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arXiv2026

Attributing Cohen's d: Training Data Attribution for Disease-Related Effects in Normative Age Biomarkers

Normative age models are trained to predict chronological age in a nominally healthy cohort. Applied to patients, they deviate, and the gap between predicted and chronological age is read as disease risk. Here, we attribute the disease-related effect size of the age gap directly to individual training samples, rather than using a prediction-level loss as the attribution target. For Cohen's $d$, the resulting closed-form influence functional, validated against leave-one-out retraining, ranks training samples by their effect on held-out case-control separation. Across four diseases and two biomarker modalities in UK Biobank, removing the 10% most influential training samples raises held-out disease-related effect size in every seed. It more than doubles the metabolomic-age effect for type-2 diabetes and raises the brain-age effect for multiple sclerosis by roughly a third. Random removal leaves effect size flat even at 50% removal, confirming the gain comes from which samples are removed, not how many. Flagged subjects carry subclinical cardiometabolic burden that diagnosis-based exclusion misses, on markers the model never sees. For type-2 diabetes, where the method gains most, the marker recovered is HbA1c, the standard measure of blood sugar control. We release pyinfluence, our influence-function package, for reproducibility and reuse.

cs.LG↗

arXiv2026

Small Molecule Optimization with Large Language Models

Molecular optimization, the process of designing molecules with desirable properties, represents a critical challenge in drug discovery. The recent advancements in large language models (LLMs) have opened new opportunities for their integration with traditional molecular optimization algorithms to improve performance. In this work, we propose Molecular Language Model powered Evolutionary Algorithm (Mol-E), an evolutionary algorithm that relies on the generative capabilities of LLMs trained on molecules and molecular properties. Scientific Contribution. Mol-E obtains the highest aggregate Top-10 AUC among the comparable full-23-task results considered here, scoring 17.500 in the task-agnostic regime, in which the oracle is treated strictly as a black box, and 20.551 in the task-informed regime, in which the optimizer receives a fixed semantic description of the objective. Mol-E also improves over the evaluated baselines on multi-property optimization with docking against DRD2, MK2, and AChE.

cs.LG↗

arXiv2026

Semi-Supervised Domain Adaptation with Latent Diffusion for Pathology Image Classification

Deep learning models in computational pathology often fail to generalize across cohorts and institutions due to domain shift. Existing approaches either fail to leverage unlabeled data from the target domain or rely on image-to-image translation, which can distort tissue structures and compromise model accuracy. In this work, we propose a semi-supervised domain adaptation (SSDA) framework that utilizes a latent diffusion model trained on unlabeled data from both the source and target domains to generate morphology-preserving and target-aware synthetic images. By conditioning the diffusion model on foundation model features, cohort identity, and tissue preparation method, we preserve tissue structure in the source domain while introducing target-domain appearance characteristics. The target-aware synthetic images, combined with real, labeled images from the source cohort, are subsequently used to train a downstream classifier, which is then tested on the target cohort. The effectiveness of the proposed SSDA framework is demonstrated on the task of lung adenocarcinoma prognostication. The proposed augmentation yielded substantially better performance on the held-out test set from the target cohort, without degrading source-cohort performance. The approach improved the weighted F1 score on the target-cohort held-out test set from 0.611 to 0.706 and the macro F1 score from 0.641 to 0.716. Our results demonstrate that target-aware diffusion-based synthetic data augmentation provides a promising and effective approach for improving domain generalization in computational pathology.

cs.CV↗

arXiv2026

Geometric Reliability of Neural Population Codes: Sampling Calibration and Within-Session Nonstationarity

Trial-to-trial variability limits how reliably neural population geometry can be estimated, while comparisons across populations depend on neuron and trial counts, response quality, and clustered sampling. We quantified within-session geometric reliability using Shesha, the Spearman correlation between representational dissimilarity matrices estimated from independent trial subsets, in all 39 Steinmetz Neuropixels sessions and in olfactory bulb and piriform cortex recordings from Bolding and Franks. Steinmetz analyses matched neurons and repetitions, compared observed reliability with a stationary residual-bootstrap expectation, and used mouse-level or mouse-clustered inference. Mean matched reliability was 0.0402 across 312 area-by-session recordings. Regional differences and reliability above the stationary benchmark did not survive correction. Temporal effects received the strongest support: interleaving early and late trials increased reliability relative to blocked allocation ($Δ=0.02666$, $q=0.001953$), and RDM similarity declined with within-session lag (mean mouse-level slope $=-0.01912$, $q=0.001953$; $n=10$ mice). Outer-cross-fitted reliability was not associated with choice-direction coupling or stimulus or response-direction decoding after correction. Olfactory comparisons remained descriptive because few paired sessions and no animal identities were available. In held-out simulations, associative recurrence outperformed feedforward subspace denoising but not divisive normalization. Representational geometry became less reproducible with temporal separation within a session, and comparisons across neural populations require sampling calibration and independent inference.

q-bio.NC↗

arXiv2026

The Accuracy Paradox: Empirical Diagnostic of Default Decision Thresholds in Multi-Label Enzyme Commission Prediction [With Code]

Automated prediction of Enzyme Commission (EC) numbers plays a central role in functional annotation and computational drug discovery. However, standard multi-label machine learning pipelines frequently rely on default decision thresholds (t=0.50), assuming balanced prior distributions across target heads. In this study, we present a systematic empirical diagnostic of uncalibrated fixed decision boundaries operating under severe class imbalance across N = 14,096 annotated compounds categorized into six primary EC classes (EC1-EC6). Our results highlight a pronounced Accuracy Paradox: while the multi-label system achieves a deceivingly high mean accuracy of 77.16%, the macro F1-score (0.3976) and macro recall (0.3872) reveal severe predictive breakdown. Majority target classes suffer from hyper-sensitivity and over-prediction, whereas minority classes exhibit sharp recall decay, culminating in a total decision boundary collapse for EC6 (Recall = 0.00%) despite underlying discriminative power (ROC-AUC = 0.5857). Feature correlation analysis further reveals high linear redundancy among topological indices relative to fingerprint density metrics. Ultimately, this diagnostic study demonstrates that standard point predictions mask critical errors in bioinformatics workflows. We establish target-specific threshold optimization and post-hoc conformal calibration as essential, open-source post-processing safeguards for reliable applied machine learning and deep learning architectures.

cs.LG↗

arXiv2026

MI-PEFT: Mixture-of-Experts Integrated Parameter-Efficient Fine-Tuning Protein Language Models Improves Acidophilic Proteins Classification

Acidophilic proteins that remain stable and functional under highly acidic conditions, are important for industrial biocatalysis, acid-related bioprocessing, and the discovery of acid-stable enzymes. However, their identification relies heavily on time-consuming experimental screening methods. With the rapid growth of protein sequence databases, the need for computational identification methods that are both accurate and efficient has become stronger. The emergence of protein language models (PLMs) has significantly improved the sequence representation of downstream biological prediction tasks. This paper proposes MI-PEFT, a mixture-of-experts integrated parameter-efficient fine-tuning framework. Built on the ESM C-600M backbone, the framework incorporates LoRA-based PEFT methods and a DeepSeekMoE-based classification head to resolve the limitations of PEFT and significantly improve computational efficiency. Notably, this task is characterized by a significant class imbalance in the dataset, making high specificity particularly challenging. The experimental results demonstrate that MI-PEFT on PLMs, especially {\text{C}}^{\text{3}}\text{A}, serves as an efficient tool for identifying acidophilic proteins and a constrained pathway that helps resolve class-imbalance by preserving the pretrained representations.

q-bio.QM↗

arXiv2026

MedGSSR: Generalizable Medical Image Super-Resolution 3D Reconstruction via Hierarchical Feed-forward Gaussian Splatting

High-resolution volumetric medical imaging is critical for clinical diagnosis, yet acquisition is often limited by scanner hardware, scan time, and for CT, radiation dose. Medical 3D Super-Resolution (Med3DSR) offers a computational alternative, but existing methods commonly rely on per-subject optimization, pretrained priors, or coordinate-based implicit representations, which compromise anatomical fidelity and limit efficiency. To address these limitations, we present MedGSSR, a fully end-to-end feed-forward framework that represents volumes as an explicit 3D Gaussian field for Med3DSR. Unlike coordinate-based implicit functions, our explicit 3D Gaussian representation naturally enhances signal continuity and local high-frequency fidelity. Specifically, MedGSSR explicitly decouples the reconstruction process into coarse-grained structural preservation and fine-grained textural refinement through the proposed Pyramid Anatomical Encoder and a Hierarchical Gaussian Projector. To support arbitrary-scale super-resolution, we introduce sub-voxel Gaussian decomposition and a Differentiable Gaussian Voxelizer that directly queries the continuous 3D intensity field, reducing discretization artifacts. Extensive experiments on MRI and CT benchmarks demonstrate that MedGSSR significantly outperforms state-of-the-art methods. Notably, our framework exhibits robust generalizability across unseen datasets without requiring per-subject optimization, enabling fast inference and high-fidelity volumetric super-resolution in practical clinical settings. Our project webpage, including code, is at https://william2ai.github.io/medgssr

eess.IV↗

arXiv2026

Agentic BAIM-LLM Evaluation (ABLE): Benchmarking LLM Use of Protein Design Tools

We introduce ABLE, a benchmark for evaluating LLM agents' ability to use biological AI models (BAIMs), such as ProteinMPNN and AlphaFold3, in dual-use protein design workflows. ABLE assesses agent performance through a set of tasks spanning structure retrieval, sequence generation, and design validation. We evaluate 15 frontier models and find that seven refuse all tasks, while the remaining models exhibit substantial performance differences. Claude Sonnet 4 and Gemini 3 Pro achieve the highest scores across information retrieval, tool selection, and tool use. We further compare model performance on a subset of tasks against an expert human baseline. Our results suggest that current LLMs can substantially lower barriers to protein design, but remain inconsistent in planning, strategy generation, and integrating biological knowledge with tool use.

cs.AI↗

arXiv2026

Fusing Sequence Motifs and Pan-Genomic Features: Antimicrobial Resistance Prediction using an Explainable Lightweight 1D CNN-XGBoost Ensemble

Antimicrobial Resistance (AMR) is a rapidly escalating global health crisis. While genomic sequencing enables rapid prediction of resistance phenotypes, current computational methods have limitations. Standard machine learning models treat the genome as an unordered collection of features, ignoring the sequential context of Single Nucleotide Polymorphisms (SNPs). State-of-the-art sequence models like Transformers are often too data-hungry and computationally expensive for the moderately sized datasets that are typical in this domain. To address these challenges, we propose AMR-EnsembleNet, an ensemble framework that synergistically combines sequence-based and feature-based learning. We developed a lightweight, custom 1D Convolutional Neural Network (CNN) to efficiently learn predictive sequence motifs from high-dimensional SNP data. This sequence-aware model was ensembled with an XGBoost model, a powerful gradient boosting system adept at capturing complex, non-local feature interactions. We trained and evaluated our framework on a benchmark dataset of 809 E. coli strains, predicting resistance across four antibiotics with varying class imbalance. Our 1D CNN-XGBoost ensemble consistently achieved top-tier performance across all the antibiotics, reaching a Matthews Correlation Coefficient (MCC) of 0.926 for Ciprofloxacin (CIP) and the highest Macro F1-score of 0.691 for the challenging Gentamicin (GEN) AMR prediction. We also show that our model consistently focuses on SNPs within well-known AMR genes like fusA and parC, confirming that it learns the correct genetic signals for resistance. Our work demonstrates that our ensemble model overcomes the limitations of using either an order-agnostic or a standalone sequence model. Our codes are publicly available on GitHub at: https://github.com/Saiful185/AMR-EnsembleNet.

cs.LG↗

arXiv2026

Simulation-free Unbalanced Dynamic Optimal Transport with General Growth Penalty

Inferring cellular dynamics from unpaired single-cell snapshots requires modeling both state transitions and population growth or death. Unbalanced dynamic optimal transport (UDOT) addresses this by penalizing growth along transport paths, making the choice of growth penalty a key way to encode biological priors on proliferation and apoptosis. However, existing UDOT solvers either rely on computationally expensive NeuralODE simulations or depend on analytical solutions of conditional paths, restricting their efficiency solely to quadratic penalties, i.e. Wasserstein-Fisher-Rao (WFR) geodesics. To enable an efficient UDOT solver for general growth penalties, we first show that concave growth penalties lead to degenerate solutions where growth and transport are separated. We then introduce \textbf{S}imulation-free \textbf{U}nbalanced \textbf{D}ynamic \textbf{O}ptimal transport (SUDO), a simulation-free framework for UDOT with general non-quadratic convex growth penalties. SUDO learns the conditional paths and transport costs, solves the induced semi-coupling problem, and subsequently leverages unbalanced flow matching to achieve a simulation-free solution. On WFR benchmarks, SUDO matches the accuracy of efficient, analytical solution-driven algorithms while outperforming simulation-based methods in computational speed. Beyond WFR, SUDO supports asymmetric penalties that encode proliferation-dominant priors and produce more plausible trajectories and growth estimates on synthetic and single-cell datasets.

cs.LG↗

arXiv2026

A Generalizable Feature Extractor for Alzheimer's-Related Brain MRI Tasks

When there is not enough labeled data to properly train deep learning models, transfer learning can help. We still do not fully understand how effective it is in neuroimaging, especially for Alzheimer's disease research. It is also not clear if these transferred models can work on new datasets without being retrained for each specific task. We evaluate whether a compact, supervised pretrained model can serve as a reusable foundation model for downstream neuroimaging tasks. We freeze the 7.18 million weights of a 3D CNN previously trained for brain-age prediction, and adapt it to each task using Low-Rank Adaptation (LoRA), requiring only ~1% additional trainable parameters. We evaluate generalizability in six experiments. Adapting the model to classify cognitively normal versus Dementia on ADNI gave an AUC of 0.964 on held-out folds (Experiment #1). Applying that adapted model unchanged to OASIS-3, with no retraining, gave an AUC of 0.871 (Experiment #2). Reusing its output logit together with age and a cognitive score distinguished stable from progressing MCI with an AUC of 0.828 (Experiment #3). Adapting the same backbone to predict amyloid positivity from structural MRI gave an AUC of 0.804 (Experiment #4). Finally, the same approach estimated ICV-normalized hippocampal and white matter hypointensity volumes directly from the T1w image, with R^2 of 0.80 and 0.91 respectively, tasks normally addressed with much larger U-Net networks (Experiments #5 and #6). A compact model supervised on brain age can therefore serve as a reusable backbone, adapting to each task with ~1% additional parameters and transferring to an unseen cohort without any training. Our findings suggest that a carefully trained brain age model can serve as an effective foundation model for Alzheimer's related tasks, even under strict data constraints.

cs.CV↗

arXiv2026

When Quantization Breaks Memory: Recurrent-State Write-Back in Low-Precision Temporal Inference

Quantization is widely used to reduce the computational and memory demands of neural-network inference. In recurrent networks, however, the quantized state is stored and returned at the next time step, so the rule used to store that state can alter subsequent computations. Here, we introduce recurrent-state write-back to denote this rule and isolate its effect in a compact GRU encoder--decoder for fluorescence lifetime imaging, a molecular imaging modality used in quantitative biological imaging. A central task is estimating two lifetime parameters, the short-lived component τ1 and the long-lived component τ2, from high-noise time-resolved fluorescence signals. Holding the trained model fixed, replacing continuous state propagation with deterministic 4-bit state storage increases estimation errors for τ1 and τ2 by approximately 70x and 300x, respectively. Failure occurs when repeated small updates remain below the write threshold, leaving the stored state nearly fixed while the network continues to propose change. Error feedback, residual memory, and direction memory carry information from these suppressed updates across time and recover accuracy without retraining. Precision sweeps show that increasing state precision can worsen a fixed recurrent solution, while matched training shows that compatibility with the state interface can be learned. To test whether this behavior extends beyond the GRU, we repeat the post-training intervention in an independently trained LSTM, where coarse write-back reproduces the failure, error feedback restores accuracy, and state-specific interventions reveal greater sensitivity of the cell state than the hidden state. Our results establish recurrent-state write-back as a key determinant of low-precision recurrent dynamics and identify the state-storage interface as a central design consideration for quantized recurrent inference.

cs.AI↗

arXiv2026

AtlasPatch: Scalable Foundation Model-based Tissue Detection and Patch Extraction for Computational Pathology

Whole-slide image (WSI) preprocessing, including tissue detection and patch extraction, is critical computational pathology, yet remains a major bottleneck for large-scale workflows. Existing methods often rely either on threshold-based heuristics that are sensitive to staining variations, tissue fragmentation, and artifacts, or on patch-wise deep learning pipelines with substantially higher computational cost. We present AtlasPatch, a scalable high-throughput WSI preprocessing method built around a foundation-model-based tissue detector that operates at thumbnail resolution: a single thumbnail-level forward pass yields a tissue mask that directly guides patch coordinate generation at the target desired magnification, avoiding repeated patch-level inference. The proposed detector's robustness and efficiency is driven by two coupled contributions: (i) a parameter-efficient adaptation of the SAM2 foundation model that updates only its layer-normalization parameters (0.076% of model weights), and (ii) a curated and semi-manually annotated multi-cohort dataset of 30,000 WSI thumbnail-mask pairs deliberately spanning multiple organs, scanners, tissue appearances, and artifacts. The detector is coupled with pyramid-aware contour mapping from thumbnail to full-resolution slide coordinates, enabling direct patch coordinate generation at the target magnification and parallelized high-throughput patch extraction. AtlasPatch's tissue detection achieves a precision of 0.986 and remains robust across slide variations. Compared with widely used deep-learning preprocessing methods, AtlasPatch is up to 16x faster while preserving downstream multiple-instance learning performance across six slide-level classification tasks. These results position AtlasPatch as a frontier of efficient preprocessing in large-scale computational pathology and pathology foundation models.

eess.IV↗

arXiv2026

SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch

Lead optimization in structure-based drug design aims to improve target binding while avoiding unintended interactions with off-target pockets. However, existing affinity-driven methods do not explicitly control specificity, whereas current specificity-aware approaches commonly require prior knowledge of off-target structures. We address off-target-agnostic specificity-aware lead optimization by analyzing the geometric mismatch between a ligand and the target pocket. We provide a conservative specificity lower bound for geometrically separated off-targets without requiring access to off-target structures. By metricizing pocket--ligand mismatch, the triangle inequality shows that reducing target--ligand mismatch improves a conservative lower bound on mismatch to a separated off-target class, which can be translated into a specificity lower bound through an empirical geometry--affinity calibration. Motivated by this analysis, we introduce SurfSpec, an off-target-agnostic lead optimization framework that iteratively grows ligands toward under-occupied regions of the target pocket surface. SurfSpec alternates between linker generation toward selected target-surface patches, which provides geometric pseudo-labels, and refinement under a pocket-conditioned ligand prior, which restores these pseudo-labels into valid ligands. On the CrossDocked2020 test set, SurfSpec reduces geometric mismatch and outperforms evaluated off-target-agnostic lead optimization baselines in empirical specificity, while maintaining competitive target-affinity improvement.

q-bio.QM↗

arXiv2026

Self-Supervised Pretraining of Molecular Graph Encoders with LeJEPA

Self-supervised pretraining has transformed language and vision, but its value for molecular graph neural networks remains contested. We ask whether pretraining on a large unlabelled corpus improves molecular property prediction. We adapt LeJEPA, a predictor-free joint-embedding predictive architecture regularised by Sketched Isotropic Gaussian Regularisation (SIGReg), to molecular graphs, evaluating GPS and Chemprop-style D-MPNN encoders on the Wong et al. [1] antibiotic-activity dataset and ogbg-molhiv using a multi-seed, bootstrap-based protocol. Pretraining improves learned representations but does not robustly improve finetuning. A frozen probe on pretrained embeddings exceeds random initialisation on both tasks (ogbg-molhiv ROC-AUC 0.788 vs 0.665; +0.123), reaching the published self-supervised band, but this does not translate into finetuning gains. On the antibiotic scaffold split, a canonical partition is significant (delta AUPRC +0.041, p = 0.010), but the effect vanishes across five partitions (pooled +0.013, p = 0.095). Finetuning is null on the random split, ogbg-molhiv, and D-MPNN. The representational edge is nevertheless recoverable. Embeddings saturate at ~16-32 effective dimensions, whereas Morgan fingerprints improve to 1024 bits. At matched dimensionality, fingerprints lead validation (0.799 vs 0.782 at 128 dimensions) but trail shifted test scaffolds (0.759 vs 0.788). Truncating embeddings and combining them with a 1024-bit Morgan fingerprint raises ogbg-molhiv ROC-AUC from 0.805 to 0.832 (delta +0.027; 95% CI [+0.003, +0.054]; p = 0.014); an untrained encoder gains nothing (delta -0.003). Thus, pretraining supplies complementary information best realised through feature-level combination, while finetuning gains are weak and partition-dependent.

q-bio.QM↗

arXiv2026

JUMP-lite: Compact, reproducible benchmarking of cell representations

Image-based profiling captures rich phenotypic signatures for drug discovery and functional genomics. Large public datasets like JUMP Cell Painting now provide millions of images for systematic study. However, JUMP alone occupies 115 TB, and fragmented evaluation practices make systematic comparisons of representation methods impractical for many researchers. Here we present Nahual, an open-source framework for reproducible model deployment, and JUMP-lite, a 92.0 GB subset of JUMP that is approximately 1,250-fold smaller, selected to cover genetic modalities and compound annotations and reduced via lossy JPEG XL compression. Using these resources, we benchmark five representation methods, including classical features (CellProfiler) and deep learning models (MorphEM, OpenPhenom, SubCell, DINOv2). Moderate compression broadly retains signal relative to uncompressed images. Standardized phenotypic activity and consistency metrics reveal meaningful performance differences across methods. Together, JUMP-lite and Nahual provide a foundation for accessible, reproducible benchmarking of image-based cell representations.

q-bio.QM↗

arXiv2026

Mudskippers use tail thrusting to help crutching to move on mud of various wetness

At the water-land interface, amphibious fishes encounter wet flowable substrates made of granular solid-water mixtures, which can stay solid or flow like a fluid. As these substrates become wetter or drier, their yield strength (at which solid-fluid transition occurs) and cohesion (how sticky they are) both change, challenging locomotion. Despite substantial understanding of tetrapod locomotion on flowable substrates (mostly dry sand), we know little about how amphibious fishes cope with wet flowable substrates of various wetness. Here, we studied mudskippers on clay mud of controlled, variable wetness over the range where solid-fluid transition occurs. As mud became wetter, its strength decreased by 100-fold, leading the animal to sink deeper, with larger areas of body and fins contacting mud. By contrast, mud stuck most easily at intermediate wetness. The increased sinkage and contact and stickiness change caused more mud to stick to and pull against the animal on wetter mud. We also tested dry mud, which stuck to animal fins as its mucus dried. Despite these challenges, the mudskipper predominately used a conserved crutching gait on all except the wettest mud tested, with a modest performance reduction. When normal crutching became less effective, the animal assisted it with tail thrusting, by bending and straightening it to push downward and backward to generate additional thrust and lift, or even thrusting the tail to jump. These observations suggest that mudskipper's crutching motor program is well adapted to its native muddy substrates but inflexible, with most novelty in tail use.

physics.bio-ph↗

arXiv2026

Score-Based Generative Data Assimilation for Integrating Aggregated Surveillance Data into Agent-Based Models in Epidemic Tracking

Reliable epidemic monitoring often requires inferring regional infection burden and transmission heterogeneity from noisy, spatially aggregated, and potentially sparse surveillance data. Agent-based models (ABMs) are attractive for this task because they represent individual behavior, contact heterogeneity, and localized interventions, but these same features make them difficult to calibrate online. We develop a generative AI-based data-assimilation (GenDA) framework for partially observed epidemic ABMs that estimates both the epidemic state and a heterogeneous parameter field while respecting the gap between observable macrostates and latent agent-level microstates. GenDA combines a training-free, score-based generative update for macrostate correction with a direct parameter update based on macrostate discrepancies, followed by a macro-micro reassignment step that restores consistency with the ABM. In controlled and geographically explicit synthetic experiments, the framework recovers regional epidemic burden, dominant hotspot structures, and effective transmission heterogeneity from aggregated observations, while improving post-assimilation forecasts relative to state-only assimilation.

math.NA↗