Identification and Counterfactual Analysis in Incomplete Models with Support and Moment Restrictions

This paper develops a unified identification framework for counterfactual analysis in incomplete models characterized by support and moment restrictions. I demonstrate that identifying structural parameters and conducting counterfactual analyses are isomorphic tasks. By embedding counterfactual restrictions within an augmented structural model specification, this approach bypasses the conventional "estimate-then-simulate" workflow and the need to simulate outcomes from models with set predictions. To make this approach operational, I extend sharp identification results for the support-function approach beyond the integrable boundedness condition that is imposed in sharp random-set characterizations but may be violated in economically relevant counterfactual analyses. Under minimal regularity conditions, I prove that the support-function approach remains sharp for the $moment$ $closure$ of the identified set. Furthermore, I introduce an irreducibility condition requiring all support implications to be made explicit. I show that for irreducible models, the identified set and its moment closure are statistically indistinguishable in finite samples. Together, these results justify using support-function methods in counterfactual settings where traditional sharpness fails and clarify the distinct roles of support and moment restrictions in empirical practice.


ForeComp: An R Package for Comparing Predictive Accuracy Using Fixed-Smoothing Asymptotics

We introduce ForeComp, an R package for comparing predictive accuracy using Diebold-Mariano type tests of equal predictive ability with standard and fixed smoothing inference. The package provides a common interface for loss differential based testing and includes Plot Tradeoff, a visual diagnostic for bandwidth sensitivity and the size-power tradeoff. We illustrate the toolkit with Survey of Professional Forecasters applications and Monte Carlo evidence on finite-sample performance.


On the Rates of Convergence of Induced Ordered Statistics and their Applications

Federico A. Bugni
Ivan A. Canay
Deborah Kim

Induced order statistics (IOS) arise when sample units are reordered according to the value of an auxiliary variable, and the associated responses are analyzed in that induced order. IOS play a central role in applications where the goal is to approximate the conditional distribution of an outcome at a fixed covariate value using observations whose covariates lie closest to that point, including regression discontinuity designs, k-nearest-neighbor methods, and distributionally robust optimization. Existing asymptotic results allow the dimension of the IOS vector to grow with the sample size only under smoothness conditions that are often too restrictive for practical data-generating processes. In particular, these conditions rule out boundary points, which are central to regression discontinuity designs. This paper develops general convergence rates for IOS under primitive and comparatively weak assumptions. We derive sharp marginal rates for the approximation of the target conditional distribution in Hellinger and total variation distances under quadratic mean differentiability and show how these marginal rates translate into joint convergence rates for the IOS vector. Our results are widely applicable: they rely on a standard smoothness condition and accommodate both interior and boundary conditioning points, as required in regression discontinuity and related settings. In the supplementary appendix, we provide complementary results under a Taylor/Holder remainder condition. Our results reveal a clear trade-off between smoothness and speed of convergence, identify regimes in which Hellinger and total variation distances behave differently, and provide explicit growth conditions on the number of nearest neighbors.


Integrating Heterogeneous Information in Randomized Experiments: A Unified Calibration Framework

In modern randomized experiments, large-scale data collection increasingly yields rich baseline covariates and auxiliary information from multiple sources. Such information offers opportunities for more precise treatment effect estimation, but it also raises the challenge of integrating heterogeneous information coherently without compromising validity. Covariate-adaptive randomization (CAR) is widely used to improve covariate balance at the design stage, but it typically balances only a small set of covariates used to form strata, making covariate adjustment at the analysis stage essential for more efficient estimation of treatment effects. Beyond standard covariate adjustment, it is often desirable to incorporate auxiliary information, including cross-stratum information, predictions from various machine learning models, and external data from historical trials or real-world sources. While this auxiliary information is widely available, existing covariate adjustment methods under CAR primarily exploit within-stratum covariates and do not provide a coherent mechanism for integrating it. We propose a unified calibration framework that integrates such information through an information proxy vector and calibration weights defined by a convex optimization problem. The resulting estimator recovers many recent covariate adjustment procedures as special cases while providing a systematic mechanism for both internal and external information borrowing within a single framework. We establish large-sample validity and a no-harm efficiency guarantee, showing that incorporating additional information sources cannot increase asymptotic variance, and we extend the theory to settings in which both the number of strata and the number of information sources grow with the sample size.


TEA-Time: Transporting Effects Across Time

Harsh Parikh
Gabriel Levin-Konigsberg
Dominique Perrault-Joncas
Alexander Volfovsky

Treatment effects estimated from randomized controlled trials are local not only to the study population but also to the time at which the trial was conducted. We develop a framework for temporal transportation: extrapolating treatment effects to time periods where no experiment was conducted. We target the transported average treatment effect (TATE) and show that under a separable temporal effects assumption, the TATE decomposes into an observed average treatment effect and a temporal ratio. We provide two identification strategies -- one using replicated trials comparing the same treatments at different times, another using common treatment arms observed across time -- and develop doubly robust, semiparametrically efficient estimators for each. Monte Carlo simulations confirm that both estimators achieve nominal coverage, with the common arm strategy yielding substantial efficiency gains when its stronger assumptions hold. We apply our methods to A/B tests from the Upworthy Research Archive, demonstrating that the two strategies exhibit a variance-bias tradeoff: the common arm approach offers greater precision but may incur bias when treatments interact heterogeneously with temporal factors.


Hippocratic Utility

A utility function has been proposed that values more those lives that are saved by not imposing a harmful treatment and values less those lives that could be saved by treating people who would otherwise die. I do not dispute the ethical motivation behind this kind of asymmetry. However, as my example illustrates, the scope of applicability of such a decision criterion may be limited.


P vs NP Problem in Portfolio Optimization: Integrating the Markowitz-CAPM Framework with Cardinality Constraints and Black-Scholes Derivative Pricing

This paper makes the Millennium Prize problem P vs NP operational in quantitative finance by studying cardinality-constrained portfolio selection. Starting from the convex Markowitz mean-variance program with CAPM-based expected returns (Rf plus beta times ERP), we impose a hard sparsity rule that limits the portfolio to K assets out of approximately 94 industry portfolios (Damodaran). The constraint couples discrete subset selection with continuous weight optimization, yielding a mixed-integer quadratic program and an NP-hard search space that grows combinatorially with n and K. We therefore evaluate scalable approximation schemes (greedy screening, Monte Carlo sampling, and genetic algorithms) under a replication-oriented protocol with random-seed control, distributional performance summaries (median and quantiles), runtime profiling, and convergence diagnostics. Dependence structure is documented via correlation and covariance diagnostics and positive-semidefinite checks to link algorithm behavior to the geometry implied by the risk matrix. To support the title's derivatives component, we add a European call option priced by the Black-Scholes model and map it into CAPM-consistent moments using delta-based linearization, validated with a bump test and moneyness/maturity sensitivity. Results highlight how the cardinality constraint reshapes the attainable efficient frontier, why stability and computational-cost trade-offs matter more than single-best runs, and how common-factor dependence can limit diversification in K-sparse solutions. The study provides a reproducible template for NP-hard portfolio optimization with transparent inputs and extensible derivative overlays.


ParetoEnsembles.jl: A Julia Package for Multiobjective Parameter Estimation Using Pareto Optimal Ensemble Techniques

Mathematical models of natural and man-made systems often have many adjustable parameters that must be estimated from multiple, potentially conflicting datasets. Rather than reporting a single best-fit parameter vector, it is often more informative to generate an ensemble of parameter sets that collectively map out the trade-offs among competing objectives. This paper presents ParetoEnsembles.jl, an open-source Julia package that generates such ensembles using Pareto Optimal Ensemble Techniques (POETs), a simulated-annealing-based algorithm that requires no gradient information. The implementation corrects the original dominance relation from weak to strict Pareto dominance, reduces the per-iteration ranking cost from $O(n^2 m)$ to $O(nm)$ through an incremental update scheme, and adds multi-chain parallel execution for improved front coverage. We demonstrate the package on a cell-free gene expression model fitted to experimental data and a blood coagulation cascade model with ten estimated rate constants and three objectives. A controlled synthetic-data study reveals parameter identifiability structure, with individual rate constants off by several-fold yet model predictions accurate to 7%. A five-replicate coverage analysis confirms that timing features are reliably covered while peak amplitude is systematically overconfident. Validation against published experimental thrombin generation data demonstrates that the ensemble predicts held-out conditions to within 10% despite inherent model approximation error. By making ensemble generation lightweight and accessible, ParetoEnsembles.jl aims to lower the barrier to routine uncertainty characterization in mechanistic modeling.


Quantifying Cross-Modal Interactions in Multimodal Glioma Survival Prediction via InterSHAP: Evidence for Additive Signal Integration

Multimodal deep learning for cancer prognosis is commonly assumed to benefit from synergistic cross-modal interactions, yet this assumption has not been directly tested in survival prediction settings. This work adapts InterSHAP, a Shapley interaction index-based metric, from classification to Cox proportional hazards models and applies it to quantify cross-modal interactions in glioma survival prediction. Using TCGA-GBM and TCGA-LGG data (n=575), we evaluate four fusion architectures combining whole-slide image (WSI) and RNA-seq features. Our central finding is an inverse relationship between predictive performance and measured interaction: architectures achieving superior discrimination (C-index 0.64$\to$0.82) exhibit equivalent or lower cross-modal interaction (4.8\%$\to$3.0\%). Variance decomposition reveals stable additive contributions across all architectures (WSI${\approx}$40\%, RNA${\approx}$55\%, Interaction${\approx}$4\%), indicating that performance gains arise from complementary signal aggregation rather than learned synergy. These findings provide a practical model auditing tool for comparing fusion strategies, reframe the role of architectural complexity in multimodal fusion, and have implications for privacy-preserving federated deployment.


Growth-rate distributions at stationarity

We propose new analytical tools for describing growth-rate distributions generated by stationary time-series. Our analysis shows how deviations from normality are not pathological behaviour, as suggested by some traditional views, but instead can be accounted for by clean and general statistical considerations. In contrast, strict normality is the effect of specific modelling choices. Systems characterized by stationary Gamma or heavy-tailed abundance distributions produce log-growth-rate distributions well described by a generalized logistic distribution, which can describe tent-shaped or nearly normal datasets and serves as a useful null model for these observables. These results prove that, for large enough time lags, in practice, growth-rate distributions cease to be time-dependent and exhibit finite variance. Based on this analysis, we identify some key stylized macroecological patterns and specific stochastic differential equations capable of reproducing them. A pragmatic workflow for heuristic selection between these models is then introduced. This approach is particularly useful for systems with limited data-tracking quality, where applying sophisticated inference methods is challenging.


Multimodal Machine Learning for Early Prediction of Metastasis in a Swedish Multi-Cancer Cohort

Franco Rugolon
Korbinian Randl
Braslav Jovanovic
Ioanna Miliou
Panagiotis Papapetrou

Multimodal Machine Learning offers a holistic view of a patient's status, integrating structured and unstructured data from electronic health records (EHR). We propose a framework to predict metastasis risk one month prior to diagnosis, using six months of clinical history from EHR data. Data from four cancer cohorts collected at Karolinska University Hospital (Stockholm, Sweden) were analyzed: breast (n = 743), colon (n = 387), lung (n = 870), and prostate (n = 1890). The dataset included demographics, comorbidities, laboratory results, medications, and clinical text. We compared traditional and deep learning classifiers across single modalities and multimodal combinations, using various fusion strategies and a Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) 2a design, with an 80-20 development-validation split to ensure a rigorous, repeatable evaluation. Performance was evaluated using AUROC, AUPRC, F1 score, sensitivity, and specificity. We then employed a multimodal adaptation of SHAP to analyze the classifiers' reasoning. Intermediate fusion achieved the highest F1 scores on breast (0.845), colon (0.786), and prostate cancer (0.845), demonstrating strong predictive performance. For lung cancer, the intermediate fusion achieved an F1 score of 0.819, while the text-only model achieved the highest, with an F1 score of 0.829. Deep learning classifiers consistently outperformed traditional models. Colon cancer, the smallest cohort, had the lowest performance, highlighting the importance of sufficient training data. SHAP analysis showed that the relative importance of modalities varied across cancer types. Fusion strategies offer distinct strengths and weaknesses. Intermediate fusion consistently delivered the best results, but strategy choices should align with data characteristics and organizational needs.


FcsIT: An Open-Source, Cross-Platform Tool for Correlation and Analysis of Fluorescence Correlation Spectroscopy Data

FcsIT is a platform-independent, open-source tool for calculating the correlation and fitting fluorescence correlation spectroscopy data. The software is written in Python and uses a powerful Dear PyGUI engine for its interface. It provides reading and correlating the TTTR data, as well as TCSPC filtering of the photon time-trace data. The circular-block bootstrap method applied to the calculation of correlation data and its variance results in data quality comparable to that obtained with commercially available software. An intuitive fitting interface provides efficient analysis of large datasets and includes nine predefined mathematical models for fitting correlation curves. Moreover, it allows users to add their own models in a user-friendly manner. Validation of the FcsIT tool against simulated FCS data and real FCS experiments confirms its usability and potential appeal to a wide variety of FCS users.


Sampling from the Solution Space and Metabolic Environments of Genome-Scale Metabolic Models

Flux sampling is an analysis that, based on a distribution, picks randomly an efficient number of points from the solution space of a metabolic model. Unlike most constraint-based analyses, flux sampling does not require an objective function to optimize, allowing for the exploration of the whole spectrum of the phenotypes a species can exhibit. However, sampling can also be restricted to a subspace where a chosen objective reaches at least a specified fraction of its optimum. This targeted approach adds value when investigating phenotypes that are optimal for a specific function. Contrary to Flux Balance Analysis, which returns a single solution, sampling leverages statistical power to uncover phenotypes that otherwise would be masked. This can be especially useful when changing the conditions (medium) in which a species lives. Here, we highlight some state-of-the-art methods for applying flux sampling at Genome-Scale Metabolic Models in different scenarios, and we showcase flux sampling applications


Retrospective Economic Evaluation of Group Testing in the COVID-19 Pandemic

Michael Balzer
Kainat Khowaja
Christiane Fuchs

Surveillance of diseases in a pandemic is an important part of public health policy. Diagnostic testing at the individual level is often infeasible due to resource constraints. To circumvent these constraints, group testing can be applied. The economic cost evaluation from the payer's perspective typically focuses only on deterministic costs which overlooks the substantial economic impact of productivity losses resulting from quarantine and workplace disruptions. The objective of this article is to develop a mathematical model for a retrospective economic evaluation of group testing that incorporates both deterministic costs and income-based economic loss. Group testing algorithms are revisited and simulated at optimized pool sizes to determine the required number of tests. Income data from the German Socio-Economic Panel are integrated into a mathematical model to capture the economic loss. Afterward, hybrid Monte Carlo experiments are conducted by evaluating the economic cost in the Coronavirus disease 2019 pandemic in Germany. Monte Carlo experiments show that the optimal choice of group testing algorithms changes substantially when income-based economic losses are included. Evaluations considering only deterministic costs systematically underestimate the total economic cost. Algorithms with a longer quarantine duration are less attractive than shorter quarantine duration if income-based economic loss is accounted for. The findings show that current evaluations underestimate the true economic cost. Group testing algorithms with shorter duration and fewer stages are preferred, even when they require a larger number of tests. These results underscore the importance of incorporating income-based economic loss into a mathematical model.


Cardiovascular-Kidney-Metabolic Health: Insights from Wearables and Blood Biomarkers

Zeinab Esmaeilpour
A. Ali Heydari
Daniel McDuff
Anthony Z Faranesh
Conor Heneghan
Shwetak Patel
Mark Malhotra
Cathy Speed
Javier L. Prieto
Ahmed A. Metwally

Cardiovascular-Kidney-Metabolic (CKM) syndrome represents a growing public health crisis, yet the subclinical heterogeneity of its component systems remains underexplored. Early detection of physiological deviation is critical for preventing irreversible organ damage and mortality. Here, we characterize the prevalence and interplay of CKM impairment in a US cohort (N=841) by integrating continuous wearable data with clinical biomarkers. We assessed cardiovascular, kidney via clinical biomarkers, namely Chol/HDL, eGFR, as well as metabolic health risk through Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We show that while metabolic and cardiovascular disruptions are significantly associated (r=0.26, p<0.001), early-stage kidney impairment manifests independently. Utilizing a normalized deviance score, we identified significant health impairments in 29.0% of the cohort. Cardiovascular deviation was the most prevalent singular phenotype (13.3%), followed by metabolic (9.1%) and renal (6.25%) deviations, with dual metabolic-cardiovascular impairment occurring in only 2.2% of participants. These findings suggest that high system-specific deviance may serve as an indicator for accelerated physiological aging within the respective organ system. Furthermore, feature ablation analysis revealed that step count, Active Zone Minutes, and resting heart rate are the most potent wearable-derived predictors of cardiovascular and metabolic decline. These findings underscore the necessity of a multi-system subtyping approach, demonstrating that wearable-derived phenotypes can facilitate the early, targeted interventions required to manage the complex landscape of CKM syndrome.


Quantitative mapping of dynamic 3D transport in growing cells via volumetric spatio-temporal image correlation spectroscopy (vSTICS)

Quantitatively mapping three-dimensional (3D) flow, diffusion, and particle density in crowded living cells remains challenging because most dynamic optical microscopy measurements are effectively planar and existing analysis methods struggle with dense, noisy volumetric data. We introduce volumetric spatio-temporal image correlation spectroscopy (vSTICS), a framework that recovers voxel-resolved flow, diffusion coefficients, and particle densities from 3D fluorescence time series. Growing Camellia japonica pollen tubes were imaged with field-synthesis lattice light-sheet microscopy, and localized 3D spatio-temporal correlation analysis was applied to overlapping volumetric samples to generate maps of velocity, diffusion, and density. Validation with synthetic flow-diffusion simulations showed accurate recovery of seeded transport parameters, including velocities near $3$ $μ$m s$^{-1}$ and diffusion near $10^{-3}$ $μ$m$^2$ s$^{-1}$. Fluorescent microsphere experiments verified particle number and point spread function readouts and measured diffusion coefficients of $0.3 \pm 0.1$ $μ$m$^2$ s$^{-1}$ in gel, consistent with imaging-FCS measurements of $0.5 \pm 0.2$ $μ$m$^2$ s$^{-1}$. Applied to mitochondria in pollen tubes, vSTICS resolved a bidirectional reverse-fountain pattern with slower anterograde transport ($0.1$-$1$ $μ$m s$^{-1}$) and faster retrograde motion peaking near $3$ $μ$m s$^{-1}$, plus a retrograde corridor about $2$ $μ$m wide. Density and diffusion maps indicated a denser, more advective core and higher peripheral diffusion. High-density sub-diffraction vesicle mapping produced similar velocity landscapes with about ten-fold higher particle densities. These results establish vSTICS as a practical method for quantitative 3D mapping of intracellular transport and refines the reverse-fountain model by revealing asymmetric, predominantly transverse circulation.


Self-evolving AI agents for protein discovery and directed evolution

Yang Tan
Lingrong Zhang
Mingchen Li
Yuanxi Yu
Bozitao Zhong
Bingxin Zhou
Nanqing Dong
Liang Hong

Protein scientific discovery is bottlenecked by the manual orchestration of information and algorithms, while general agents are insufficient in complex domain projects. VenusFactory2 provides an autonomous framework that shifts from static tool usage to dynamic workflow synthesis via a self-evolving multi-agent infrastructure to address protein-related demands. It outperforms a set of well-known agents on the VenusAgentEval benchmark, and autonomously organizes the discovery and optimization of proteins from a single natural language prompt.


Autonomous Agent-Orchestrated Digital Twins (AADT): Leveraging the OpenClaw Framework for State Synchronization in Rare Genetic Disorders

Hongzhuo Chen
Zhanliang Wang
Quan M. Nguyen
Gongbo Zhang
Chunhua Weng
Kai Wang

Background: Medical Digital Twins (MDTs) are computational representations of individual patients that integrate clinical, genomic, and physiological data to support diagnosis, treatment planning, and outcome prediction. However, most MDTs remain static or passively updated, creating a critical synchronization gap, especially in rare genetic disorders where phenotypes, genomic interpretations, and care guidelines evolve over time.   Methods: We propose an agent-orchestrated digital twin framework using OpenClaw's proactive "heartbeat" mechanism and modular Agent Skills. This Autonomous Agent-orchestrated Digital Twin (AADT) system continuously monitors local and external data streams (e.g., patient-reported phenotypes and updates in variant classification databases) and executes automated workflows for data ingestion, normalization, state updates, and trigger-based analysis.   Results: A prototype implementation demonstrates that agent orchestration can continuously synchronize MDT states with both longitudinal phenotype updates and evolving genomic knowledge. In rare disease settings, this enables earlier diagnosis and more accurate modeling of disease progression. We present two case studies, including variant reinterpretation and longitudinal phenotype tracking, highlighting how AADTs support timely, auditable updates for both research and clinical care.   Conclusion: The AADT framework addresses the key bottleneck of real-time synchronization in MDTs, enabling scalable and continuously updated patient models. We also discuss data security considerations and mitigation strategies through human-in-the-loop system design.


Beyond BMI: Smartphone Body Composition Phenotyping for Cardiometabolic Risk Assessment

Dr Menglian Zhou
Mr Arno Charton
Ms Emily Blanchard
Mr Lawrence Cai
Dr Tracy Giest
Dr Herschel Watkins
Dr Mohamed Bouterfa
Ms Jackie Wasson
Dr Keerthana Natarajan
Mr Aniket Deshpande
Dr Jiening Zhan
Dr Shelten Yuen
Dr Xavi Prieto
Jacqueline Shreibati
Mark Malhotra
Shwetak Patel
Ms Lindsey Sunden
Dr Cathy Speed
Ms Alicia Kokoszka
Dr Aravind Natarajan
Dr Alexandros Pantelopoulos
Dr Ahmed Metwally

Body Mass Index (BMI) is a widely accessible but imprecise proxy of cardiometabolic health. While assessing true body composition is superior, gold-standard methods like Dual-Energy X-ray Absorptiometry (DXA) are not scalable. We address this gap by developing and validating "PhotoScan," a method to estimate body composition from smartphone imagery. We pretrained a deep learning model on UK Biobank participants (N=35,323) and fine-tuned on a newly recruited clinical cohort (PhotoBIA cohort, N=677) with diverse ethnicity, age, and body fat distribution, achieving high accuracy against DXA for total body fat percentage (BF%, MAE = 2.15%), Android-to-Gynoid fat ratio (A/G, MAE = 0.11), and visceral-to-subcutaneous fat area ratio (V/S, MAE = 0.09). Generalizability of the model was demonstrated on an independent metabolic health study cohort (MetabolicMosaic cohort, N=132 participants), achieving MAEs of 2.13% for BF%, 0.09 for A/G, and 0.09 for V/S. We then evaluated the clinical utility of these metrics in the MetabolicMosaic cohort by predicting insulin resistance (IR). Adding PhotoScan-derived body composition metrics to baseline demographics model (Age, Sex, BMI) significantly improved insulin resistance classification (Area Under the Receiver Operating Characteristic Curve "AUROC" 76.0% vs 69.2%, DeLong test p=0.002, Net Reclassification Index "NRI" 0.593). Crucially, this accessible smartphone method achieved performance nearly equivalent to adding clinical-grade DXA data to baseline demographics model (AUROC 77.3% vs 69.2%, DeLong test p=0.004, NRI 0.748). These findings demonstrate that smartphone-based phenotyping captures clinically meaningful risk signals missed by BMI and anthropometrics, offering a scalable alternative to DXA for cardiometabolic risk stratification.


ImmSET: Sequence-Based Predictor of TCR-pMHC Specificity at Scale

Marco Garcia Noceda
Matthew T Noakes
Andrew FigPope
Daniel E Mattox
Bryan Howie
Harlan Robins

T cells are a critical component of the adaptive immune system, playing a role in infectious disease, autoimmunity, and cancer. T cell function is mediated by the T cell receptor (TCR) protein, a highly diverse receptor targeting specific peptides presented by the major histocompatibility complex (pMHCs). Predicting the specificity of TCRs for their cognate pMHCs is central to understanding adaptive immunity and enabling personalized therapies. However, accurate prediction of this protein-protein interaction remains challenging due to the extreme diversity of both TCRs and pMHCs. Here, we present ImmSET (Immune Synapse Encoding Transformer), a novel sequence-based architecture designed to model interactions among sets of variable-length biological sequences. We train this model across a range of dataset sizes and compositions and study the resulting models' generalization to pMHC targets. We describe a failure mode in prior sequence-based approaches that inflates previously reported performance on this task and show that ImmSET remains robust under stricter evaluation. In systematically testing the scaling behavior of ImmSET with training data, we show that performance scales consistently with data volume across multiple data types and compares favorably with the pre-trained protein language model ESM2 fine-tuned on the same datasets. Finally, we demonstrate that ImmSET can outperform AlphaFold2 and AlphaFold3-based pipelines on TCR-pMHC specificity prediction when provided sufficient training data. This work establishes ImmSET as a scalable modeling paradigm for multi-sequence interaction problems, demonstrated in the TCR-pMHC setting but generalizable to other biological domains where high-throughput sequence-driven reasoning complements structure prediction and experimental mapping.


Development of a European Union Time-Indexed Reference Dataset for Assessing the Performance of Signal Detection Methods in Pharmacovigilance using a Large Language Model

Maria Kefala
Jeffery L. Painter
Syed Tauhid Bukhari
Maurizio Sessa

Background: The identification of optimal signal detection methods is hindered by the lack of reliable reference datasets. Existing datasets do not capture when adverse events (AEs) are officially recognized by regulatory authorities, preventing restriction of analyses to pre-confirmation periods and limiting evaluation of early detection performance. This study addresses this gap by developing a time-indexed reference dataset for the European Union (EU), incorporating the timing of AE inclusion in product labels along with regulatory metadata. Methods: Current and historical Summaries of Product Characteristics (SmPCs) for all centrally authorized products (n=1,513) were retrieved from the EU Union Register of Medicinal Products (data lock: 15 December 2025). Section 4.8 was extracted and processed using DeepSeek V3 to identify AEs. Regulatory metadata, including labelling changes, were programmatically extracted. Time indexing was based on the date of AE inclusion in the SmPC. Results: The database includes 17,763 SmPC versions spanning 1995-2025, comprising 125,026 drug-AE associations. The time-indexed reference dataset, restricted to active products, included 1,479 medicinal products and 110,823 drug-AE associations. Most AEs were identified pre-marketing (74.5%) versus post-marketing (25.5%). Safety updates peaked around 2012. Gastrointestinal, skin, and nervous system disorders were the most represented System Organ Classes. Drugs had a median of 48 AEs across 14 SOCs. Conclusions: The proposed dataset addresses a critical gap in pharmacovigilance by incorporating temporal information on AE recognition for the EU, supporting more accurate assessment of signal detection performance and facilitating methodological comparisons across analytical approaches.


Multi-scale Metabolic Modeling and Simulation

Peter E. Carstensen
Teddy Groves
Lars K. Nielsen
Ulrich Krühne
Krist V. Gernaey
John B. Jørgensen

Biological systems are governed by coupled interactions between intracellular metabolism and bioreactor operation that span multiple time scales. Constraint-based metabolic models are widely used to describe intracellular metabolism, but repeatedly solving the optimization problem at each time step in dynamic models introduces numerical challenges related to infeasibility and computational efficiency. This work presents a multi-scale modeling framework that integrates genome-scale, constraint-based metabolic models with dynamic bioreactor simulations. Intracellular metabolism is described using positive flux variables in a parsimonious flux balance analysis, and the resulting embedded optimization problem is replaced by a neural network surrogate. The surrogate provides a smooth approximation of the embedded optimization mapping and eliminates repeated linear program solves during simulation. The approach is demonstrated for fed-batch fermentation of Escherichia coli, in which the surrogate model yields intracellular fluxes under substrate-limited conditions, whereas the underlying linear program would otherwise be infeasible. The framework provides a continuous representation of intracellular metabolism suitable for dynamic simulation of genome-scale models in bioreactor configurations.


TurboESM: Ultra-Efficient 3-Bit KV Cache Quantization for Protein Language Models with Orthogonal Rotation and QJL Correction

The rapid scaling of Protein Language Models (PLMs) has unlocked unprecedented accuracy in protein structure prediction and design, but the quadratic memory growth of the Key-Value (KV) cache during inference remains a prohibitive barrier for single-GPU deployment and high-throughput generation. While 8-bit quantization is now standard, 3-bit quantization remains elusive due to severe numerical outliers in activations. This paper presents TurboESM, an adaptation of Google's TurboQuant to the PLM domain. We solve the fundamental incompatibility between Rotary Position Embeddings (RoPE) and orthogonal transformations by deriving a RoPE-first rotation pipeline. We introduce a head-wise SVD calibration method tailored to the amino acid activation manifold, a dual look-up table (LUT) strategy for asymmetric K/V distributions, and a 1-bit Quantized Johnson-Lindenstrauss (QJL) residual correction. All experiments are conducted on ESM-2 650M, where our implementation achieves a 7.1x memory reduction (330 MB to 47 MB) while maintaining cosine similarity > 0.96 in autoregressive decoding across diverse protein families, including short peptides, transmembrane helices, enzyme active site fragments, and intrinsically disordered regions. We further implement a Triton-based fused decode attention kernel that eliminates intermediate dequantization memory allocations, achieving a 1.96x speedup over the PyTorch two-step path for the KV fetch operation alone; however, TurboESM incurs a prefill overhead of 21-27 ms relative to the original model due to KV quantization and packing, making it most suitable for memory-bound scenarios rather than latency-critical short-sequence workloads. Analysis reveals that PLMs exhibit sharper outlier profiles than large language models (LLMs) due to amino acid vocabulary sparsity, and our method effectively addresses these distributions.


Evaluating Phylogenetic Comparative Methods under Reticulate Evolutionary Scenarios

Phylogenetic comparative methods (PCMs) are widely used to study trait evolution. However, many evolutionary histories involve reticulate evolutionary scenarios, such as hybridization, that violate core assumptions of these methods. In this study, we evaluate how such violations affect the performance of PCMs. In particular, we focus on the ancestral character estimation, evolutionary rate estimation, and model selection. We simulate continuous trait evolution on various phylogenetic network topologies and assess the performance of PCMs that assume a bifurcating tree (i.e., major tree of the network) as the underlying model of evolution. We found that the performance of the tested PCMs was suboptimal. Using random forest, generalized linear models, and model-based clustering, we identified key factors contributing to these inaccuracies. Our results show that frequent and/or recent hybridization accompanied by one ore more transgressive events and rapidly evolving traits (i.e., high evolutionary rate) lead to significant estimation error, especially with respect to rate estimation and model choice. These factors substantially shift trait values away from tree-based model expectations, leading to overall increased error in parameter estimates. Our study demonstrates cases in which PCMs that rely on trees are likely to misinterpret biological histories and offers recommendations for researchers studying systems with complex evolutionary histories.


Spectral Coherence Index: A Model-Free Metric for Protein Structural Ensemble Quality Assessment

Yuda Bi
Huaiwen Zhang
Jingnan Sun
Vince D Calhoun

Protein structural ensembles from NMR spectroscopy capture biologically important conformational heterogeneity, but it remains difficult to determine whether observed variation reflects coordinated motion or noise-like artifacts. We evaluate the Spectral Coherence Index (SCI), a model-free, rotation-invariant summary derived from the participation-ratio effective rank of the inter-model pairwise distance-variance matrix. Under grouped primary analysis of a Main110 cohort of 110 NMR ensembles (30--403 residues; 10--30 models per entry), SCI separated experimental ensembles from matched synthetic incoherent controls with AUC-ROC $= 0.973$ and Cliff's $δ= -0.945$. Relative to an internal 27-protein pilot, discrimination softened modestly, showing that pilot-era thresholds do not transfer perfectly to a larger, more heterogeneous cohort: the primary operating point $τ= 0.811$ yielded 95.5\% sensitivity and 89.1\% specificity. PDB-level sensitivity remained nearly unchanged (AUC $= 0.972$), and an independent 11-protein holdout reached AUC $= 0.983$. Across 5-fold grouped stratified cross-validation and leave-one-function-class-out testing, SCI remained strong (AUC $= 0.968$ and $0.971$), although $σ_{R_g}$ was the stronger single-feature discriminator and a QC-augmented multifeature model generalized best (AUC $= 0.989$ and $0.990$). Residue-level validation linked SCI-derived contributions to experimental RMSF across 110 proteins and showed broad concordance with GNM-based flexibility patterns. Rescue analyses showed that Main110 softening arose mainly from size and ensemble normalization rather than from loss of spectral signal. Together, these results establish SCI as an interpretable, bounded coherence summary that is most useful when embedded in a multimetric QC workflow for heterogeneous protein ensembles.


Compiling molecular ultrastructure into neural dynamics

Konrad P. Kording
Anton Arkhipov
Davy Deng
Sean Escola
Seth G. N. Grant
Gal Haspel
Michał Januszewski
Narayanan Kasthuri
Nina Khera
Richie E. Kohman
Grace Lindsay
Jeantine Lunshof
Adam Marblestone
David A. Markowitz
Jordan Matelsky
Brett Mensh
Patrick Mineault
Andrew Payne
Joanne Peng
Xaq Pitkow
Philip Shiu
Gregor Schuhknecht
Sven Truckenbrodt
Joshua T. Vogelstein
Edward S. Boyden

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


Dictionary-based Pathology Mining with Hard-instance-assisted Classifier Debiasing for Genetic Biomarker Prediction from WSIs

Ling Zhang
Boxiang Yun
Ting Jin
Qingli Li
Xinxing Li
Yan Wang

Prediction of genetic biomarkers, e.g., microsatellite instability in colorectal cancer is crucial for clinical decision making. But, two primary challenges hamper accurate prediction: (1) It is difficult to construct a pathology-aware representation involving the complex interconnections among pathological components. (2) WSIs contain a large proportion of areas unrelated to genetic biomarkers, which make the model easily overfit simple but irrelative instances. We hereby propose a Dictionary-based hierarchical pathology mining with hard-instance-assisted classifier Debiasing framework to address these challenges, dubbed as D2Bio. Our first module, dictionary-based hierarchical pathology mining, is able to mine diverse and very fine-grained pathological contextual interaction without the limit to the distances between patches. The second module, hard-instance-assisted classfier debiasing, learns a debiased classifier via focusing on hard but task-related features, without any additional annotations. Experimental results on five cohorts show the superiority of our method, with over 4% improvement in AUROC compared with the second best on the TCGA-CRC-MSI cohort. Our analysis further shows the clinical interpretability of D2Bio in genetic biomarker diagnosis and potential clinical utility in survival analysis. Code will be available at https://github.com/DeepMed-Lab-ECNU/D2Bio.


A Bayesian Gamma-power-mixture survival regression model: predicting the recurrence of prostate cancer post-prostatectomy

Tommy Walker Mackay
Mingtong Xu
Shahrokh F. Shariat
Roger Sewell

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


A Gait Foundation Model Predicts Multi-System Health Phenotypes from 3D Skeletal Motion

Adam Gabet
Sarah Kohn
Guy Lutsker
Shira Gelman
Anastasia Godneva
Gil Sasson
Arad Zulti
David Krongauz
Rotem Shaulitch
Assaf Rotem
Ohad Doron
Yuval Brodsky
Adina Weinberger
Eran Segal

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


Lingshu-Cell: A generative cellular world model for transcriptome modeling toward virtual cells

Han Zhang
Guo-Hua Yuan
Chaohao Yuan
Tingyang Xu
Tian Bian
Hong Cheng
Wenbing Huang
Deli Zhao
Yu Rong

Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening.


Learning relationships in epidemiological data using graph neural networks

Anthony J Wood
Aeron R Sanchez
Rowland R Kao

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


OpenCap Monocular: 3D Human Kinematics and Musculoskeletal Dynamics from a Single Smartphone Video

Selim Gilon
Emily Y. Miller
Scott D. Uhlrich

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


Analyzing animal movement using deep learning

Thibault Fronville
Maximilian Pichler
Johannes Signer
Marius Grabow
Stephanie Kramer-Schadt
Viktoriia Radchuk
Florian Hartig

Understanding how animals move through heterogeneous landscapes is central to ecology and conservation. In this context, step selection functions (SSFs) have emerged as the main statistical framework to analyze how biotic and abiotic predictors influence movement paths observed by radio tracking, GPS tags, or similar sensors. A traditional SSF consists of a generalized linear model (GLM) that infers the animal's habitat preferences (selection coefficients) by comparing each observed movement step to random steps. Such GLM-SSFs, however, cannot flexibly consider non-linear or interacting effects, unless those have been specified a priori. To address this problem, generalized additive models have been integrated in the SSF framework, but those GAM-SSFs are still limited in their ability to represent complex habitat preferences and inter-individual variability. Here we explore the utility of deep neural networks (DNNs) to overcome these limitations. We find that DNN-SSFs, coupled with explainable AI to extract selection coefficients, offer many advantages for analyzing movement data. In the case of linear effects, they effectively retrieve the same effect sizes and p-values as conventional GLMs. At the same time, however, they can automatically detect complex interaction effects, nonlinear responses, and inter-individual variability if those are present in the data. We conclude that DNN-SSFs are a promising extension of traditional SSF. Our analysis extends previous research on DNN-SSF by exploring differences and similarities of GLM, GAM and DNN-based SSF models in more depth, in particular regarding the validity of statistical indicators that are derived from the DNN. We also propose new DNN structures to capture inter-individual effects that can be viewed as a nonlinear random effect. All methods used in this paper are available via the 'citoMove' R package.


KANEL: Kolmogorov-Arnold Network Ensemble Learning Enables Early Hit Enrichment in High-Throughput Virtual Screening

Pavel Koptev
Nikita Krainov
Konstantin Malkov
Alexander Tropsha

Machine learning models of chemical bioactivity are increasingly used for prioritizing a small number of compounds in virtual screening libraries for experimental follow-up. In these applications, assessing model accuracy by early hit enrichment such as Positive Predicted Value (PPV) calculated for top N hits (PPV@N) is more appropriate and actionable than traditional global metrics such as AUC. We present KANEL, an ensemble workflow that combines interpretable Kolmogorov-Arnold Networks (KANs) with XGBoost, random forest, and multilayer perceptron models trained on complementary molecular representations (LillyMol descriptors, RDKit-derived descriptors, and Morgan fingerprints).


Subspace Tensor Orthogonal Rotation Model (STORM) for Batch Alignment, Cell Type Deconvolution, and Gene Imputation in Spatial Transcriptomic Data

Spatial transcriptomics data analysis integrates cellular transcriptional activity with spatial coordinates to identify spatial domains, infer cell-type dynamics, and characterize gene expression patterns within tissues. Despite recent advances, significant challenges remain, including the treatment of batch effects, the handling of mixed cell-type signals, and the imputation of poorly measured or missing gene expression. This work addresses these challenges by introducing a novel Subspace Tensor Orthogonal Rotation Model (STORM) that aligns multiple slices which vary in their spatial dimensions and geometry by considering them at the level of physical patterns or microenvironments. To this end, STORM presents an irregular tensor factorization technique for decomposing a collection of gene expression matrices and integrating them into a shared latent space for downstream analysis. In contrast to black-box deep learning approaches, the proposed model is inherently interpretable. Numerical experiments demonstrate state-of-the-art performance in vertical and horizontal batch integration, cell-type deconvolution, and unmeasured gene imputation for spatial transcriptomics data.


CellFluxRL: Biologically-Constrained Virtual Cell Modeling via Reinforcement Learning

Dongxia Wu
Shiye Su
Yuhui Zhang
Elaine Sui
Emma Lundberg
Emily B. Fox
Serena Yeung-Levy

Building virtual cells with generative models to simulate cellular behavior in silico is emerging as a promising paradigm for accelerating drug discovery. However, prior image-based generative approaches can produce implausible cell images that violate basic physical and biological constraints. To address this, we propose to post-train virtual cell models with reinforcement learning (RL), leveraging biologically meaningful evaluators as reward functions. We design seven rewards spanning three categories-biological function, structural validity, and morphological correctness-and optimize the state-of-the-art CellFlux model to yield CellFluxRL. CellFluxRL consistently improves over CellFlux across all rewards, with further performance boosts from test-time scaling. Overall, our results present a virtual cell modeling framework that enforces physically-based constraints through RL, advancing beyond "visually realistic" generations towards "biologically meaningful" ones.


Characterizing Long-Range Dependencies in Knee Joint Contact Mechanics: A Comparison of Topology Diffusion, Global Routing, and Hybrid Graph Neural Networks

Finite element analysis of knee joint contact mechanics is computationally expensive, which has motivated the development of graph neural network surrogate models. However, effectively representing long-range dependencies in joint mechanical responses remains challenging. This study systematically compared topology diffusion, global routing, and their hybridization for surrogate modeling of knee joint contact mechanics. Using kinematic and force data from nine soccer players performing change-of-direction maneuvers, finite element simulations were used to generate graph-structured samples for training and evaluation under a grouped three-fold cross-subject evaluation framework. Five architectures were compared: standard MeshGraphNet, hierarchical MeshGraphNet, a routing-only transformer, a topology-biased routing transformer, and a hybrid model. The hybrid model achieved the best overall performance, yielding the lowest full-field error and peak stress error, together with the highest spatial agreement for high-risk regions. Among the non-hybrid models, the standard topology-diffusion model performed best overall, whereas routing-only strategies were less effective. These findings indicate that topology diffusion provides a robust basis for surrogate modeling of knee joint contact mechanics within the present benchmark, while the addition of global routing can further improve reconstruction of clinically relevant high-stress patterns.


CERN: Correcting Errors in Raw Nanopore Signals Using Hidden Markov Models

Simon Ambrozak
Ulysse McConnell
Bhargav Srinivasan
Burak Ozkan
Can Firtina

Nanopore sequencing can read substantially longer sequences of nucleic acid molecules than other sequencing methods, which has led to advances in genomic analysis such as the gapless human genome assembly. By analyzing the raw electrical signal reads that nanopore sequencing generates from molecules, existing works can map these reads without translating them into DNA characters (i.e., basecalling), allowing for quick and efficient analysis of sequencing data. However, raw signals often contain errors due to noise and mistakes when processing them, which limits the overall accuracy of raw signal analysis.   Our goal in this work is to detect and correct errors in raw signals to improve the accuracy of raw signal analyses. To this end, we propose CERN, a mechanism that trains and utilizes a Hidden Markov Model (HMM) to accurately correct signal errors. Our extensive evaluation on various datasets including E. coli, Fruit Fly, and Human genomes shows that CERN 1) consistently improves the overall mapping accuracy of the underlying raw signal analysis tools, 2) minimizes the burden on segmentation algorithm optimization with newer nanopore chemistries, and 3) functions without causing substantial computational overhead. We conclude that CERN provides an effective mechanism to systematically identify and correct the errors in raw nanopore signals before further analysis, which can enable the development of a new class of error correction mechanisms purely designed for raw nanopore signals.   CERN is available at https://github.com/STORMgroup/CERN. We also provide the scripts to fully reproduce our results on our GitHub page.


Conditioning Protein Generation via Hopfield Pattern Multiplicity

Protein sequence generation via stochastic attention produces plausible family members from small alignments without training, but treats all stored sequences equally and cannot direct generation toward a functional subset of interest. We show that a single scalar parameter, added as a bias to the sampler's attention logits, continuously shifts generation from the full family toward a user-specified subset, with no retraining and no change to the model architecture. A practitioner supplies a small set of sequences (for example, hits from a binding screen) and a multiplicity ratio that controls how strongly generation favors them. The method is agnostic to what the subset represents: binding, stability, specificity, or any other property. We find that the conditioning is exact at the level of the sampler's internal representation, but that the decoded sequence phenotype can fall short because the dimensionality reduction used to encode sequences does not always preserve the residue-level variation that defines the functional split. We term this discrepancy the calibration gap and show that it is predicted by a simple geometric measure of how well the encoding separates the functional subset from the rest of the family. Experiments on five Pfam families (Kunitz, SH3, WW, Homeobox, and Forkhead domains) confirm the monotonic relationship between separation and gap across a fourfold range of geometries. Applied to omega-conotoxin peptides targeting a calcium channel involved in pain signaling, curated seeding from 23 characterized binders produces over a thousand candidates that preserve the primary pharmacophore and all experimentally identified binding determinants. These results show that stochastic attention enables practitioners to expand a handful of experimentally characterized sequences into diverse candidate libraries without retraining a generative model.


Towards Improved Short-term Hypoglycemia Prediction and Diabetes Management based on Refined Heart Rate Data

Vaibhav Gupta
Florian Grensing
Beyza Cinar
Louisa van den Boom
Maria Maleshkova

Hypoglycemia is a severe condition of decreased blood glucose, specifically below 70 mg/dL (3.9 mmol/L). This condition can often be asymptomatic and challenging to predict in individuals with type 1 diabetes (T1D). Research on hypoglycemic prediction typically uses a combination of blood glucose readings and heart rate data to predict hypoglycemic events. Given that these features are collected through wearable sensors, they can sometimes have missing values, necessitating efficient imputation methods. This work makes significant contributions to the current state of the art by introducing two novel imputation techniques for imputing heart rate values over short-term horizons: Controlled Weighted Rational Bézier Curves (CRBC) and Controlled Piecewise Cubic Hermite Interpolating Polynomial with mapped peaks and valleys of Control Points (CMPV). In addition to these imputation methods, we employ two metrics to capture data patterns, alongside a combined metric that integrates the strengths of both individual metrics with RMSE scores for a comprehensive evaluation of the imputation techniques. According to our combined metric assessment, CMPV outperforms the alternatives with an average score of 0.33 across all time gaps, while CRBC follows with a score of 0.48. These findings clearly demonstrate the effectiveness of the proposed imputation methods in accurately filling in missing heart rate values. Moreover, this study facilitates the detection of abnormal physiological signals, enabling the implementation of early preventive measures for more accurate diagnosis.


Multimodal branched transport infers anatomically aligned brain reaction maps

How external stimulation is transformed into distributed reaction patterns remains unresolved at the level of propagation architecture. Existing large-scale control models quantify transition costs on prescribed networks but do not infer the routing map itself from source and target activity. Here we combine task-related blood-oxygen-level-dependent responses, source-reconstructed electrophysiology and tractography-derived anisotropy to estimate stimulation and reaction measures, define an anatomical transport cost, and infer a branched propagation architecture by variational optimisation. Unlike standard transport formulations, branched transport favours aggregation of signal into shared neural highways before redistribution. We further attach a stochastic graph-induced dynamics to the inferred map and quantify the trade-off between geometric efficiency and dynamical controllability. We show that multimodal data generate anatomically aligned brain reaction maps, that anisotropic costs qualitatively reshape routing backbones relative to isotropic baselines, and that hybrid geometric--dynamical optimisation reveals non-trivial rank reversals across branching regimes.


Branched Optimal Transport for Stimulus to Reaction Brain Mapping

A central problem in systems neuroscience is to determine how an external stimulation is propagated through the brain so as to produce a reaction. Current deterministic and stochastic control models quantify transition costs between brain states on a prescribed network, but do not treat the transport network itself as an unknown. Here we propose a variational framework in which the inferred object is a graph/current connecting a stimulation source measure to a reaction target measure. The model is posed as an anisotropic branched optimal transport problem, where concavity of the flux cost promotes aggregation and branching. The support of an optimal current defines a stimulus-to-reaction routing architecture, interpreted as a brain reaction map. We prove existence of minimizers in discrete and continuous formulations and introduce a hybrid stochastic extension combining ramified transport with a path-space Kullback--Leibler control cost on the induced graph dynamics. This approach provides a mathematical mechanism for inferring propagation architectures rather than controlling trajectories on fixed substrates.


Stochastic Averaging and Statistical Inference of Glycolytic Pathway

Many biological processes exhibit oscillatory behavior. Among these, glycolytic oscillations have been extensively studied due to their well-characterized biochemical reaction networks. However, the complexity of these networks necessitates low-dimensional ordinary differential equation (ODE) models to identify core mechanisms and perform stability analysis. While previous studies proposed reduced ODE models, these were typically introduced from deterministic descriptions rather than the underlying stochastic dynamics, which more accurately represent discrete reaction events occurring at random times. In this paper, we develop a rigorous probabilistic framework for deriving a reduced Othmer-Aldridge model of the glycolytic pathway from its stochastic formulation. The full system is modeled as a multiscale continuous-time Markov chain with different time and abundance scales. Under an appropriate scaling regime and specific structural conditions, we prove that the dynamics of the slow components are approximated by a two-dimensional ODE. The proof is technically involved due to the network's complexity and strong coupling between its components. We further consider the problem of parameter estimation when observations are limited to the slow species: fructose-6-phosphate and ADP. The reduced system yields a tractable loss function depending solely on these variables. We prove that the resulting estimators are statistically consistent when the data originate from the full stochastic reaction network. Together, these results provide a mathematically rigorous framework linking stochastic biochemical reaction networks, reduced deterministic dynamics, and statistically reliable parameter estimation.


Assessing 3D tree model quality and species classification using imbalance indices

We investigate the use of additional 3D and phylogenetic non-3D tree balance indices for analyzing and monitoring forests using an exemplary "virtual forest" dataset from the Wytham Woods, Oxford, UK. This study assesses 3D model quality, species classification performance, and the relevance of these indices. Our study shows that indices stemming from the study of ancestry trees of species can be successfully applied to 3D models of organic trees and, accompanied with recently introduced 3D imbalance indices, offer a complementary perspective on 3D tree models and improve the detection of deviations. Their computational efficiency combined with the simple and reproducible workflow presented in this manuscript form a computationally feasible quality control step in the 3D model construction.   Species classification models reached an estimated accuracy of up to 81.8% and allowed to make confident species predictions for a large portion of the unlabeled trees in the dataset. While conventional tree metrics can already provide strong predictive performance, the addition of filtered 3D and non-3D statistics improved results consistently, particularly for minority species classes.   Alongside this manuscript, we provide updated functionality in the R package treeDbalance to include the necessary functionalities and release the derived index datasets and species predictions.


CAPSUL: A Comprehensive Human Protein Benchmark for Subcellular Localization

Yicheng Hu
Xinyu Lin
Shulin Li
Wenjie Wang
Fengbin Zhu
Fuli Feng

Subcellular localization is a crucial biological task for drug target identification and function annotation. Although it has been biologically realized that subcellular localization is closely associated with protein structure, no existing dataset offers comprehensive 3D structural information with detailed subcellular localization annotations, thus severely hindering the application of promising structure-based models on this task. To address this gap, we introduce a new benchmark called $\mathbf{CAPSUL}$, a $\mathbf{C}$omprehensive hum$\mathbf{A}$n $\mathbf{P}$rotein benchmark for $\mathbf{SU}$bcellular $\mathbf{L}$ocalization. It features a dataset that integrates diverse 3D structural representations with fine-grained subcellular localization annotations carefully curated by domain experts. We evaluate this benchmark using a variety of state-of-the-art sequence-based and structure-based models, showcasing the importance of involving structural features in this task. Furthermore, we explore reweighting and single-label classification strategies to facilitate future investigation on structure-based methods for this task. Lastly, we showcase the powerful interpretability of structure-based methods through a case study on the Golgi apparatus, where we discover a decisive localization pattern $α$-helix from attention mechanisms, demonstrating the potential for bridging the gap with intuitive biological interpretability and paving the way for data-driven discoveries in cell biology.


Recovering Sparse Neural Connectivity from Partial Measurements: A Covariance-Based Approach with Granger-Causality Refinement

Inferring the connectivity of neural circuits from incomplete observations is a fundamental challenge in neuroscience. We present a covariance-based method for estimating the weight matrix of a recurrent neural network from sparse, partial measurements across multiple recording sessions. By accumulating pairwise covariance estimates across sessions where different subsets of neurons are observed, we reconstruct the full connectivity matrix without requiring simultaneous recording of all neurons. A Granger-causality refinement step enforces biological constraints via projected gradient descent. Through systematic experiments on synthetic networks modeling small brain circuits, we characterize a fundamental control-estimation tradeoff: stimulation aids identifiability but disrupts intrinsic dynamics, with the optimal level depending on measurement density. We discover that the ``incorrect'' linear approximation acts as implicit regularization -- outperforming the oracle estimator with known nonlinearity at all operating regimes -- and provide an exact characterization via the Stein--Price identity.


RAFT-UP: Robust Alignment for Spatial Transcriptomics with Explicit Control of Spatial Distortion

Yaqi Wu
Jingfeng Wang
Xin Maizie Zhou
Yanxiang Zhao
Zixuan Cang

Spatial transcriptomics (ST) profiles gene expression across a tissue section while preserving the spatial coordinates. Because current ST technologies typically profile two-dimensional tissue slices, integrating and aligning slices from different regions of the same three-dimensional tissue or from samples under different conditions enables analyses that reveal 3D organization and condition-associated spatial patterns. Two major challenges remain. First, interpretable and flexible control over spatial distortion is needed because rigid transformations can be overly restrictive, whereas highly deformable mappings may arbitrarily distort spatial proximity. Second, biologically plausible matching is also needed, especially when the slices overlap partially. Here, we introduce RAFT-UP, a tool for robust ST alignment that provides explicit control over spatial distance preservation through a fused supervised Gromov-Wasserstein (FsGW) optimal transport framework. FsGW combines expression and spatial information, incorporates spot-wise constraints to discourage biologically implausible matches, and enforces a pairwise distance-consistency constraint that prevents mapping two pairs of spots when their spatial distances differ beyond a specified tolerance. We demonstrate that RAFT-UP accurately aligns slices from different regions of the same tissue and slices from different samples. Benchmarking shows that RAFT-UP improves spatial distance preservation while achieving spot label matching accuracy comparable to state-of-the-art methods. Finally, we demonstrate RAFT-UP on two spatially constrained downstream applications, including spatiotemporal mapping of developing mouse midbrain and comparative cross-slice analysis of cell-cell communication. RAFT-UP is available as open-source software.


Impact of automatic speech recognition quality on Alzheimer's disease detection from spontaneous speech: a reproducible benchmark study with lexical modeling and statistical validation

Early detection of Alzheimer's disease from spontaneous speech has emerged as a promising non-invasive screening approach. However, the influence of automatic speech recognition (ASR) quality on downstream clinical language modeling remains insufficiently understood. In this study, we investigate Alzheimer's disease detection using lexical features derived from Whisper ASR transcripts on the ADReSSo 2021 diagnosis dataset. We evaluate interpretable machine-learning models, including Logistic Regression and Linear Support Vector Machines, using TF-IDF text representations under repeated 5x5 stratified cross-validation.   Our results demonstrate that transcript quality has a statistically significant impact on classification performance. Models trained on Whisper-small transcripts consistently outperform those using Whisper-base transcripts, achieving balanced accuracy above 0.7850 with Linear SVM. Paired statistical testing confirms that the observed improvements are significant. Importantly, classifier complexity contributes less to performance variation than ASR transcription quality. Feature analysis reveals that cognitively normal speakers produce more semantically precise object- and scene-descriptive language, whereas Alzheimer's speech is characterized by vagueness, discourse markers, and increased hesitation patterns.   These findings suggest that high-quality ASR can enable simple, interpretable lexical models to achieve competitive Alzheimer's detection performance without explicit acoustic modeling. The study provides a reproducible benchmark pipeline and highlights ASR selection as a critical modeling decision in clinical speech-based artificial intelligence systems.


Grounded Multimodal Retrieval-Augmented Drafting of Radiology Impressions Using Case-Based Similarity Search

Automated radiology report generation has gained increasing attention with the rise of deep learning and large language models. However, fully generative approaches often suffer from hallucinations and lack clinical grounding, limiting their reliability in real-world workflows. In this study, we propose a multimodal retrieval-augmented generation (RAG) system for grounded drafting of chest radiograph impressions. The system combines contrastive image-text embeddings, case-based similarity retrieval, and citation-constrained draft generation to ensure factual alignment with historical radiology reports. A curated subset of the MIMIC-CXR dataset was used to construct a multimodal retrieval database. Image embeddings were generated using CLIP encoders, while textual embeddings were derived from structured impression sections. A fusion similarity framework was implemented using FAISS indexing for scalable nearest-neighbor retrieval. Retrieved cases were used to construct grounded prompts for draft impression generation, with safety mechanisms enforcing citation coverage and confidence-based refusal. Experimental results demonstrate that multimodal fusion significantly improves retrieval performance compared to image-only retrieval, achieving Recall@5 above 0.95 on clinically relevant findings. The grounded drafting pipeline produces interpretable outputs with explicit citation traceability, enabling improved trustworthiness compared to conventional generative approaches. This work highlights the potential of retrieval-augmented multimodal systems for reliable clinical decision support and radiology workflow augmentation


SCALE:Scalable Conditional Atlas-Level Endpoint transport for virtual cell perturbation prediction

Shuizhou Chen
Lang Yu
Kedu Jin
Songming Zhang
Hao Wu
Wenxuan Huang
Sheng Xu
Quan Qian
Qin Chen
Lei Bai
Siqi Sun
Zhangyang Gao

Virtual cell models aim to enable in silico experimentation by predicting how cells respond to genetic, chemical, or cytokine perturbations from single-cell measurements. In practice, however, large-scale perturbation prediction remains constrained by three coupled bottlenecks: inefficient training and inference pipelines, unstable modeling in high-dimensional sparse expression space, and evaluation protocols that overemphasize reconstruction-like accuracy while underestimating biological fidelity. In this work we present a specialized large-scale foundation model SCALE for virtual cell perturbation prediction that addresses the above limitations jointly. First, we build a BioNeMo-based training and inference framework that substantially improves data throughput, distributed scalability, and deployment efficiency, yielding 12.51* speedup on pretrain and 1.29* on inference over the prior SOTA pipeline under matched system settings. Second, we formulate perturbation prediction as conditional transport and implement it with a set-aware flow architecture that couples LLaMA-based cellular encoding with endpoint-oriented supervision. This design yields more stable training and stronger recovery of perturbation effects. Third, we evaluate the model on Tahoe-100M using a rigorous cell-level protocol centered on biologically meaningful metrics rather than reconstruction alone. On this benchmark, our model improves PDCorr by 12.02% and DE Overlap by 10.66% over STATE. Together, these results suggest that advancing virtual cells requires not only better generative objectives, but also the co-design of scalable infrastructure, stable transport modeling, and biologically faithful evaluation.


Mathematical Modeling of Cancer-Bacterial Therapy: Analysis and Numerical Simulation via Physics-Informed Neural Networks

Bacterial cancer therapy exploits anaerobic bacteria's ability to target hypoxia tumor regions, yet the interactions among tumor growth, bacterial colonization, oxygen levels, immunosuppressive cytokines, and bacterial communication remain poorly quantified. We present a mathematical model of five coupled nonlinear reaction-diffusion equations in a two-dimensional tissue domain. We proved the global well-posedness of the model and identified its steady states to analyze stability. Furthermore, a physics-informed neural network (PINN) solves the system without a mesh and without requiring extensive data. It provides convergence guarantees by combining residual stability and Sobolev approximation error bounds. This results in an overall error rate of O(n^-2 ln^4(n) + N^-1/2), which depends on the network width n and the number of collocation points N. We conducted several numerical experiments, including predicting the tumor's response to therapy. We also performed a sensitivity analysis of certain parameters. The results suggest that long-term therapeutic efficacy may require the maintenance of hypoxia regions in the tumor, or using bacteria that tolerate oxygen better, may be necessary for long-lasting tumor control.


Binary Latent Protein Fitness Landscapes for Quantum Annealing Optimization

We propose Q-BIOLAT, a framework for modeling and optimizing protein fitness landscapes in binary latent spaces. Starting from protein sequences, we leverage pretrained protein language models to obtain continuous embeddings, which are then transformed into compact binary latent representations. In this space, protein fitness is approximated using a quadratic unconstrained binary optimization (QUBO) model, enabling efficient combinatorial search via classical heuristics such as simulated annealing and genetic algorithms.   On the ProteinGym benchmark, we demonstrate that Q-BIOLAT captures meaningful structure in protein fitness landscapes and enables the identification of high-fitness variants. Despite using a simple binarization scheme, our method consistently retrieves sequences whose nearest neighbors lie within the top fraction of the training fitness distribution, particularly under the strongest configurations. We further show that different optimization strategies exhibit distinct behaviors, with evolutionary search performing better in higher-dimensional latent spaces and local search remaining competitive in preserving realistic sequences.   Beyond its empirical performance, Q-BIOLAT provides a natural bridge between protein representation learning and combinatorial optimization. By formulating protein fitness as a QUBO problem, our framework is directly compatible with emerging quantum annealing hardware, opening new directions for quantum-assisted protein engineering.   Our implementation is publicly available at: https://github.com/HySonLab/Q-BIOLAT


Tabular LLMs for Interpretable Few-Shot Alzheimer's Disease Prediction with Multimodal Biomedical Data

Sophie Kearney
Shu Yang
Zixuan Wen
Weimin Lyu
Bojian Hou
Duy Duong-Tran
Tianlong Chen
Jason H. Moore
Marylyn D. Ritchie
Chao Chen
Li Shen

Accurate diagnosis of Alzheimer's disease (AD) requires handling tabular biomarker data, yet such data are often small and incomplete, where deep learning models frequently fail to outperform classical methods. Pretrained large language models (LLMs) offer few-shot generalization, structured reasoning, and interpretable outputs, providing a powerful paradigm shift for clinical prediction. We propose TAP-GPT Tabular Alzheimer's Prediction GPT, a domain-adapted tabular LLM framework built on TableGPT2 and fine-tuned for few-shot AD classification using tabular prompts rather than plain texts. We evaluate TAP-GPT across four ADNI-derived datasets, including QT-PAD biomarkers and region-level structural MRI, amyloid PET, and tau PET for binary AD classification. Across multimodal and unimodal settings, TAP-GPT improves upon its backbone models and outperforms traditional machine learning baselines in the few-shot setting while remaining competitive with state-of-the-art general-purpose LLMs. We show that feature selection mitigates degradation in high-dimensional inputs and that TAP-GPT maintains stable performance under simulated and real-world missingness without imputation. Additionally, TAP-GPT produces structured, modality-aware reasoning aligned with established AD biology and shows greater stability under self-reflection, supporting its use in iterative multi-agent systems. To our knowledge, this is the first systematic application of a tabular-specialized LLM to multimodal biomarker-based AD prediction, demonstrating that such pretrained models can effectively address structured clinical prediction tasks and laying the foundation for tabular LLM-driven multi-agent clinical decision-support systems. The source code is publicly available on GitHub: https://github.com/sophie-kearney/TAP-GPT.


Conservative Continuous-Time Treatment Optimization

Nora Schneider
Georg Manten
Niki Kilbertus

We develop a conservative continuous-time stochastic control framework for treatment optimization from irregularly sampled patient trajectories. The unknown patient dynamics are modeled as a controlled stochastic differential equation with treatment as a continuous-time control. Naive model-based optimization can exploit model errors and propose out-of-support controls, so optimizing the estimated dynamics may not optimize the true dynamics. To limit extrapolation, we add a consistent signature-based MMD regularizer on path space that penalizes treatment plans whose induced trajectory distribution deviates from observed trajectories. The resulting objective minimizes a computable upper bound on the true cost. Experiments on benchmark datasets show improved robustness and performance compared to non-conservative baselines.


Intermitotic timing and motility patterns in the cell division of the diatom Seminavis robusta

Many diatoms follow a size diminuation - size restoration cycle in their vegetative phase, leading to daughter cells that differ in size. For the diatom Seminavis robusta, we investigated by cell tracking over several generations whether the size difference reflects also in different intermitotic times or in the mobility of the cells. A tracking setup and machine-learning based detection algorithm was developed that revealed no significant difference in intermitotic times, a weak coupling to the day- night cycle, and a higher motility of the hypothecal, smaller daughter cell.


Bayesian Inference of Psychometric Variables From Brain and Behavior in Implicit Association Tests

Christian A. Kothe
Sean Mullen
Michael V. Bronstein
Grant Hanada
Marcelo Cicconet
Aaron N. McInnes
Tim Mullen
Marc Aafjes
Scott R. Sponheim
Alik S. Widge

Objective. We establish a principled method for inferring mental health related psychometric variables from neural and behavioral data using the Implicit Association Test (IAT) as the data generation engine, aiming to overcome the limited predictive performance (typically under 0.7 AUC) of the gold-standard D-score method, which relies solely on reaction times.   Approach. We propose a sparse hierarchical Bayesian model that leverages multi-modal data to predict experiences related to mental illness symptoms in new participants. The model is a multivariate generalization of the D-score with trainable parameters, engineered for parameter efficiency in the small-cohort regime typical of IAT studies. Data from two IAT variants were analyzed: a suicidality-related E-IAT ($n=39$) and a psychosis-related PSY-IAT ($n=34$).   Main Results. Our approach overcomes a high inter-individual variability and low within-session effect size in the dataset, reaching AUCs of 0.73 (E-IAT) and 0.76 (PSY-IAT) in the best modality configurations, though corrected 95% confidence intervals are wide ($\pm 0.18$) and results are marginally significant after FDR correction ($q=0.10$). Restricting the E-IAT to MDD participants improves AUC to 0.79 $[0.62, 0.97]$ (significant at $q=0.05$). Performance is on par with the best reference methods (shrinkage LDA and EEGNet) for each task, even when the latter were adapted to the task, while the proposed method was not. Accuracy was substantially above near-chance D-scores (0.50-0.53 AUC) in both tasks, with more consistent cross-task performance than any single reference method.   Significance. Our framework shows promise for enhancing IAT-based assessment of experiences related to entrapment and psychosis, and potentially other mental health conditions, though further validation on larger and independent cohorts will be needed to establish clinical utility.


HistoAtlas: A Pan-Cancer Morphology Atlas Linking Histomics to Molecular Programs and Clinical Outcomes

We present HistoAtlas, a pan-cancer computational atlas that extracts 38 interpretable histomic features from 6,745 diagnostic H&E slides across 21 TCGA cancer types and systematically links every feature to survival, gene expression, somatic mutations, and immune subtypes. All associations are covariate-adjusted, multiple-testing corrected, and classified into evidence-strength tiers. The atlas recovers known biology, from immune infiltration and prognosis to proliferation and kinase signaling, while uncovering compartment-specific immune signals and morphological subtypes with divergent outcomes. Every result is spatially traceable to tissue compartments and individual cells, statistically calibrated, and openly queryable. HistoAtlas enables systematic, large-scale biomarker discovery from routine H&E without specialized staining or sequencing. Data and an interactive web atlas are freely available at https://histoatlas.com .


Understanding Cell Fate Decisions with Temporal Attention

Florian Bürger
Martim Dias Gomes
Adrián E. Granada
Noémie Moreau
Katarzyna Bozek

Understanding non-genetic determinants of cell fate is critical for developing and improving cancer therapies, as genetically identical cells can exhibit divergent outcomes under the same treatment conditions. In this work, we present a deep learning approach for cell fate prediction from raw long-term live-cell recordings of cancer cell populations under chemotherapeutic treatment. Our Transformer model is trained to predict cell fate directly from raw image sequences, without relying on predefined morphological or molecular features. Beyond classification, we introduce a comprehensive explainability framework for interpreting the temporal and morphological cues guiding the model's predictions. We demonstrate that prediction of cell outcomes is possible based on the video only, our model achieves balanced accuracy of 0.94 and an F1-score of 0.93. Attention and masking experiments further indicate that the signal predictive of the cell fate is not uniquely located in the final frames of a cell trajectory, as reliable predictions are possible up to 10 h before the event. Our analysis reveals distinct temporal distribution of predictive information in the mitotic and apoptotic sequences, as well as the role of cell morphology and p53 signaling in determining cell outcomes. Together, these findings demonstrate that attention-based temporal models enable accurate cell fate prediction while providing biologically interpretable insights into non-genetic determinants of cellular decision-making. The code is available at https://github.com/bozeklab/Cell-Fate-Prediction.


Sample-Efficient Adaptation of Drug-Response Models to Patient Tumors under Strong Biological Domain Shift

Camille Jimenez Cortes
Philippe Lalanda
German Vega

Predicting drug response in patients from preclinical data remains a major challenge in precision oncology due to the substantial biological gap between in vitro cell lines and patient tumors. Rather than aiming to improve absolute in vitro prediction accuracy, this work examines whether explicitly separating representation learning from task supervision enables more sample-efficient adaptation of drug-response models to patient data under strong biological domain shift. We propose a staged transfer-learning framework in which cellular and drug representations are first learned independently from large collections of unlabeled pharmacogenomic data using autoencoder-based representation learning. These representations are then aligned with drug-response labels on cell-line data and subsequently adapted to patient tumors using few-shot supervision. Through a systematic evaluation spanning in-domain, cross-dataset, and patient-level settings, we show that unsupervised pretraining provides limited benefit when source and target domains overlap substantially, but yields clear gains when adapting to patient tumors with very limited labeled data. In particular, the proposed framework achieves faster performance improvements during few-shot patient-level adaptation while maintaining comparable accuracy to single-phase baselines on standard cell-line benchmarks. Overall, these results demonstrate that learning structured and transferable representations from unlabeled molecular profiles can substantially reduce the amount of clinical supervision required for effective drug-response prediction, offering a practical pathway toward data-efficient preclinical-to-clinical translation.


Topology-Guided Biomechanical Profiling: A White-Box Framework for Opportunistic Screening of Spinal Instability on Routine CT

Zanting Ye
Xuanbin Wu
Guoqing Zhong
Shengyuan Liu
Jiashuai Liu
Ge Song
Zhisong Wang
Jing Hao
Xiaolong Niu
Yefeng Zheng
Yu Zhang
Lijun Lu

Routine oncologic computed tomography (CT) presents an ideal opportunity for screening spinal instability, yet prophylactic stabilization windows are frequently missed due to the complex geometric reasoning required by the Spinal Instability Neoplastic Score (SINS). Automating SINS is fundamentally hindered by metastatic osteolysis, which induces topological ambiguity that confounds standard segmentation and black-box AI. We propose Topology-Guided Biomechanical Profiling (TGBP), an auditable white-box framework decoupling anatomical perception from structural reasoning. TGBP anchors SINS assessment on two deterministic geometric innovations: (i) canal-referenced partitioning to resolve posterolateral boundary ambiguity, and (ii) context-aware morphometric normalization via covariance-based oriented bounding boxes (OBB) to quantify vertebral collapse. Integrated with auxiliary radiomic and large language model (LLM) modules, TGBP provides an end-to-end, interpretable SINS evaluation. Validated on a multi-center, multi-cancer cohort ($N=482$), TGBP achieved 90.2\% accuracy in 3-tier stability triage. In a blinded reader study ($N=30$), TGBP significantly outperformed medical oncologists on complex structural features ($κ=0.857$ vs.\ $0.570$) and prevented compounding errors in Total Score estimation ($κ=0.625$ vs.\ $0.207$), democratizing expert-level opportunistic screening.


Non-perturbative Bacterial Identification Directly from Solid Agar Plates Using Raman

Jeong Hee Kim
Jia Dong
Marissa Morales
Loza Tadesse

Raman spectroscopy is a promising tool for microbial identification, yet its implementation in microbiology and clinical workflow is still restricted due to the accompanying additional preparation required to focus on microbial signals. Here, we demonstrate Raman-based bacterial identification directly from unopened, inverted agar plates, the same conditions used during incubation. Our approach enabled identification with single gene-level sensitivity using two Escherichia coli variants, differing only in green fluorescent protein (GFP) expression, across diverse media and substrate material conditions, despite the interrogation path traversing 3-4 mm thick background material. We integrated traditional density functional theory (DFT)-based material computation with machine learning analysis, achieving over 97.7% classification accuracy, surpassing the performance of standard measurements from opened plates by 10.8% higher mean accuracy and 0.76% less variance. We further demonstrated Raman mapping-based colony identification via Raman peaks characteristic to GFPmut3 chromophore structure generated by DFT. Our approach is robust to changes in algorithms or substrate materials and promises real-time, non-perturbative monitoring of bacterial growth, biofilm formation, and antimicrobial resistance development.


Knowledge Graph Extraction from Biomedical Literature for Alkaptonuria Rare Disease

Giang Pham
Rebecca Finetti
Caterina Graziani
Bianca Roncaglia
Asma Bendjeddou
Linda Brodo
Sara Brunetti
Moreno Falaschi
Stefano Forti
Silvia Giulia Galfré
Paolo Milazzo
Corrado Priami
Annalisa Santucci
Ottavia Spiga
Alina Sîrbu

Alkaptonuria (AKU) is an ultra-rare autosomal recessive metabolic disorder caused by mutations in the HGD (Homogentisate 1,2-Dioxygenase) gene, leading to a pathological accumulation of homogentisic acid (HGA) in body fluids and tissues. This leads to systemic manifestations, including premature spondyloarthropathy, renal and prostatic stones, and cardiovascular complications. Being ultra-rare, the amount of data related to the disease is limited, both in terms of clinical data and literature. Knowledge graphs (KGs) can help connect the limited knowledge about the disease (basic mechanisms, manifestations and existing therapies) with other knowledge; however, AKU is frequently underrepresented or entirely absent in existing biomedical KGs. In this work, we apply a text-mining methodology based on PubTator3 for large-scale extraction of biomedical relations. We construct two KGs of different sizes, validate them using existing biochemical knowledge and use them to extract genes, diseases and therapies possibly related to AKU. This computational framework reveals the systemic interactions of the disease, its comorbidities, and potential therapeutic targets, demonstrating the efficacy of our approach in analyzing rare metabolic disorders.