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2603.13126 2026-03-16 q-bio.NC cs.AI

Developing the PsyCogMetrics AI Lab to Evaluate Large Language Models and Advance Cognitive Science -- A Three-Cycle Action Design Science Study

Zhiye Jin, Yibai Li, K. D. Joshi, Xuefei, Deng, Xiaobing, Li

Comments 10 pages. Prepared: April 2025; submitted: June 15, 2025; accepted: August 2025. In: Proceedings of the 59th Hawaii International Conference on System Sciences (HICSS 2026), January 2026

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Journal ref
Proceedings of the 59th Hawaii International Conference on System Sciences (HICSS), January 2026, pp. 6952-6961
英文摘要

This study presents the development of the PsyCogMetrics AI Lab (psycogmetrics.ai), an integrated, cloud-based platform that operationalizes psychometric and cognitive-science methodologies for Large Language Model (LLM) evaluation. Framed as a three-cycle Action Design Science study, the Relevance Cycle identifies key limitations in current evaluation methods and unfulfilled stakeholder needs. The Rigor Cycle draws on kernel theories such as Popperian falsifiability, Classical Test Theory, and Cognitive Load Theory to derive deductive design objectives. The Design Cycle operationalizes these objectives through nested Build-Intervene-Evaluate loops. The study contributes a novel IT artifact, a validated design for LLM evaluation, benefiting research at the intersection of AI, psychology, cognitive science, and the social and behavioral sciences.

2603.13051 2026-03-16 cs.LG q-bio.QM

Causal Cellular Context Transfer Learning (C3TL): An Efficient Architecture for Prediction of Unseen Perturbation Effects

Michael Scholkemper, Sach Mukherjee

Comments 12 Pages, 3 figures, Keywords: perturbation prediction, context transfer, lightweight, machine learning

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英文摘要

Predicting the effects of chemical and genetic perturbations on quantitative cell states is a central challenge in computational biology, molecular medicine and drug discovery. Recent work has leveraged large-scale single-cell data and massive foundation models to address this task. However, such computational resources and extensive datasets are not always accessible in academic or clinical settings, hence limiting utility. Here we propose a lightweight framework for perturbation effect prediction that exploits the structured nature of biological interventions and specific inductive biases/invariances. Our approach leverages available information concerning perturbation effects to allow generalization to novel contexts and requires only widely-available bulk molecular data. Extensive testing, comparing predictions of context-specific perturbation effects against real, large-scale interventional experiments, demonstrates accurate prediction in new contexts. The proposed approach is competitive with SOTA foundation models but requires simpler data, much smaller model sizes and less time. Focusing on robust bulk signals and efficient architectures, we show that accurate prediction of perturbation effects is possible without proprietary hardware or very large models, hence opening up ways to leverage causal learning approaches in biomedicine generally.

2603.12107 2026-03-16 cs.GT math.DS q-bio.PE

Social Distancing Equilibria in Games under Conventional SI Dynamics

Connor D Olson, Timothy C Reluga

Comments 20 pages, 8 figures

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英文摘要

The mathematical characterization of social-distancing games in classical epidemic theory remains an important question, for their applications to both infectious-disease theory and memetic theory. We consider a special case of the dynamic finite-duration SI social-distancing game where payoffs are accounted using Markov decision theory with zero-discounting, while distancing is constrained by threshold-linear running-costs, and the running-cost of perfect-distancing is finite. In this special case, we are able construct strategic equilibria satisfying the Nash best-response condition explicitly by integration. Our constructions are obtained using a new change of variables which simplifies the geometry and analysis. As it turns out, there are no singular solutions, and a time-dependent bang-bang strategy consisting of a wait-and-see phase followed by a lock-down phase is always the unique strategic equilibrium. We also show that in a restricted strategy space the bang-bang Nash equilibrium is an ESS, and that the optimal public policy exactly corresponds with the equilibrium strategy.

2603.11663 2026-03-16 q-bio.NC

Neural network-based encoding in free-viewing fMRI with gaze-aware models

Dora Gozukara, Nasir Ahmad, Katja Seeliger, Djamari Oetringer, Linda Geerligs

Comments 24 pages, 3 figures, 6 supplementary figures

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Journal ref
Neurons, Behavior, Data analysis, and Theory, 2026
英文摘要

Representations learned by convolutional neural networks (CNNs) exhibit a remarkable resemblance to information processing patterns observed in the primate visual system on large neuroimaging datasets collected under diverse, naturalistic visual stimulation, but with instruction for participants to maintain central fixation. This viewing condition, however, diverges significantly from ecologically valid visual behaviour, suppresses activity in visually active regions, and imposes substantial cognitive load on the viewing task. We present a modification of the encoding model framework, adapting it for use with naturalistic vision datasets acquired under fully natural viewing conditions, without fixation, by incorporating eye-tracking data. Our gaze-aware encoding models were trained on the StudyForrest dataset, which features task-free naturalistic movie viewing. By combining eye-tracking data with the visual content of movie frames, we generate combined subject-wise gaze-stimulus specific feature time series. These time series are constructed by sampling only the locally and temporally relevant elements of the CNN feature map for each fixation. Our results demonstrate that gaze-aware encoding models match the performance of conventional encoding models with 112x fewer model parameters. Gaze-aware encoding models were especially beneficial for participants with more dynamic eye-movement patterns. Therefore, this approach opens the door to more ecologically valid models that can be built in more naturalistic settings, such as playing games or navigating virtual environments.

2507.17058 2026-03-16 q-bio.PE cond-mat.stat-mech

How animal movement influences wildlife-vehicle collision risk: a mathematical framework for range-resident species

Benjamin Garcia de Figueiredo, Inês Silva, Michael J. Noonan, Christen H. Fleming, William F. Fagan, Justin M. Calabrese, Ricardo Martinez-Garcia

Comments 24 pages, 5 figures

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英文摘要

Wildlife-vehicle collisions (WVC) threaten both biodiversity and human safety worldwide. Despite empirical efforts to characterize the major determinants of WVC risk and optimize mitigation strategies, we still lack a theoretical framework linking traffic, landscape, and individual movement features to collision risk. Here, we introduce such a framework by leveraging recent advances in movement ecology and reaction-diffusion stochastic processes with partially absorbing boundaries. Focusing on range-resident terrestrial mammals -- responsible for most fatal WVCs -- we model interactions with a single linear road and derive exact expressions for key survival statistics, including mean collision time and road-induced lifespan reduction. These quantities are expressed in terms of measurable parameters, such as traffic intensity or road width, and movement parameters that can be robustly estimated from relocation data, such as home-range crossing times, home-range sizes, or distance between home-range center and road. Therefore, our work provides an effective theoretical framework integrating movement and road ecology, laying the foundation for data-driven, evidence-based strategies to mitigate WVCs and promote safer, more sustainable transportation networks.

2506.01787 2026-03-16 math.PR q-bio.PE

Branch lengths for geodesics in the directed landscape and mutation patterns in growing spatially structured populations

Shirshendu Ganguly, Jason Schweinsberg, Yubo Shuai

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英文摘要

Consider a population that is expanding in two-dimensional space. Suppose we collect data from a sample of individuals taken at random either from the entire population, or from near the outer boundary of the population. A quantity of interest in population genetics is the site frequency spectrum, which is the number of mutations that appear on $k$ of the $n$ sampled individuals, for $k = 1, \dots, n-1$. As long as the mutation rate is constant, this number will be roughly proportional to the total length of all branches in the genealogical tree that are on the ancestral line of $k$ sampled individuals. While the rigorous literature has primarily focused on models without any spatial structure, in many natural settings, such as tumors or bacteria colonies, growth is dictated by spatial constraints. Many such two dimensional growth models are expected to fall in the KPZ universality class. In this article we adopt the perspective that for population models in the KPZ universality class, the genealogical tree can be approximated by the tree formed by the infinite upward geodesics in the directed landscape, a universal scaling limit constructed in \cite{dov22}, starting from $n$ randomly chosen points. Relying on geodesic coalescence, we prove new asymptotic results for the lengths of the portions of these geodesics that are ancestral to $k$ of the $n$ sampled points and consequently obtain exponents driving the site frequency spectrum as predicted in \cite{fgkah16}. An important ingredient in the proof is a new tight estimate of the probability that three infinite upward geodesics stay disjoint up to time $t$, i.e., a sharp quantitative version of the well studied N3G problem, which is of independent interest.

2603.12878 2026-03-16 q-bio.NC math.DS nlin.AO nlin.CD

Pulse desynchronization of neural populations by targeting the centroid of the limit cycle in phase space

Ramón Guevara, Marco Zenari, Giorgio Nicoletti, Elisa Marini, Samir Suweis, Sandro Azaele, Marco Formentin

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英文摘要

The synchronized activity of neuronal populations can lead to pathological over-synchronization in conditions such as epilepsy and Parkinson disease. Such states can be desynchronized by brief electrical pulses. But when the underlying oscillating system is not known, as in most practical applications, to determine the specific times and intensities of pulses used for desynchronizaton is a difficult inverse problem. Here we propose a desynchronization scheme for neuronal models of bi-variate neural activity, with possible applications in the medical setting. Our main argument is the existence of a peculiar point in the phase space of the system, the centroid, that is both easy to calculate and robust under changes in the coupling constant. This important target point can be used in a control procedure because it lies in the region of minimal return times of the system.

2603.12694 2026-03-16 cs.LG q-bio.QM

RXNRECer Enables Fine-grained Enzymatic Function Annotation through Active Learning and Protein Language Models

Zhenkun Shi, Jun Zhu, Dehang Wang, BoYu Chen, Qianqian Yuan, Zhitao Mao, Fan Wei, Weining Wu, Xiaoping Liao, Hongwu Ma

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英文摘要

A key challenge in enzyme annotation is identifying the biochemical reactions catalyzed by proteins. Most existing methods rely on Enzyme Commission (EC) numbers as intermediaries: they first predict an EC number and then retrieve the associated reactions. This indirect strategy introduces ambiguity due to the complex many-to-many mappings among proteins, EC numbers, and reactions, and is further complicated by frequent updates to EC numbers and inconsistencies across databases. To address these challenges, we present RXNRECer, a transformer-based ensemble framework that directly predicts enzyme-catalyzed reactions without relying on EC numbers. It integrates protein language modeling and active learning to capture both high-level sequence semantics and fine-grained transformation patterns. Evaluations on curated cross-validation and temporal test sets demonstrate consistent improvements over six EC-based baselines, with gains of 16.54% in F1 score and 15.43% in accuracy. Beyond accuracy gains, the framework offers clear advantages for downstream applications, including scalable proteome-wide reaction annotation, enhanced specificity in refining generic reaction schemas, systematic annotation of previously uncurated proteins, and reliable identification of enzyme promiscuity. By incorporating large language models, it also provides interpretable rationales for predictions. These capabilities make RXNRECer a robust and versatile solution for EC-free, fine-grained enzyme function prediction, with potential applications across multiple areas of enzyme research and industrial applications.

2603.12628 2026-03-16 q-bio.NC cs.AI eess.SP

Towards unified brain-to-text decoding across speech production and perception

Zhizhang Yuan, Yang Yang, Gaorui Zhang, Baowen Cheng, Zehan Wu, Yuhao Xu, Xiaoying Liu, Liang Chen, Ying Mao, Meng Li

Comments 37 pages, 9 figures

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英文摘要

Speech production and perception are the main ways humans communicate daily. Prior brain-to-text decoding studies have largely focused on a single modality and alphabetic languages. Here, we present a unified brain-to-sentence decoding framework for both speech production and perception in Mandarin Chinese. The framework exhibits strong generalization ability, enabling sentence-level decoding when trained only on single-character data and supporting characters and syllables unseen during training. In addition, it allows direct and controlled comparison of neural dynamics across modalities. Mandarin speech is decoded by first classifying syllable components in Hanyu Pinyin, namely initials and finals, from neural signals, followed by a post-trained large language model (LLM) that maps sequences of toneless Pinyin syllables to Chinese sentences. To enhance LLM decoding, we designed a three-stage post-training and two-stage inference framework based on a 7-billion-parameter LLM, achieving overall performance that exceeds larger commercial LLMs with hundreds of billions of parameters or more. In addition, several characteristics were observed in Mandarin speech production and perception: speech production involved neural responses across broader cortical regions than auditory perception; channels responsive to both modalities exhibited similar activity patterns, with speech perception showing a temporal delay relative to production; and decoding performance was broadly comparable across hemispheres. Our work not only establishes the feasibility of a unified decoding framework but also provides insights into the neural characteristics of Mandarin speech production and perception. These advances contribute to brain-to-text decoding in logosyllabic languages and pave the way toward neural language decoding systems supporting multiple modalities.

2603.12351 2026-03-16 stat.ML cs.LG q-bio.QM stat.CO stat.ME

Probabilistic Joint and Individual Variation Explained (ProJIVE) for Data Integration

Raphiel J. Murden, Ganzhong Tian, Deqiang Qiu, Benajmin B. Risk

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Journal ref
Journal of Computational and Graphical Statistics (2026)
英文摘要

Collecting multiple types of data on the same set of subjects is common in modern scientific applications including, genomics, metabolomics, and neuroimaging. Joint and Individual Variance Explained (JIVE) seeks a low-rank approximation of the joint variation between two or more sets of features captured on common subjects and isolates this variation from that unique to eachset of features. We develop an expectation-maximization (EM) algorithm to estimate a probabilistic model for the JIVE framework. The model extends probabilistic principal components analysis to multiple data sets. Our maximum likelihood approach simultaneously estimates joint and individual components, which can lead to greater accuracy compared to other methods. We apply ProJIVE to measures of brain morphometry and cognition in Alzheimer's disease. ProJIVE learns biologically meaningful courses of variation, and the joint morphometry and cognition subject scores are strongly related to more expensive existing biomarkers. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Code to reproduce the analysis is available on our GitHub page.

2603.12349 2026-03-16 cs.LG cs.AI q-bio.QM stat.ML

Budget-Sensitive Discovery Scoring: A Formally Verified Framework for Evaluating AI-Guided Scientific Selection

Abhinaba Basu, Pavan Chakraborty

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Scientific discovery increasingly relies on AI systems to select candidates for expensive experimental validation, yet no principled, budget-aware evaluation framework exists for comparing selection strategies -- a gap intensified by large language models (LLMs), which generate plausible scientific proposals without reliable downstream evaluation. We introduce the Budget-Sensitive Discovery Score (BSDS), a formally verified metric -- 20 theorems machine-checked by the Lean 4 proof assistant -- that jointly penalizes false discoveries (lambda-weighted FDR) and excessive abstention (gamma-weighted coverage gap) at each budget level. Its budget-averaged form, the Discovery Quality Score (DQS), provides a single summary statistic that no proposer can inflate by performing well at a cherry-picked budget. As a case study, we apply BSDS/DQS to: do LLMs add marginal value to an existing ML pipeline for drug discovery candidate selection? We evaluate 39 proposers -- 11 mechanistic variants, 14 zero-shot LLM configurations, and 14 few-shot LLM configurations -- using SMILES representations on MoleculeNet HIV (41,127 compounds, 3.5% active, 1,000 bootstrap replicates) under both random and scaffold splits. Three findings emerge. First, the simple RF-based Greedy-ML proposer achieves the best DQS (-0.046), outperforming all MLP variants and LLM configurations. Second, no LLM surpasses the Greedy-ML baseline under zero-shot or few-shot evaluation on HIV or Tox21, establishing that LLMs provide no marginal value over an existing trained classifier. Third, the proposer hierarchy generalizes across five MoleculeNet benchmarks spanning 0.18%-46.2% prevalence, a non-drug AV safety domain, and a 9x7 grid of penalty parameters (tau >= 0.636, mean tau = 0.863). The framework applies to any setting where candidates are selected under budget constraints and asymmetric error costs.

2603.12341 2026-03-16 cs.SI q-bio.QM

Self-Reported Side Effects of Semaglutide and Tirzepatide in Online Communities

Neil K. R. Sehgal, Jena Shaw Tronieri, Lyle Ungar, Sharath Chandra Guntuku

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Social media can reveal patient experiences with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) that extend beyond clinical trial data. We analyzed 410,198 Reddit posts (May 2019-June 2025) mentioning semaglutide or tirzepatide. A total of 67,008 users self-reported using these medications, and 43.5% described at least one side effect. Gastrointestinal symptoms predominated, including nausea (36.9%), fatigue (16.7%), vomiting (16.3%), constipation (15.3%), and diarrhea (12.6%). Notably, reproductive symptoms (e.g., menstrual irregularities) and temperature-related complaints (e.g., chills, hot flashes) emerged as unrecognized potential effects. These findings highlight patient concerns not well captured in current labeling or trials. Large-scale social media analysis can complement traditional pharmacovigilance by detecting emerging safety signals and expanding understanding of the real-world safety profile of GLP-1 RAs.

2603.12307 2026-03-16 q-bio.QM eess.IV

SHREC: A Spectral Embedding-Based Approach for Ab-Initio Reconstruction of Helical Molecules

Guy Shapira, Yoel Shkolnisky

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Cryo-electron microscopy (cryo-EM) has emerged as a powerful technique for determining the three-dimensional structures of biological molecules at near-atomic resolution. However, reconstructing helical assemblies presents unique challenges due to their inherent symmetry and the need to determine unknown helical symmetry parameters. Traditional approaches require an accurate initial estimation of these parameters, which is often obtained through trial and error or prior knowledge. These requirements can lead to incorrect reconstructions, limiting the reliability of ab initio helical reconstruction. In this work, we present SHREC (Spectral Helical REConstruction), an algorithm that directly recovers the projection angles of helical segments from their two-dimensional cryo-EM images, without requiring prior knowledge of helical symmetry parameters. Our approach leverages the insight that projections of helical segments form a one-dimensional manifold, which can be recovered using spectral embedding techniques. Experimental validation on publicly available datasets demonstrates that SHREC achieves high resolution reconstructions while accurately recovering helical parameters, requiring only knowledge of the specimen's axial symmetry group. By eliminating the need for initial symmetry estimates, SHREC offers a more robust and automated pathway for determining helical structures in cryo-EM.

2603.12281 2026-03-16 q-bio.TO eess.IV

Artificial intelligence applications in Parkinson's disease via retinal imaging

Ali Jafarizadeh, Hamidreza Ashayeri, Hadi Vahedi, Parsa Khalafi, Mirsaeed Abdollahi, Navid Sobhi, Ru-San Tan, Roohallah Alizadehsani, U. Rajendra Acharya

Comments 41 pages, 6 figures, 2 tables, 72 references

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英文摘要

Parkinson's disease (PD) is projected to increase substantially due to population aging, making early diagnosis increasingly important, as timely detection may delay progression and reduce long-term complications. Retinal microvasculature has emerged as a promising anatomical biomarker of neurodegeneration, and when combined with artificial intelligence AI, retinal imaging may provide an advanced, noninvasive, and cost-effective screening strategy for PD. This study evaluated the evidence from the past 35 years regarding the capability of AI to detect early PD-related changes in retinal vascular structure. Five electronic databases including PubMed, Web of Science, Scopus, ScienceDirect, and ProQuest were systematically searched from January 1990 to January 2025. In addition, Annals of Neurology and Frontiers in Neuroscience were hand-searched, and the reference lists of included studies were screened for additional eligible publications. Nineteen studies met the inclusion criteria. Three principal diagnostic AI tasks were identified, including disease classification, retinal vessel segmentation, and PD risk stratification. The best-performing models were ShAMBi-LSTM on the Drishti dataset with 97.2 percent accuracy, 99.5 percent precision, 96.9 percent sensitivity, and an F1 score of 0.981 for classification, nnU-Net with 99.7 percent accuracy, 98.7 percent precision, 98.9 percent sensitivity, 99.8 percent specificity, and a Dice score of 98.9 percent for segmentation, and AlexNet for risk prediction with area under the curve values of 0.77, 0.68, and 0.73 across datasets. Overall, application of AI algorithms to retinal vasculature for detecting early signs of PD and predicting disease severity suggests that integration of AI with retinal biomarkers holds substantial potential for earlier and more accurate detection compared with traditional clinical evaluation alone.

2603.11234 2026-03-16 physics.bio-ph cond-mat.soft q-bio.TO

Biology and Physics

Stuart A. Newman, Sahotra Sarkar

Comments Prepared for Comprehensive Philosophy of Science (Ed. Sven Ove Hansson; Elsevier), Section on Philosophy of Biology (ed. Francesca Merlin)

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This article frames the relation between biology and physics by characterizing the former as a subdiscipline rather than a special case of the latter. To do this, we posit biological physics as the science of living matter in contrast to classic biophysics, the study of organismal properties by physical techniques. At the scale of the individual cell, living matter is nonunitary, i.e., not composed of aggregated subunits, and has features (e.g., intracellular organizational arrangements and biomolecular condensates) that are unlike any materials of the nonliving world. In transiently or constitutively multicellular forms (social microorganisms, animals, plants), living matter sustains physical processes that are generic (shared with nonliving matter, e.g., subunit communication by molecular diffusion in cellular slime molds), biogeneric (analogous to nonliving matter but realized through cellular activities, e.g., subunit demixing in animal embryos) or nongeneric (pertaining to sui generis materials, e.g., budding of active solids in plants). This "forms of matter" perspective is philosophically situated in the dialectical materialism of Engels and Hessen and the multilevel physicalism of Neurath and the logical empiricists. We counterpose this view to informationism and to genetic and other hierarchically reductionist physical theories of biological systems and highlight open questions regarding incompletely characterized and enigmatic forms of living matter.

2603.10161 2026-03-16 q-bio.GN

Omics Data Discovery Agents

Alexandre Hutton, Jesse G. Meyer

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英文摘要

The biomedical literature contains a vast collection of omics studies, yet most published data remain functionally inaccessible for computational reuse. When raw data are deposited in public repositories, essential information for reproducing reported results is dispersed across main text, supplementary files, and code repositories. In rarer instances where intermediate data is made available (e.g. protein abundance files), its location is irregular. In this article, we present an agentic framework that fetches omics-related articles and transforms the unstructured information into searchable research objects. Our system employs large language model (LLM) agents with access to tools for fetching omics studies, extracting article metadata, identifying and downloading published data, executing containerized quantification pipelines, and running analyses to address novel question. We demonstrate automated metadata extraction from PubMed Central articles, achieving 80% precision for dataset identification from standard data repositories. Using model context protocol (MCP) servers to expose containerized analysis tools, our set of agents were able to identify a set of relevant articles, download the associated datasets, and re-quantify the proteomics data. The results had a 63% overlap in differentially expressed proteins when matching reported preprocessing methods. Furthermore, we show that agents can identify semantically similar studies, determine data compatibility, and perform cross-study comparisons, revealing consistent protein regulation patterns in liver fibrosis. This work establishes a foundation for converting the static biomedical literature into an executable, queryable resource that enables automated data reuse at scale.

2602.07805 2026-03-16 q-bio.GN

MetaHQ: Harmonized, high-quality metadata annotations of public omics samples and studies

Parker Hicks, Lydia E Valtadoros, Christopher A Mancuso, Faisal Alquadoomi, Kayla A Johnson, Sneha Sundar, Arjun Krishnan

Comments 7 pages main text, 4 pages Supplemental Figures, 1 page Supplemental Table, 1 page Supplemental File. The replacement added three references that were missing in the original submission and made minor formatting changes

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英文摘要

Public omics databases like the Gene Expression Omnibus and the Sequence Read Archive offer substantial opportunities for data reuse to address novel biomedical questions. However, it is still difficult to find samples and studies of interest since they are described by free-text metadata and lack standardized annotations. To address this issue, multiple research groups have undertaken curation efforts to add standardized annotations to large collections of these data, but these annotations are fragmented across online resources and are stored in different formats subject to varying standardization criteria, hindering the integration of annotations across sources. We developed MetaHQ to harmonize and distribute standardized metadata for public omics samples. MetaHQ comprises a database with nearly 200,000 annotations from 13 sources and a user-friendly command-line interface (CLI) to query the database and retrieve annotations. The MetaHQ CLI is deployed as a Python Package on PyPI at https://pypi.org/project/metahq-cli that accesses the MetaHQ database available at https://doi.org/10.5281/zenodo.18462463. Project source code and documentation are available at https://github.com/krishnanlab/meta-hq.

2510.09816 2026-03-16 q-bio.NC math.OC physics.bio-ph physics.data-an stat.ML

A mathematical theory for understanding when abstract representations emerge in neural networks

Bin Wang, W. Jeffrey Johnston, Stefano Fusi

Comments 19 pages, 8 figures

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Recent experiments in neuroscience reveal that task-relevant variables are often encoded in approximately orthogonal subspaces of neural population activity. These disentangled, or abstract, representations have been observed in multiple brain areas and across different species. These representations have been shown to support out of distribution generalization and rapid learning of novel tasks. The mechanisms by which these representations emerge remain poorly understood, especially in the case of supervised task behavior. Here, we show mathematically that abstract representations of latent variables are guaranteed to appear in the hidden layer of feedforward nonlinear networks when they are trained on tasks that depend directly on these latent variables. These learned abstract representations reflect the semantics of the input stimuli. To show this, we reformulate the usual optimization over the network weights into a mean field optimization problem over the distribution of neural preactivations. We then apply this framework to finite-width ReLU networks and show that the hidden layer of these networks will exhibit an abstract representation at all global minima of the task objective. Finally, we extend our findings to two broad families of activation functions as well as deep feedforward architectures. Together, our results provide an explanation for the widely observed abstract representations in both the brain and artificial neural networks. In addition, the general framework that we develop here provides a mathematically tractable toolkit for understanding the emergence of different kinds of representations in task-optimized, feature-learning network models.

2507.20205 2026-03-16 q-bio.NC cs.GR

HOI-Brain: a novel multi-channel transformers framework for brain disorder diagnosis by accurately extracting signed higher-order interactions from fMRI

Dengyi Zhao, Zhiheng Zhou, Guiying Yan, Dongxiao Yu, Xingqin Qi

Comments accepted by Medical Image Analysis

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Accurately characterizing higher-order interactions of brain regions and extracting interpretable organizational patterns from Functional Magnetic Resonance Imaging data is crucial for brain disease diagnosis. Current graph-based deep learning models primarily focus on pairwise or triadic patterns while neglecting signed higher-order interactions, limiting comprehensive understanding of brain-wide communication. We propose HOI-Brain, a novel computational framework leveraging signed higher-order interactions and organizational patterns in fMRI data for brain disease diagnosis. First, we introduce a co-fluctuation measure based on Multiplication of Temporal Derivatives to detect higher-order interactions with temporal resolution. We then distinguish positive and negative synergistic interactions, encoding them in signed weighted simplicial complexes to reveal brain communication insights. Using Persistent Homology theory, we apply two filtration processes to these complexes to extract signed higher-dimensional neural organizations spatiotemporally. Finally, we propose a multi-channel brain Transformer to integrate heterogeneous topological features. Experiments on Alzheimer' s disease, Parkinson' s syndrome, and autism spectrum disorder datasets demonstrate our framework' s superiority, effectiveness, and interpretability. The identified key brain regions and higher-order patterns align with neuroscience literature, providing meaningful biological insights.

2507.18557 2026-03-16 q-bio.QM

Deep Learning for Blood-Brain Barrier Permeability Prediction: From Discriminative Models to Mechanism-Aware Design

Zihan Yang, Yuchen Xiao

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Predicting whether a molecule can cross the blood-brain barrier (BBB) is a key step in early-stage neuro-pharmaceutical design, directly influencing the efficiency and success rate of drug development. Traditional methods based on physicochemical properties are prone to systematic misjudgements due to their reliance on previous empirical evidence. Early machine learning (ML) models, although data-driven, often suffer from limited capacity, poor generalization, and insufficient interpretability. In recent years, more advanced models have become essential tools for predicting BBB permeability and guiding related drug design, owing to their ability to simulate molecular structures and capture complex biological mechanisms. This article systematically reviews the evolution of this field-from deep neural networks to graph-based structural modelling-highlighting the advantages of multi-task and multimodal learning strategies in identifying mechanism-related features. We further explore the emerging potential of generative models and causal inference methods for integrating permeability prediction with mechanism-aware drug design. Nowadays, ML-based BBB crossing prediction is in the critical transition from mere discriminative classification toward structure-function modelling from a mechanistic perspective. This paradigm shift provides a methodological progression and future roadmap for the integration of AI into neuropharmacological development.

2502.20600 2026-03-16 physics.bio-ph cond-mat.stat-mech q-bio.QM

Evolution and Pathogenicity of SARS-CoVs: A Microcanonical Analysis of Receptor-Binding Motifs

Rafael B. Frigori

Comments 7 pages, 4 figures

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Journal ref
Phys Rev E . 2025 Mar;111(3-1):034401
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The rapid evolution and global impact of coronaviruses, notably SARS-CoV-1 and SARS-CoV-2, underscore the importance of understanding their molecular mechanisms in detail. This study focuses on the receptor-binding motif (RBM) within the Spike protein of these viruses, a critical element for viral entry through interaction with the ACE2 receptor. We investigate the sequence variations in the RBM across SARS-CoV-1, SARS-CoV-2 and its early variants of concern (VOCs). Utilizing multicanonical simulations and microcanonical analysis, we examine how these variations influence the folding dynamics, thermostability, and solubility of the RBMs. Our methodology includes calculating the density of states (DoS) to identify structural phase transitions and assess thermodynamic properties. Furthermore, we solve the Poisson-Boltzmann equation to model the solubility of the RBMs in aqueous environments. This methodology is expected to elucidate structural and functional differences in viral evolution and pathogenicity, likely improving targeted treatments and vaccines.

2401.02739 2026-03-16 cs.LG q-bio.QM stat.ML

Denoising Diffusion Variational Inference: Diffusion Models as Expressive Variational Posteriors

Wasu Top Piriyakulkij, Yingheng Wang, Volodymyr Kuleshov

Comments published at AAAI 2025; the first two authors contribute equally to this work; code available at https://github.com/topwasu/DDVI

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We propose denoising diffusion variational inference (DDVI), a black-box variational inference algorithm for latent variable models which relies on diffusion models as flexible approximate posteriors. Specifically, our method introduces an expressive class of diffusion-based variational posteriors that perform iterative refinement in latent space; we train these posteriors with a novel regularized evidence lower bound (ELBO) on the marginal likelihood inspired by the wake-sleep algorithm. Our method is easy to implement (it fits a regularized extension of the ELBO), is compatible with black-box variational inference, and outperforms alternative classes of approximate posteriors based on normalizing flows or adversarial networks. We find that DDVI improves inference and learning in deep latent variable models across common benchmarks as well as on a motivating task in biology -- inferring latent ancestry from human genomes -- where it outperforms strong baselines on the Thousand Genomes dataset.

2311.09838 2026-03-16 stat.ME q-bio.GN q-bio.PE stat.AP stat.CO

Bayesian Inference of Reproduction Number from Epidemiological and Genetic Data Using Particle MCMC

Alicia Gill, Jere Koskela, Xavier Didelot, Richard G. Everitt

Comments 24 pages, 11 figures (30 pages, 19 figures including appendices)

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英文摘要

Inference of the reproduction number through time is of vital importance during an epidemic outbreak. Typically, epidemiologists tackle this using observed prevalence or incidence data. However, prevalence and incidence data alone is often noisy or partial. Models can also have identifiability issues with determining whether a large amount of a small epidemic or a small amount of a large epidemic has been observed. Sequencing data however is becoming more abundant, so approaches which can incorporate genetic data are an active area of research. We propose using particle MCMC methods to infer the time-varying reproduction number from a combination of prevalence data reported at a set of discrete times and a dated phylogeny reconstructed from sequences. We validate our approach on simulated epidemics with a variety of scenarios. We then apply the method to real data sets of HIV-1 in North Carolina, USA and tuberculosis in Buenos Aires, Argentina. The models and algorithms are implemented in an open source R package called EpiSky which is available at https://github.com/alicia-gill/EpiSky.

2208.10228 2026-03-16 cs.CL cs.LG q-bio.BM

Review of Natural Language Processing in Pharmacology

Dimitar Trajanov, Vangel Trajkovski, Makedonka Dimitrieva, Jovana Dobreva, Milos Jovanovik, Matej Klemen, Aleš Žagar, Marko Robnik-Šikonja

Comments 42 pages, 2 figures, 7 tables

详情
Journal ref
Pharmacological Reviews, Volume 75, Issue 4, pp. 714-738, 2023
英文摘要

Natural language processing (NLP) is an area of artificial intelligence that applies information technologies to process the human language, understand it to a certain degree, and use it in various applications. This area has rapidly developed in the last few years and now employs modern variants of deep neural networks to extract relevant patterns from large text corpora. The main objective of this work is to survey the recent use of NLP in the field of pharmacology. As our work shows, NLP is a highly relevant information extraction and processing approach for pharmacology. It has been used extensively, from intelligent searches through thousands of medical documents to finding traces of adversarial drug interactions in social media. We split our coverage into five categories to survey modern NLP methodology, commonly addressed tasks, relevant textual data, knowledge bases, and useful programming libraries. We split each of the five categories into appropriate subcategories, describe their main properties and ideas, and summarize them in a tabular form. The resulting survey presents a comprehensive overview of the area, useful to practitioners and interested observers.