Spatial transcriptomics (ST) enables spatially resolved gene profiling but remains expensive and low-throughput, limiting large-cohort studies and routine clinical use. Predicting spatial gene expression from routine hematoxylin and eosin (H&E) slides is a promising alternative, yet under realistic leave-one-slide-out evaluation, existing models often suffer from slide-level appearance shifts and regression-driven over-smoothing that suppress biologically meaningful variation. CHRep is a two-phase framework for robust histology-to-expression prediction. In the training phase, CHRep learns a structure-aware representation by jointly optimizing correlation-aware regression, symmetric image-expression alignment, and coordinate-induced spatial topology regularization. In the inference phase, cross-slide robustness is improved without backbone fine-tuning through a lightweight calibration module trained on the training slides, which combines a non-parametric estimate from a training gallery with a magnitude-regularized correction module. Unlike prior embedding-alignment or retrieval-based transfer methods that rely on a single prediction route, CHRep couples topology-preserving representation learning with post-hoc calibration, enabling stable neighborhood retrieval and controlled bias correction under slide-level shifts. Across the three cohorts, CHRep consistently improves gene-wise correlation under leave-one-slide-out evaluation, with the largest gains observed on Alex+10x. Relative to HAGE, the Pearson correlation coefficient on all considered genes [PCC(ACG)] increases by 4.0% on cSCC and 9.8% on HER2+. Relative to mclSTExp, PCC(ACG) further improves by 39.5% on Alex+10x, together with 9.7% and 9.0% reductions in mean squared error (MSE) and mean absolute error (MAE), respectively.

Protein-ligand bioactivity data published in the literature are essential for drug discovery, yet manual curation struggles to keep pace with rapidly growing literature. Automated bioactivity extraction remains challenging because it requires not only interpreting biochemical semantics distributed across text, tables, and figures, but also reconstructing chemically exact ligand structures (e.g., Markush structures). To address this bottleneck, we introduce BioMiner, a multi-modal extraction framework that explicitly separates bioactivity semantic interpretation from ligand structure construction. Within BioMiner, bioactivity semantics are inferred through direct reasoning, while chemical structures are resolved via a chemical-structure-grounded visual semantic reasoning paradigm, in which multi-modal large language models operate on chemically grounded visual representations to infer inter-structure relationships, and exact molecular construction is delegated to domain chemistry tools. For rigorous evaluation and method development, we further establish BioVista, a comprehensive benchmark comprising 16,457 bioactivity entries curated from 500 publications. BioMiner validates its extraction ability and provides a quantitative baseline, achieving an F1 score of 0.32 for bioactivity triplets. BioMiner's practical utility is demonstrated via three applications: (1) extracting 82,262 data from 11,683 papers to build a pre-training database that improves downstream models performance by 3.9%; (2) enabling a human-in-the-loop workflow that doubles the number of high-quality NLRP3 bioactivity data, helping 38.6% improvement over 28 QSAR models and identification of 16 hit candidates with novel scaffolds; and (3) accelerating protein-ligand complex bioactivity annotation, achieving a 5.59-fold speed increase and 5.75% accuracy improvement over manual workflows in PoseBusters dataset.

\textbf{Background:} Regulatory frameworks for AI in healthcare, including the EU AI Act and FDA guidance on AI/ML-based medical devices, require clinical decision support to demonstrate not only accuracy but auditability. Existing formal languages for clinical logic validate syntactic and structural correctness but not whether decision rules use epistemologically appropriate evidence. \textbf{Methods:} Drawing on design-by-contract principles, we introduce meta-predicates -- predicates about predicates -- for asserting epistemological constraints on clinical decision rules expressed in a DSL. An epistemological type system classifies annotations along four dimensions: purpose, knowledge domain, scale, and method of acquisition. Meta-predicates assert which evidence types are permissible in any given rule. The framework is instantiated in AnFiSA, an open-source platform for genetic variant curation, and demonstrated using the Brigham Genomics Medicine protocol on 5.6 million variants from the Genome in a Bottle benchmark. \textbf{Results:} Decision trees used in variant interpretation can be reformulated as unate cascades, enabling per-variant audit trails that identify which rule classified each variant and why. Meta-predicate validation catches epistemological errors before deployment, whether rules are human-written or AI-generated. The approach complements post-hoc methods such as LIME and SHAP: where explanation reveals what evidence was used after the fact, meta-predicates constrain what evidence may be used before deployment, while preserving human readability. \textbf{Conclusions:} Meta-predicate validation is a step toward demonstrating not only that decisions are accurate but that they rest on appropriate evidence in ways that can be independently audited. While demonstrated in genomics, the approach generalises to any domain requiring auditable decision logic.

We study semisupervised mean estimation with a small labeled sample, a large unlabeled sample, and a black-box prediction model whose output may be miscalibrated. A standard approach in this setting is augmented inverse-probability weighting (AIPW) [Robins et al., 1994], which protects against prediction-model misspecification but can be inefficient when the prediction score is poorly aligned with the outcome scale. We introduce Calibrated Prediction-Powered Inference, which post-hoc calibrates the prediction score on the labeled sample before using it for semisupervised estimation. This simple step requires no retraining and can improve the original score both as a predictor of the outcome and as a regression adjustment for semisupervised inference. We study both linear and isotonic calibration. For isotonic calibration, we establish first-order optimality guarantees: isotonic post-processing can improve predictive accuracy and estimator efficiency relative to the original score and simpler post-processing rules, while no further post-processing of the fitted isotonic score yields additional first-order gains. For linear calibration, we show first-order equivalence to PPI++. We also clarify the relationship among existing estimators, showing that the original PPI estimator is a special case of AIPW and can be inefficient when the prediction model is accurate, while PPI++ is AIPW with empirical efficiency maximization [Rubin et al., 2008]. In simulations and real-data experiments, our calibrated estimators often outperform PPI and are competitive with, or outperform, AIPW and PPI++. We provide an accompanying Python package, ppi_aipw, at https://larsvanderlaan.github.io/ppi-aipw/.

Motivation: Modern bioinformatics workflows, particularly in imaging and representation learning, can generate thousands to tens of thousands of quantitative phenotypes from a single cohort. In such settings, running genome-wide association analyses trait by trait rapidly becomes a computational bottleneck. While established GWAS tools are highly effective for individual traits, they are not optimized for phenotype-rich screening workflows in which the same genotype matrix is reused across a large phenotype panel. Results: We present TorchGWAS, a framework for high-throughput association testing of large phenotype panels through hardware acceleration. The current public release provides stable Python and command-line workflows for linear GWAS and multivariate phenotype screening, supports NumPy, PLINK, and BGEN genotype inputs, aligns phenotype and covariate tables by sample identifier, and performs covariate adjustment internally. In a benchmark with 8.9 million markers and 23,000 samples, fastGWA required approximately 100 second per phenotype on an AMD EPYC 7763 64-core CPU, whereas TorchGWAS completed 2,048 phenotypes in 10 minute and 20,480 phenotypes in 20 minutes on a single NVIDIA A100 GPU, corresponding to an approximately 300- to 1700-fold increase in phenotype throughput. TorchGWAS therefore makes large-scale GWAS screening practical in phenotype-rich settings where thousands of quantitative traits must be evaluated efficiently. Availability and implementation: TorchGWAS is implemented in Python and distributed as a documented source repository at https://github.com/ZhiGroup/TorchGWAS. The current release provides a command-line interface, packaged source code, tutorials, benchmark scripts, and example workflows.

Micro-actions are subtle, localized movements lasting 1-3 seconds such as scratching one's head or tapping fingers. Such subtle actions are essential for social communication, ubiquitously used in natural interactions, and thus critical for fine-grained video understanding, yet remain poorly understood by current computer vision systems. We identify a fundamental challenge: micro-actions exhibit diverse spatio-temporal characteristics where some are defined by spatial configurations while others manifest through temporal dynamics. Existing methods that commit to a single spatio-temporal decomposition cannot accommodate this diversity. We propose a dual-path network that processes anatomically-grounded spatial entities through parallel Spatial-Temporal (ST) and Temporal-Spatial (TS) pathways. The ST path captures spatial configurations before modeling temporal dynamics, while the TS path inverts this order to prioritize temporal dynamics. Rather than fixed fusion, we introduce entity-level adaptive routing where each body part learns its optimal processing preference, complemented by Mutual Action Consistency (MAC) loss that enforces cross-path coherence. Extensive experiments demonstrate competitive performance on MA-52 dataset and state-of-the-art results on iMiGUE dataset. Our work reveals that architectural adaptation to the inherent complexity of micro-actions is essential for advancing fine-grained video understanding.

Pancreatic tumor segmentation in contrast-enhanced computed tomography (CT) is clinically important yet technically challenging: lesions are often small, heterogeneous, and easily confused with surrounding soft tissue, and models that perform well on one cohort frequently degrade under cohort shift. Our goal is to improve cross-cohort generalization while keeping the model architecture simple, efficient, and practical for 3D CT segmentation. We introduce PanGuide3D, a cohort-robust architecture with a shared 3D encoder, a pancreas decoder that predicts a probabilistic pancreas map, and a tumor decoder that is explicitly conditioned on this pancreas probability at multiple scales via differentiable soft gating. To capture long-range context under distribution shift, we further add a lightweight Transformer bottleneck in the U-Net bottleneck representation. We evaluate cohort transfer by training on the PanTS (Pancreatic Tumor Segmentation) cohort and testing both in-cohort (PanTS) and out-of-cohort on MSD (Medical Segmentation Decathlon) Task07 Pancreas, using matched preprocessing and training protocols across strong baselines. We collect voxel-level segmentation metrics, patient-level tumor detection, subgroup analyses by tumor size and anatomical location, volume-conditioned performance analyses, and calibration measurements to assess reliability. Across the evaluated models, PanGuide3D achieves the best overall tumor performance and shows improved cross-cohort generalization, particularly for small tumors and challenging anatomical locations, while reducing anatomically implausible false positives. These findings support probabilistic anatomical conditioning as a practical strategy for improving cross-cohort robustness in an end-to-end model and suggest potential utility for contouring support, treatment planning, and multi-institutional studies.

A comprehensive analysis of viral mutations is essential for understanding viral evolution, disease epidemiology, diagnosis, drug resistance, etc. However, challenges remain in capturing complex mutation patterns and supporting diverse viral families with varying genome architectures. To address these needs, we present VARIANT, an web server for mutational analysis of RNA viral genomes and associated viral products across both single- and multi-segment virus genomes. The server takes as input a viral reference genome, a reference protein sequence, and/or multiple sequence alignment, and automatically provides full annotation of mutation types, including standard categories such as point mutations (missense, silent, and nonsense), insertions, deletions, or frameshift events in both coding and non-coding regions. In addition, VARIANT detects three biologically significant mutation patterns that are overlooked by conventional software/packages: ``row mutations'' (consecutive substitutions within a window of 3 nts), ``hot mutations'' (two non-consecutive substitutions within a window of 3 nts), and potential programmed ribosomal frameshifting (PRF) regions. The server currently contains automatic analysis of major viral pathogens, including SARS-CoV-2, HIV-1, Influenza H3N2, Ebola virus, and Chikungunya virus. It also allows users to analyze customized viruses. Users can track VARIANT analysis progress in real time, visualize mutation distributions, and download structured results in ZIP format. VARIANT also incorporates dual graph topology analysis to classify frameshifting element structures from dot-bracket notation input. This feature enables systematic comparison of RNA secondary structure motifs across viral families by mapping structures to a comprehensive library of dual graph topologies. The web server is freely available at https://variant.up.railway.app.

This paper develops a physical framework for the prebiotic emergence of information and meaning. Building on Constructor Theory, we define information as a reproducible physical difference and meaning as a difference with stable functional consequences. Casimir-Lifshitz-coupled protocell clusters serve as a minimal model that exhibits reproducible attractors, ordered transitions, and autonomous task structures. We show that such clusters carry both informational states (e.g., distances, geometries, gradients) and meaningful states that regulate prebiotic tasks such as approach, exchange, or stabilization. This approach integrates physical mechanisms, computational mechanics, and early proto-semantic functions into a coherent account of information formation before biology.

What is the meaning of physical causal closure? Jaegwon Kim explicitly adopts a conception of causation according to which physical causation is effectively identified with deterministic physical lawfulness, and equates it with physical determinism. While this conception is internally coherent, it differs from currently dominant theories of causation. Physics and the theory of causation serve different descriptive purposes. In this study, we refer to them, respectively, as the Physical Stance and the Causal Stance. Within this framework, physical determinism belongs to the Physical Stance, and physical causal closure is defined only within the Causal Stance. Consequently, the two should not be equated. On this basis, this study reconstructs Davidson's anomalous monism as a materialist position that acknowledges mental causation without contradicting physical determinism. Furthermore, we propose a linguistic framework in which physical causal closure does not hold in the Causal Stance while physical determinism remains intact in the Physical Stance.

We introduce a reversible deep learning model for 13C NMR that uses a single conditional invertible neural network for both directions between molecular structures and spectra. The network is built from i-RevNet style bijective blocks, so the forward map and its inverse are available by construction. We train the model to predict a 128-bit binned spectrum code from a graph-based structure encoding, while the remaining latent dimensions capture residual variability. At inference time, we invert the same trained network to generate structure candidates from a spectrum code, which explicitly represents the one-to-many nature of spectrum-to-structure inference. On a filtered subset, the model is numerically invertible on trained examples, achieves spectrum-code prediction above chance, and produces coarse but meaningful structural signals when inverted on validation spectra. These results demonstrate that invertible architectures can unify spectrum prediction and uncertainty-aware candidate generation within one end-to-end model.

We present the unified computational framework for modeling the sulcal patterns of human brain obtained from the magnetic resonance images. The Wasserstein distance is used to align the sulcal patterns nonlinearly. These patterns are topologically different across subjects making the pattern matching a challenge. We work out the mathematical details and develop the gradient descent algorithms for estimating the deformation field. We further quantify the image registration performance. This method is applied in identifying the differences between male and female sulcal patterns.