicholas Chia, Paul A. Jensen, Marina R. S. Walther-Antonio
Monotherapy cancer drug response prediction (DRP) models predict the response of a cell line to a given drug. Analyzing these models’ performance includes assessing their ability to predict the response of cell lines to new drugs, i.e., drugs that are not in the training set. Drug-blind prediction displays greatly diminished performance or outright failure across a wide range of model architectures and different large pharmacogenomic datasets. Drug-blind failure is hypothesized to be caused by the relatively limited set of drugs present in these datasets. The time and cost associated with further cell line experiments is significant, and it is impossible to predict beforehand how much data would be enough to overcome drug-blind failure. We must first define how current data contributes to drug-blind failure before attempting to remedy drug-blind failure with further data collection. In this work, we quantify the extent to which drug-blind generalizability relies on mechanistic overlap of drugs between training and testing splits. We first identify that the majority of mixed set DRP model performance can be attributed to drug overfitting, likely inhibiting generalization and preventing accurate analysis. Then, by specifically probing the drug-blind ability of models, we reveal the sources of generalizable drug features are confined to shared mechanisms of action and related pathways. Furthermore, we observed that, for certain mechanisms, we can significantly improve performance by limiting the training of models to a single mechanism compared to training on all drugs simultaneously. Across multiple different model architectures examined in this paper, we observe that drug-blind performance is a poor benchmark for DRP as it does not describe model behavior, it describes dataset behavior. Our investigation displays that these deep learning models trained on large, monotherapy cell line panels can more accurately describe mechanism of action of drugs rather than their advertised connection to broader cancer biology.La benchmarking large language models for extracting biobank-derived insights into health and disease
by Manuel Corpas, Alfredo Iacoangeli
Biobank-scale datasets such as the UK Biobank have become foundational resources for advancing biomedical discovery. Yet the complexity and heterogeneity of these resources, spanning genomics, imaging, clinical records, and metadata, pose substantial barriers to access and interpretation. Large Language Models (LLMs) offer a promising avenue for making such datasets more navigable through natural language interfaces. However, the extent to which current general-purpose LLMs can retrieve and synthesize biobank-specific insights has not yet been systematically evaluated. In this study, we present a reproducible, multi-metric evaluation framework to benchmark the capabilities of leading LLMs. We evaluated six leading large language models: Gemini 3 Pro, Claude Opus 4.5, Claude Sonnet 4, GPT-5.2, Mistral Large, and DeepSeek V3, on four benchmark tasks designed to assess biobank-related knowledge retrieval. We evaluate model performance across six dimensions (coverage, semantic accuracy, factual correctness, domain knowledge, reasoning quality, and biobank specificity) and assessed output consistency using curated UK Biobank references and a robust random baseline. All models outperformed the baseline by 16× to 25 × , with strong statistical separation (p < 0.001), confirming meaningful biobank-specific knowledge retrieval. Gemini 3 Pro achieved the highest overall accuracy across tasks such as keyword synthesis, institution recognition, and topic inference, while Claude Sonnet 4 demonstrated the most uniform performance across evaluation dimensions. Our benchmark provides a rigorous framework for evaluating LLMs in biomedical settings. Using the UK Biobank as a real-world testbed, we highlight both the capabilities and limitations of current models, measuring their capacity to recall structured biomedical knowledge consistent with authoritative biobank metadata.‘Backpropagation and the brain’ realized in cortical error neuron microcircuits
by Kevin Max, Ismael Jaras, Arno Granier, Katharina A. Wilmes, Mihai A. Petrovici
Neural responses to mismatches between expected and actual stimuli have been widely reported across different species. How does the brain use such error signals for learning? While global error signals can be useful, their ability to learn complex computation at the scale observed in the brain is lacking. In comparison, more local, neuron-specific error signals enable superior performance, but their computation and propagation remain unclear. Motivated by the breakthrough of deep learning, this has inspired the ‘backpropagation and the brain’ hypothesis, i.e., that the brain implements a form of the error backpropagation algorithm. In this work, we introduce a biologically motivated, multi-area cortical microcircuit model, implementing error backpropagation under consideration of recent physiological evidence. We model populations of cortical pyramidal cells acting as representation and error neurons, with bio-plausible local and inter-area connectivity, guided by experimental observations of connectivity of the primate visual cortex. In our model, all information transfer is biologically motivated, inference and learning occur without phases, and network dynamics demonstrably approximate those of error backpropagation. We show the capabilities of our model on a wide range of benchmarks, and compare to other models, such as dendritic hierarchical predictive coding. In particular, our model addresses shortcomings of other theories in terms of scalability to many cortical areas. Finally, we make concrete predictions, which differentiate it from other theories, and which can be tested experimentally.Coherent cross-modal generation of synthetic biomedical data to advance multimodal precision medicine
by Raffaele Marchesi, Nicolò Lazzaro, Walter Endrizzi, Gianluca Leonardi, Matteo Pozzi, Flavio Ragni, Stefano Bovo, Monica Moroni, Venet Osmani, Giuseppe Jurman
Integration of multimodal, multi-omics data is critical for advancing precision medicine, yet its application is frequently limited by incomplete datasets where one or more modalities are missing. To address this challenge, we developed a generative framework capable of synthesizing any missing modality from an arbitrary subset of available modalities. We introduce Coherent Denoising, a novel ensemble-based generative diffusion method that aggregates predictions from multiple specialized, single-condition models and enforces consensus during the sampling process. We compare this approach against a multi-condition, generative model that uses a flexible masking strategy to handle arbitrary subsets of inputs. The results show that our architectures successfully generate high-fidelity data that preserve the complex biological signals required for downstream tasks. We demonstrate that the generated synthetic data can be used to maintain the performance of predictive models on incomplete patient profiles and can leverage counterfactual analysis to guide the prioritization of diagnostic tests. We validated the framework’s efficacy on a large-scale multimodal, multi-omics cohort from The Cancer Genome Atlas (TCGA) of over 10,000 samples spanning across 20 tumor types, using data modalities such as copy-number alterations (CNA), transcriptomics (RNA-Seq), proteomics (RPPA), and histopathology (WSI). This work establishes a robust and flexible generative framework to address sparsity in multimodal datasets, providing a key step toward improving precision oncology.Developmental and aging changes in brain network switching dynamics revealed by EEG phase synchronization
by Dionysios Perdikis, Rita Sleimen-Malkoun, Viktor Müller, Viktor Jirsa
Adaptive behavior depends on the brain’s capacity to vary its activity across multiple spatial and temporal scales. Yet, how distinct facets of this variability evolve from childhood to older adulthood remains poorly understood, limiting mechanistic models of neurocognitive aging. Here, we characterize lifespan neural variability using an integrated empirical-computational approach. We analyzed high-density EEG cohort data spanning 111 healthy individuals aged 9–75 years, recorded at rest and during passive and attended auditory oddball stimulation task. We extracted scale-dependent measures of EEG fluctuations amplitude and entropy, together with millisecond-resolved phase-synchrony networks in the 2–20 Hz range. Multi-condition partial least squares decomposition analysis revealed two independent lifespan trajectories. First, slow-frequency power, variance and complexity at longer timescales declined monotonically with age, indicating a progressive dampening of low-frequency fluctuations and large-scale coherence. Second, the temporal organization of phase-synchrony reconfigurations followed an inverted U-trend: young adults exhibited the slowest yet most diverse switching—characterized by low mean but high variance and low kurtosis of jump lengths at 2–6 Hz and the opposite pattern at 8–20 Hz—whereas children and older adults showed faster, more stereotyped dynamics. To mechanistically account for these patterns, we fitted a ten-node phase-oscillator model constrained by the human structural connectome. Only an intermediate, metastable coupling regime reproduced qualitatively the empirical finding of maximally heterogeneous synchrony dynamics observed in young adults, whereas deviations toward weaker or stronger coupling mimicked the children’s and older adults’ profiles. Our results demonstrate that development and aging entail changes in the switching dynamics of EEG phase synchronization, by differentially sculpting stationary and transient aspects of neural variability. This establishes time-resolved phase-synchrony metrics as sensitive, mechanistically grounded markers of neurocognitive status across the lifespan.Forecastability of infectious disease time series: are some seasons and pathogens intrinsically more difficult to forecast?
by Lauren A. White, Tomás M. León
For infectious disease forecasting challenges, individual model performance typically varies across space and time. This phenomenon raises the question: are there properties of the target time series that contribute to a particular season, location, or disease being more difficult to forecast? Here we characterize a time series’ future predictability using a forecastability metric that calculates the spectral entropy of the time series. Forecastability of syndromic influenza hospital admissions for the state of California varied widely across seasons and was positively correlated with peak burden. Next, using archived U.S. state and national forecasts targeting laboratory-confirmed COVID-19 and influenza hospital admissions, we investigated the relationship between forecastability and: (i) population size of the forecasting target, and (ii) forecast performance as measured by mean absolute error, weighted interval score (WIS), and scaled relative WIS. Forecastability increased with increasing population size of the forecasting target, and forecasting performance generally improved with higher forecastability when mitigating the effects of population size across scales. These preliminary results support the idea that some targets and respiratory virus seasons may be inherently more difficult to forecast and could help explain inter-seasonal variation in model performance.How muscle ageing affects rapid goal-directed movement: mechanistic insights from a simple model
by Delyle T. Polet, Christopher T. Richards
As humans and other animals age, passive and active muscle properties change markedly, with reduced peak tension, peak strain rate, activation and deactivation rate, and increased parallel stiffness. It is thought that these alterations modify locomotor performance, but establishing causal links is difficult when many parameters vary at once. We developed a simplified model of an elbow joint with two antagonistic Hill-type muscles, and varied the associated muscle parameters combinatorially over a large range. For a given parameter combination, we found optimal joint movements that minimized cumulative squared error to a target while starting and ending at rest. Emergent behaviour from the optimisations compared well to ballistic point-to-point arm movements in humans. Age-associated reductions of maximum isometric force, maximum strain rate and activation rate all had detrimental effects on performance, independent of other parameters. In contrast, deactivation time and passive parallel stiffness had no effect on performance on their own, but pronounced interactive effects with each other. Increasing stiffness reduced joint movement time at fast deactivation rates, but increased movement time at slow deactivation rates. This occurs because antagonist muscles resist the passive tension at rest, but are stretched eccentrically by the agonist, amplifying their active resistive force. Fast-deactivating muscles can avoid this resistive effect, allowing the passive stiffness to amplify accelerating force and enhance performance. In all cases, coactivation emerged as optimal during and after the braking period, and during the acceleration phase when stiffness increased. As deactivation time increased, so too did coactivation levels– but coactivation was not generally associated with a reduction in performance. Our simulations offer evidence that age-related changes in muscle strength, activation time and maximum contraction velocity can reduce ballistic performance in a goal-directed task, but the effects of increased muscle stiffness and deactivation time depend on their relative values.