Daily Papers

The rapid growth of single-cell transcriptomic data has enabled the development of foundation models pretrained primarily by reconstructing masked expression values. This objective encourages these models to learn gene dependencies but does not directly optimize whole-cell representations, which are essential for many downstream tasks. To bridge this gap, we propose a contrastive pretraining framework that learns cell representations through complementary transcriptomic views. Since standard contrastive learning is not readily applicable to single-cell pretraining, we introduce specific adaptations along three dimensions --- co-expression-guided gene partitioning, expression-aware contrast-set construction, and competence-gated contrastive onset. Specifically, we first construct two complementary views of each cell by partitioning its genes according to their co-expression structure. Then, to prevent the model from using gene-set identity as a shortcut, we construct hard negatives by permuting expression values while keeping gene identities unchanged. Finally, we introduce a competence-aware controller to determine how the contrastive objective is applied. Experiments on cell-type annotation and gene regulatory network inference demonstrate competitive transfer under the evaluated protocols. In the six-network GRN evaluation, our method records the highest mean AUROC and AUPRC point estimates among the compared variants, while the highest-scoring variant differs across individual networks. These results establish complementary-view contrastive learning as an effective direction for single-cell pretraining beyond gene reconstruction.

Discovery of causal relationships in high-dimensional Gene Regulatory Networks (GRN) is computationally challenging and often difficult to interpret due to dense connections. Therefore, grouping genes together into functional modules can improve tractability and biological interpretability. However, existing cluster level causal discovery methods assume access to a predefined admissible partitions, requiring the graph over clusters to be acyclic. Constructing such partitions is therefore challenging. In this work, we introduce GO-based Clustering for Causal Discovery (GO4CD), an algorithm that uses Gene Ontology (GO) to construct biologically meaningful gene partitions at multiple levels of granularity, while favoring those more likely to be admissible for causal discovery. GO4CD groups together genes participating in a shared biological process, and propagates gene annotations through the ontology hierarchy to achieve different granularity of partitions. Furthermore, we integrate GO4CD with Causal Learning over Clusters (CLOC) algorithm and evaluate recovery of true Markov equivalence class both with an oracle of conditional independencies and on simulated gene expression data using multivariate conditional independence tests. We evaluate GO4CD on multiple E.coli regulatory subnetworks and find that it is inadmissible in 18.1% of the cases, compared with 65.3-82.3% for the semantic-similarity baselines. Our results indicate that GO4CD is substantially better suited to learning causal GRNs defined over biologically meaningful gene clusters.

Spatial transcriptomics (ST) provides spatially resolved gene expression profiling but remains expensive, motivating the prediction of ST from histology images. Generative models have emerged as a mainstream paradigm for ST prediction due to their ability to model the conditional distribution of gene expression and capture its inherent stochasticity. However, these methods typically treat genes as independent prediction targets and overlook the intrinsic gene-gene interactions in biological systems, which limits their ability to preserve biologically meaningful co-expression patterns. We argue that gene-gene interactions, which reflect shared pathways and regulatory mechanisms, are essential for generating numerically accurate and biologically coherent ST profiles. In this paper, we propose CorrFlow, a correlation-guided flow matching framework for histology-to-ST prediction that explicitly models gene-gene dependencies through two complementary mechanisms. First, we introduce an annealed masked flow matching strategy, where subsets of genes are progressively masked following a timestep-dependent annealing schedule, encouraging the model to infer masked genes conditioned on the remaining genes and promoting joint conditional modeling beyond per-gene marginal estimation. Second, we devise a gene graph-regularized optimization scheme that integrates prior knowledge from the STRING database and data-driven co-expression estimated by WGCNA to construct a gene affinity graph, which enforces both local consistency and global smoothness in the predicted expression. Extensive experiments across 12 datasets show that CorrFlow achieves the best average PCC and HPCC among evaluated methods, leading to more biologically coherent ST predictions.

A central task in virtual cell modeling is predicting single-cell transcriptional responses to unseen genetic perturbations and drug combinations, and biological networks provide valuable priors on gene relationships. Existing graph-based models commonly use the same network to structure gene representations and mediate intergene interactions, thereby implicitly treating stable associations as perturbation-response pathways. Gene Ontology and control-derived coexpression networks encode relatively stable relationships rather than intervention-specific response directions or magnitudes. We therefore propose GeneGeoFlow, which conditions a control-anchored residual flow on gene-wise geometry derived from biological networks to learn intervention-specific transcriptional responses. GeneGeoFlow derives multi-scale spectral coordinates from Gene Ontology and control-derived coexpression networks. A perturbation-conditioned, gene-wise gating module selects relevant structural scales and network sources, yielding intervention-specific gene geometry. The resulting geometry conditions a control-anchored residual flow without explicitly propagating target-derived signals along the graph. Condition-wise optimal transport couples unpaired control and perturbed populations for training, while a Delta-correlation objective aligns the predicted and observed condition-level expression-shift directions. GeneGeoFlow achieves Pearson Delta scores of 0.8979 on the Norman additive benchmark and 0.9088 on five held-out drug combinations in the fixed ComboSciPlex test split. These results support perturbation-conditioned gene geometry as an effective structural prior for intervention-specific response prediction, without conflating stable gene relationships with response propagation.

High-dimensional, low-sample-size bulk gene expression data poses a fundamental challenge in transcriptomics, which typically includes tens of thousands of genes but relatively few samples, leading to overfitting and unstable selection for key features as biomarkers. We propose a regression by community centers (RCC) framework tailored for such data. RCC converts gene expression data into a feature proximity network and leverages the phase transition of the giant connected component to identify a critical distance threshold that yields a sparse yet maximally informative network representation, indicated by a minimum normalized shortest compression length. Intuitively, at the criticality, the network balances fragmentation and over-connectivity, allowing meaningful gene-gene associations communities to emerge while filtering noises, such that community-centers capture the most informative and non-redundant signals. These representative genes are then fed to a simple ordinary least squares (OLS) model for downstream predictions. Across five bulk gene expression datasets, RCC displays exceptional prediction performance, clearly outperforming benchmark methods, remains robust to missing data and noises, and does not rely on external biological knowledge. These results suggest that network-based representations provide an effective and general framework for high-dimensional, low-sample-size prediction tasks beyond transcriptomics and illustrate how network-science ideas can support robust learning in data-scarce regimes.

Spatial Transcriptomics (ST) offers spatially resolved gene expression but remains costly. Predicting expression directly from widely available Hematoxylin and Eosin (H&E) stained images presents a cost-effective alternative. However, most computational approaches (i) predict each gene independently, overlooking co-expression structure, and (ii) cast the task as continuous regression despite expression being discrete counts. This mismatch can yield biologically implausible outputs and complicate downstream analyses. We introduce GenAR, a multi-scale autoregressive framework that refines predictions from coarse to fine. GenAR clusters genes into hierarchical groups to expose cross-gene dependencies, models expression as codebook-free discrete token generation to directly predict raw counts, and conditions decoding on fused histological and spatial embeddings. From an information-theoretic perspective, the discrete formulation avoids log-induced biases and the coarse-to-fine factorization aligns with a principled conditional decomposition. Extensive experimental results on four Spatial Transcriptomics datasets across different tissue types demonstrate that GenAR achieves state-of-the-art performance, offering potential implications for precision medicine and cost-effective molecular profiling. Code is publicly available at https://github.com/oyjr/genar.

Gene panel selection aims to identify the most informative genomic biomarkers in label-free genomic datasets. Traditional approaches, which rely on domain expertise, embedded machine learning models, or heuristic-based iterative optimization, often introduce biases and inefficiencies, potentially obscuring critical biological signals. To address these challenges, we present an iterative gene panel selection strategy that harnesses ensemble knowledge from existing gene selection algorithms to establish preliminary boundaries or prior knowledge, which guide the initial search space. Subsequently, we incorporate reinforcement learning through a reward function shaped by expert behavior, enabling dynamic refinement and targeted selection of gene panels. This integration mitigates biases stemming from initial boundaries while capitalizing on RL's stochastic adaptability. Comprehensive comparative experiments, case studies, and downstream analyses demonstrate the effectiveness of our method, highlighting its improved precision and efficiency for label-free biomarker discovery. Our results underscore the potential of this approach to advance single-cell genomics data analysis.

Single-cell transcriptomes are sparse observations of coordinated biological programmes, yet most self-supervised models learn by reconstructing individual genes. Here we present BioM-JEPA, a joint-embedding predictive architecture that instead predicts aggregate representations of graph-connected gene blocks defined by protein-association and corpus-derived coexpression evidence. A student network infers each target-block representation from the remaining genes in a cell, while a slowly updated teacher supplies the corresponding target from the full observed gene set. Under the reported extraction procedure, block-level prediction produced embeddings with higher effective rank and weaker association with detected-gene depth in the tested diagnostics than token-prediction, random-block and reconstruction controls. Across CellBench tasks, frozen BioM-JEPA embeddings retained expression, pathway and neighbourhood information and achieved the lowest aggregate perturbation-response error among the evaluated models. Representation diagnostics were also consistent with canonical pancreatic programmes and compositional relationships between genetic perturbations. Linear attention avoids constructing a quadratic gene-by-gene attention matrix; in a matched one-epoch hPancreas experiment at batch size 8, BioM-JEPA provided 5.75-fold higher fine-tuning throughput and 3.76-fold higher held-out embedding throughput than scFoundation. Together, these results support graph-connected gene blocks as useful prediction units for JEPA-style representation learning in single-cell biology.

Inferring spatial transcriptomics (ST) from histology enables scalable histogenomic profiling, yet current methods are largely restricted to single-tissue models. This fragmentation fails to leverage biological principles shared across cancer types and hinders application to data-scarce scenarios. While pan-cancer training offers a solution, the resulting heterogeneity challenges monolithic architectures. To bridge this gap, we introduce MoLF (Mixture-of-Latent-Flow), a generative model for pan-cancer histogenomic prediction. MoLF leverages a conditional Flow Matching objective to map noise to the gene latent manifold, parameterized by a Mixture-of-Experts (MoE) velocity field. By dynamically routing inputs to specialized sub-networks, this architecture effectively decouples the optimization of diverse tissue patterns. Our experiments demonstrate that MoLF establishes a new state-of-the-art, consistently outperforming both specialized and foundation model baselines on pan-cancer benchmarks. Furthermore, MoLF exhibits zero-shot generalization to cross-species data, suggesting it captures fundamental, conserved histo-molecular mechanisms.

Predicting transcriptional responses to specific perturbations is critical for understanding cellular regulatory mechanisms and accelerating drug discovery. Single-cell RNA sequencing destroys each measured cell, yielding only unpaired populations of control and perturbed cells. However, existing methods typically model perturbation prediction at the single-cell level and assume cell-to-cell correspondence, which conflicts with the unpaired nature of the observed data. To address this challenge, we propose PopPert, a framework that explicitly parameterizes population-level joint gene expression distributions for collective transcriptional state modeling. Given a control population distribution and a perturbation condition, PopPert predicts perturbation-induced changes in distribution parameters, eliminating the need for cell-level correspondence and reducing sensitivity to single-cell noise. To effectively capture gene co-expression patterns, PopPert leverages a low-rank Gaussian Copula to model cross-gene statistical dependencies and construct the joint gene expression distribution, additionally allowing sampling of synthetic perturbed single-cell profiles. Across multiple single-cell benchmarks spanning both genetic and chemical perturbations, PopPert achieves superior overall performance in differential expression recovery, perturbation effect estimation, and population-level distribution matching. These results establish population-level joint distribution learning as an effective paradigm for predicting transcriptional responses from unpaired single-cell populations. Code for PopPert is publicly available at https://github.com/whd1125/PopPert.

Spatial transcriptomics (ST) provides spatially resolved measurements of gene expression, enabling characterization of the molecular landscape of human tissue beyond histological assessment as well as localized readouts that can be aligned with morphology. Concurrently, the success of multimodal foundation models that integrate vision with complementary modalities suggests that morphomolecular coupling between local expression and morphology can be systematically used to improve histological representations themselves. We introduce Spatial Expression-Aligned Learning (SEAL), a vision-omics self-supervised learning framework that infuses localized molecular information into pathology vision encoders. Rather than training new encoders from scratch, SEAL is designed as a parameter-efficient vision-omics finetuning method that can be flexibly applied to widely used pathology foundation models. We instantiate SEAL by training on over 700,000 paired gene expression spot-tissue region examples spanning tumor and normal samples from 14 organs. Tested across 38 slide-level and 15 patch-level downstream tasks, SEAL provides a drop-in replacement for pathology foundation models that consistently improves performance over widely used vision-only and ST prediction baselines on slide-level molecular status, pathway activity, and treatment response prediction, as well as patch-level gene expression prediction tasks. Additionally, SEAL encoders exhibit robust domain generalization on out-of-distribution evaluations and enable new cross-modal capabilities such as gene-to-image retrieval. Our work proposes a general framework for ST-guided finetuning of pathology foundation models, showing that augmenting existing models with localized molecular supervision is an effective and practical step for improving visual representations and expanding their cross-modal utility.

Predicting cellular responses to genetic perturbations helps prioritize experiments in single-cell genomics, where exhaustive measurement is infeasible. While computational models increasingly predict these responses, three evaluation deficiencies obscure what their scores demonstrate. First, absolute metrics cannot separate target-specific predictions from a shared background response. Second, common metrics remain high under gene shuffling, so gene-level accuracy is never verified. Third, a score at one training size says nothing about coverage, which depends on representation-space proximity and response-constraining power. We propose AmbiModBench, a specificity-aware, gene-resolved and coverage-aware benchmark. It pairs every score with a training-mean reference fitted on the same split, screens each readout by gene-coordinate permutation, and links embedding distance to response variation. Across K562, RPE1 and Norman, strong absolute scores largely reflect shared background rather than target-specific learning. Widely used readouts track response magnitude distributions rather than the affected genes. Detectable gain follows representation-space coverage rather than training-set size. Nonetheless, on RPE1 the protocol yields a reproducible target-specific gain across five additional splits and three gene selections, which absolute scores alone cannot distinguish from shared background.

Accurately predicting gene expression from histopathology images offers a scalable and non-invasive approach to molecular profiling, with significant implications for precision medicine and computational pathology. However, existing methods often underutilize the cross-modal representation alignment between histopathology images and gene expression profiles across multiple representational levels, thereby limiting their prediction performance. To address this, we propose Gene-DML, a unified framework that structures latent space through Dual-pathway Multi-Level discrimination to enhance correspondence between morphological and transcriptional modalities. The multi-scale instance-level discrimination pathway aligns hierarchical histopathology representations extracted at local, neighbor, and global levels with gene expression profiles, capturing scale-aware morphological-transcriptional relationships. In parallel, the cross-level instance-group discrimination pathway enforces structural consistency between individual (image/gene) instances and modality-crossed (gene/image, respectively) groups, strengthening the alignment across modalities. By jointly modelling fine-grained and structural-level discrimination, Gene-DML is able to learn robust cross-modal representations, enhancing both predictive accuracy and generalization across diverse biological contexts. Extensive experiments on public spatial transcriptomics datasets demonstrate that Gene-DML achieves state-of-the-art performance in gene expression prediction. The code and checkpoints will be released soon.

Predicting transcriptional responses to genetic perturbations could reduce the experimental burden of functional genomics, but extrapolation to genes that were never perturbed during training remains difficult. We present Stable-Shift, a structured method for estimating unseen-gene responses. Stable-Shift aggregates single-cell measurements into perturbation-level expression shifts, fits a low-rank response basis using training perturbations only, and predicts an unseen gene's coordinates in that basis from biological context. The context combines STRING interactions, network structure, control-cell expression statistics, and Gene Ontology annotations; the evaluated implementation uses graph convolution to integrate these inputs. On the supplied K562 Perturb-seq benchmark, Stable-Shift obtained 0.592 cosine similarity, compared with 0.569 for GEARS, together with higher Spearman correlation and top-gene precision among the evaluated methods. Its mean cosine similarity over five unseen-gene splits was 0.589 +/- 0.008. The same ordering was observed in the supplied graph-aware, residualized, gene-space, and Norman-dataset comparisons. These results support further study of biologically structured latent-response prediction, while the lower gene-space accuracy and sensitivity to sparse graph neighborhoods limit the scope of the present conclusions.

Predicting transcriptional responses to unseen compounds is limited by fragmented chemical coverage and heterogeneous experimental platforms and gene panels. To assess molecular generalization across these settings, we build on Chem-PerturBridge to benchmark eight datasets with 16,771 compounds, withholding test compounds from every training dataset. This comparison reveals that high overall response agreement can coexist with weak prediction of drug-specific differences, despite reproducible signals across repeated measurements. To exploit complementary chemical supervision while targeting these differences, we introduce Bison: a shared gene representation connects native panels, while two discrete diffusion models compose context-dependent responses with molecular deviations learned through matched drug-contrast supervision. A single Bison model jointly trained across all eight datasets achieves the highest mean overall-response and drug-contrast Pearson correlations on the full benchmark in comparison with 11 methods trained independently per dataset. Compared with dataset-specific training of the same architecture, joint training increases mean drug-contrast correlation by 27.4\%, with gains across all eight datasets and improvements in overall response prediction. These results demonstrate how matched drug contrasts turn complementary screens into shared molecular supervision for unseen-drug response prediction while preserving native gene measurements.

Predicting transcriptomic responses to small-molecule perturbations across cell lines is central to drug discovery, but exhaustive profiling of drug-cell combinations is infeasible. We frame molecular perturbation prediction as retrieve-and-aggregate: approximate an unmeasured drug's response in a cell line by aggregating measured responses of a small set of biologically related compounds. We propose LLM-Guided Retrieval (LGR), where a large language model (LLM) ranks candidate neighbor drugs (restricted to those profiled in the target cell line); after which a fixed mean aggregator combines their observed expression deltas to form the prediction. We evaluate on the Tahoe-100M single-cell perturbation atlas under unseen-drug, unseen-cell-line, and open-world regimes. LGR consistently improves over drug mean, ChemCPA, and chemistry-based kNN baselines, with the strongest gains for unseen cell-line generalization, where it achieves higher correlation and lower error than mean baselines. Across settings, LGR improves directional (sign) accuracy of gene regulation, indicating better recovery of biologically meaningful perturbation effects even when magnitude-based metrics are similar. These results suggest that retrieval quality, rather than predictor complexity, is a key driver of zero-shot molecular perturbation prediction, and that LLMs can provide a useful biological prior when used as constrained retrieval modules.

Large language models (LLMs) have shown growing promise in biomedical research, particularly for knowledge-driven interpretation tasks. However, their ability to reliably reason from gene-level knowledge to functional understanding, a core requirement for knowledge-enhanced cell atlas interpretation, remains largely underexplored. To address this gap, we introduce SciHorizon-GENE, a large-scale gene-centric benchmark constructed from authoritative biological databases. The benchmark integrates curated knowledge for over 190K human genes and comprises more than 540K questions covering diverse gene-to-function reasoning scenarios relevant to cell type annotation, functional interpretation, and mechanism-oriented analysis. Motivated by behavioral patterns observed in preliminary examinations, SciHorizon-GENE evaluates LLMs along four biologically critical perspectives: research attention sensitivity, hallucination tendency, answer completeness, and literature influence, explicitly targeting failure modes that limit the safe adoption of LLMs in biological interpretation pipelines. We systematically evaluate a wide range of state-of-the-art general-purpose and biomedical LLMs, revealing substantial heterogeneity in gene-level reasoning capabilities and persistent challenges in generating faithful, complete, and literature-grounded functional interpretations. Our benchmark establishes a systematic foundation for analyzing LLM behavior at the gene scale and offers insights for model selection and development, with direct relevance to knowledge-enhanced biological interpretation.

Drug mechanism-of-action (MoA) modeling commonly relies on perturbational transcriptomes, but matched microRNA (miRNA) measurements are often unavailable. Inferred regulatory features offer a scalable way to reuse these data. Here, we present MIRCID, a framework comparing gene expression with inferred transcription factor (TF) activity and miRNA expression across pathway classification and similarity-based MoA retrieval. HubmiRNet infers 414 pan-cancer hub miRNAs (HubmiRs) from 977 L1000 landmark genes, achieving a Pearson correlation coefficient of 87.72%; its 1,298-output variant also outperformed SiCmiR on the full-miRNA task (71.21% versus 67.30%). In the evaluated comparisons, miRNA augmentation provided more consistent gains than TF activity. Generic embedding controls showed model-dependent utility, while complementarity analyses identified a distinct, partially linearly recoverable representation that retained gene-derived structure. Illustrative rescue cases linked improved classification to biologically plausible miRNA patterns in samples with weak transcriptional signatures. These findings support inferred HubmiRs as a biologically informed recoding of transcriptomic data for perturbational drug modeling, while leaving recovery of measured perturbational miRNA responses to further validation.

Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity, but its complexity, which is marked by high dimensionality, sparsity, and batch effects, which poses major computational challenges. Transformer-based models have made significant advances in this domain but are often limited by their quadratic complexity and suboptimal handling of long-range dependencies. In this work, we introduce GeneMamba, a scalable and efficient foundation model for single-cell transcriptomics built on state space modeling. Leveraging the Bi-Mamba architecture, GeneMamba captures bidirectional gene context with linear-time complexity, offering substantial computational gains over transformer baselines. The model is pretrained on nearly 30 million cells and incorporates biologically informed objectives, including pathway-aware contrastive loss and rank-based gene encoding. We evaluate GeneMamba across diverse tasks, including multi-batch integration, cell type annotation, and gene-gene correlation, demonstrating strong performance, interpretability, and robustness. These results position GeneMamba as a practical and powerful alternative to transformer-based methods, advancing the development of biologically grounded, scalable tools for large-scale single-cell data analysis.

Histopathological examination primarily relies on hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. Although IHC provides critical molecular information, it is costly and requires specialized expertise. Stain transfer provides an efficient alternative by computationally generating IHC from H&E images, but remains challenged by unified and interpretable modeling for heterogeneous biomarkers under pixel-unaligned supervision. We propose DMCoStain, a novel Data-Model Co-optimization framework for Stain transfer. It iteratively co-refines training data and model capability, improving staining accuracy and interpretability in both pathological and structural consistency. To refine training data in a clinically meaningful manner, it incorporates the Multimodal Expert-Guided Finer Selection (MEGFS) strategy, built upon a pioneering IHC-positive-expression (IPE) vision-language model (VLM) that emulates pathologist reasoning. To support MEGFS, we construct ImmunoInstruction, the first large-scale IPE instruction-following dataset with 150K VQA samples. Extensive experiments on multiple tissues and biomarkers demonstrate that DMCoStain achieves state-of-the-art (SOTA) accuracy. This paradigm offers strong practical value, and MEGFS also functions as a specialized evaluation tool for future model development. Dataset, code, and more details are in https://github.com/SikangSHU/DMCoStain.

Spatial transcriptomics enables simultaneous measurement of gene expression and tissue morphology, offering unprecedented insights into cellular organization and disease mechanisms. However, the field lacks comprehensive benchmarks for evaluating multimodal learning methods that leverage both histology images and gene expression data. Here, we present HESCAPE, a large-scale benchmark for cross-modal contrastive pretraining in spatial transcriptomics, built on a curated pan-organ dataset spanning 6 different gene panels and 54 donors. We systematically evaluated state-of-the-art image and gene expression encoders across multiple pretraining strategies and assessed their effectiveness on two downstream tasks: gene mutation classification and gene expression prediction. Our benchmark demonstrates that gene expression encoders are the primary determinant of strong representational alignment, and that gene models pretrained on spatial transcriptomics data outperform both those trained without spatial data and simple baseline approaches. However, downstream task evaluation reveals a striking contradiction: while contrastive pretraining consistently improves gene mutation classification performance, it degrades direct gene expression prediction compared to baseline encoders trained without cross-modal objectives. We identify batch effects as a key factor that interferes with effective cross-modal alignment. Our findings highlight the critical need for batch-robust multimodal learning approaches in spatial transcriptomics. To accelerate progress in this direction, we release HESCAPE, providing standardized datasets, evaluation protocols, and benchmarking tools for the community

In the rapidly evolving field of metabolic engineering, the quest for efficient and precise gene target identification for metabolite production enhancement presents significant challenges. Traditional approaches, whether knowledge-based or model-based, are notably time-consuming and labor-intensive, due to the vast scale of research literature and the approximation nature of genome-scale metabolic model (GEM) simulations. Therefore, we propose a new task, Gene-Metabolite Association Prediction based on metabolic graphs, to automate the process of candidate gene discovery for a given pair of metabolite and candidate-associated genes, as well as presenting the first benchmark containing 2474 metabolites and 1947 genes of two commonly used microorganisms Saccharomyces cerevisiae (SC) and Issatchenkia orientalis (IO). This task is challenging due to the incompleteness of the metabolic graphs and the heterogeneity among distinct metabolisms. To overcome these limitations, we propose an Interactive Knowledge Transfer mechanism based on Metabolism Graph (IKT4Meta), which improves the association prediction accuracy by integrating the knowledge from different metabolism graphs. First, to build a bridge between two graphs for knowledge transfer, we utilize Pretrained Language Models (PLMs) with external knowledge of genes and metabolites to help generate inter-graph links, significantly alleviating the impact of heterogeneity. Second, we propagate intra-graph links from different metabolic graphs using inter-graph links as anchors. Finally, we conduct the gene-metabolite association prediction based on the enriched metabolism graphs, which integrate the knowledge from multiple microorganisms. Experiments on both types of organisms demonstrate that our proposed methodology outperforms baselines by up to 12.3% across various link prediction frameworks.

Spatial transcriptomics (ST) provides unprecedented insights into tumor heterogeneity by capturing spatially resolved gene expression, yet its high experimental cost hinders large-scale adoption. Consequently, computational approaches that predict spatial gene expression directly from hematoxylin and eosin slides, termed virtual ST, have rapidly emerged. Despite this progress, assessing advances in the field remains difficult due to insufficient benchmarking: prior studies rely on small, heterogeneous datasets, inconsistent training and inference pipelines, and limited evaluation of biological interpretability and model robustness. To address these gaps, we present STP-BENCH, a standardized benchmark for virtual ST models. STP-BENCH comprises six cancer types spanning two ST platforms (Visium and Xenium), with each training dataset containing more than 30,000 spots and at least 15 slides to ensure statistical reliability. We evaluate 21 predictive approaches, re-implemented with a unified pathology foundation model as the morphological encoder when architecturally applicable. Beyond conventional benchmarks that report average predictive accuracy on highly variable genes, we systematically examine which genes and gene sets are recoverable from histomorphology. We further evaluate the downstream biological utility of predicted profiles through cell-type deconvolution and spatial domain identification, and assess model reliability under domain shifts and data scaling. Notably, unified morphological encoding substantially re-orders model rankings established in prior studies, indicating that architectural innovations and image encoding have been conflated in previous evaluations. We publicly release STP-BENCH to support reproducibility and serve as a community benchmark at https://github.com/NEXGEM/STP-Bench.

Transcriptome foundation models TFMs hold great promises of deciphering the transcriptomic language that dictate diverse cell functions by self-supervised learning on large-scale single-cell gene expression data, and ultimately unraveling the complex mechanisms of human diseases. However, current TFMs treat cells as independent samples and ignore the taxonomic relationships between cell types, which are available in cell ontology graphs. We argue that effectively leveraging this ontology information during the TFM pre-training can improve learning biologically meaningful gene co-expression patterns while preserving TFM as a general purpose foundation model for downstream zero-shot and fine-tuning tasks. To this end, we present single cell, Cell-ontology guided TFM scCello. We introduce cell-type coherence loss and ontology alignment loss, which are minimized along with the masked gene expression prediction loss during the pre-training. The novel loss component guide scCello to learn the cell-type-specific representation and the structural relation between cell types from the cell ontology graph, respectively. We pre-trained scCello on 22 million cells from CellxGene database leveraging their cell-type labels mapped to the cell ontology graph from Open Biological and Biomedical Ontology Foundry. Our TFM demonstrates competitive generalization and transferability performance over the existing TFMs on biologically important tasks including identifying novel cell types of unseen cells, prediction of cell-type-specific marker genes, and cancer drug responses.

Gene perturbation analysis plays a critical role in drug discovery by enabling researchers to investigate how interventions on specific genes influence global gene expression patterns within cells. Recent advances in artificial intelligence-driven virtual cell models have made it possible to predict gene expression outcomes for a wide range of perturbation strategies in silico, substantially reducing reliance on costly and time-consuming biological experiments. However, effectively exploring and interpreting the high-dimensional perturbation spaces produced by these models remains challenging because of the combinatorial nature of perturbations and the complex cell-specific gene expression responses they generate. In this work, we present CellPrism, a visual analytics system designed to support the systematic exploration of gene perturbation strategies for drug discovery. Specifically, CellPrism integrates clustering-based overviews to summarize perturbation outcomes, a glyph-based representation to compactly encode gene expression patterns across cell types, and coordinated views that enable fine-grained comparison and interpretation of perturbation effects. We demonstrate the effectiveness of CellPrism through a real-world case study and expert interviews. This work highlights the value of visual analytics in bridging virtual cell modeling with expert-driven decision making in drug discovery.

Recent advancements in machine learning have significantly improved the identification of disease-associated genes from gene expression datasets. However, these processes often require extensive expertise and manual effort, limiting their scalability. Large Language Model (LLM)-based agents have shown promise in automating these tasks due to their increasing problem-solving abilities. To support the evaluation and development of such methods, we introduce GenoTEX, a benchmark dataset for the automated analysis of gene expression data. GenoTEX provides annotated code and results for solving a wide range of gene identification problems, encompassing dataset selection, preprocessing, and statistical analysis, in a pipeline that follows computational genomics standards. The benchmark includes expert-curated annotations from bioinformaticians to ensure accuracy and reliability. To provide baselines for these tasks, we present GenoAgent, a team of LLM-based agents that adopt a multi-step programming workflow with flexible self-correction, to collaboratively analyze gene expression datasets. Our experiments demonstrate the potential of LLM-based methods in analyzing genomic data, while error analysis highlights the challenges and areas for future improvement. We propose GenoTEX as a promising resource for benchmarking and enhancing automated methods for gene expression data analysis. The benchmark is available at https://github.com/Liu-Hy/GenoTex.

The rapid growth of biomedical literature and curated databases has made it increasingly difficult for researchers to systematically connect biomarker mechanisms to actionable drug combination hypotheses. We present AI Co-Scientist (CoDHy), an interactive, human-in-the-loop system for biomarker-guided drug combination hypothesis generation in cancer research. CoDHy integrates structured biomedical databases and unstructured literature evidence into a task-specific knowledge graph, which serves as the basis for graph-based reasoning and hypothesis construction. The system combines knowledge graph embeddings with agent-based reasoning to generate, validate, and rank candidate drug combinations, while explicitly grounding each hypothesis in retrievable evidence. Through a web-based interface, users can configure the scientific context, inspect intermediate results, and iteratively refine hypotheses, enabling transparent and researcher-steerable exploration rather than automated decision-making. We demonstrate CoDHy as a system for exploratory hypothesis generation and decision support in translational oncology, highlighting its design, interaction workflow, and practical use cases.

Optimal transport (OT) theory focuses, among all maps T:R^drightarrow R^d that can morph a probability measure onto another, on those that are the ``thriftiest'', i.e. such that the averaged cost c(x, T(x)) between x and its image T(x) be as small as possible. Many computational approaches have been proposed to estimate such Monge maps when c is the ell_2^2 distance, e.g., using entropic maps [Pooladian'22], or neural networks [Makkuva'20, Korotin'20]. We propose a new model for transport maps, built on a family of translation invariant costs c(x, y):=h(x-y), where h:=1{2}|cdot|_2^2+tau and tau is a regularizer. We propose a generalization of the entropic map suitable for h, and highlight a surprising link tying it with the Bregman centroids of the divergence D_h generated by h, and the proximal operator of tau. We show that choosing a sparsity-inducing norm for tau results in maps that apply Occam's razor to transport, in the sense that the displacement vectors Delta(x):= T(x)-x they induce are sparse, with a sparsity pattern that varies depending on x. We showcase the ability of our method to estimate meaningful OT maps for high-dimensional single-cell transcription data, in the 34000-d space of gene counts for cells, without using dimensionality reduction, thus retaining the ability to interpret all displacements at the gene level.

Single-cell and spatial foundation models promise transferable biological representations, yet their generality remains largely untested across modalities, biological domains and analytical tasks. We benchmarked six representative models, Nicheformer, CellPLM, scGPT-spatial, GenePT, scELMo and Novae, using a harmonised framework spanning scRNA-seq, spatial transcriptomics and Perturb-seq. We evaluated zero-shot and continually pretrained clustering, supervised annotation, marker-gene concordance and perturbation prediction. Model performance was strongly conditional: expression-trained cell-level transformers best resolved many cell-identity tasks, spatial and graph-aware models better preserved tissue architecture, and language-derived gene embeddings were competitive for selected perturbation-response metrics. No model dominated across tasks, and rankings shifted with modality, preprocessing, tokenisation, biological prior, domain shift and metric choice. This benchmark provides practical guidance for model selection and argues that future models should be judged by biological generalisation, interpretability and perturbation-grounded validity, not by scale or leaderboard performance alone.

Synthetic gene expression data is increasingly proposed as a privacy-preserving substitute for controlled-access genomic repositories, but its safety depends on empirical auditing. Membership inference attacks (MIAs) provide that audit by testing whether a patient's gene expression profile was used to train a generative model. We report a red-team study on synthetic gene expression data derived from bulk RNA-seq profiles in The Cancer Genome Atlas, released by the ELSA Health 2026 Challenge. We unify five no-box attacks under a single weighted-distance framework in which each variant differs only in how it weights genes: uniformly (baseline), by variance, by synthetic-versus-reference KL divergence, by spectral residualization removing dominant principal components, and by curated pathway membership. Against a conditional variational autoencoder, spectral residualization raises AUC from 0.8251 to 0.8951 and TPR at 1% FPR from 0.3842 to 0.5970 on pan-cancer TCGA. Biological pathway priors did not transfer across targets.

Predicting spatial gene expression from hematoxylin and eosin (H\&E)-stained images offers a cost-effective alternative to spatial transcriptomics (ST). However, existing methods treat H\&E images as generic visual inputs and ignore their intrinsic biological hierarchy, where spatially organized cell types collectively form functional tissue microenvironments that govern local gene expression programs. To bridge this gap, we formulate H\&E-to-ST prediction as a cross-modal semantic translation task and propose Path2ST, a hierarchically grounded autoregressive framework featuring three key components: (i) a Hierarchical Cell-Tissue Conditioning mechanism that fuses explicit and implicit cellular features with tissue-level semantic representations to construct hierarchical conditioning signals; (ii) a Scale-Adaptive Autoregressive Generation process over a hierarchical semantic vocabulary, enabling coarse-to-fine, biologically consistent expression synthesis; and (iii) SpectraLoss, a full-spectrum objective that jointly enforces ordinal fidelity, models transcriptional bursts, and aligns semantic structures with cell types. Extensive experiments on three datasets demonstrate state-of-the-art performance, validating that Path2ST generates highly accurate and spatially coherent transcriptomic profiles. The related code is released at https://github.com/RuochenLiu23/Path2ST.

Large language models can describe mechanisms, yet scalable post-training still depends on costly, manually curated biological reasoning traces. Here we show that cellular perturbation atlases can instead become reinforcement-learning environments, where measured gene responses provide computable rewards for biological reasoning. We introduce PertMind, which combines trusted-trajectory supervised initialization with gene-, pathway-, and format-level reinforcement signals. Although trained only on forward perturbation-response prediction, PertMind improves response inference in unseen cellular contexts while retaining general language capabilities. It also transfers, without task-specific post-training, to reverse perturbation identification, double-perturbation reasoning, phenotypic-screen prioritization, and biological-process interpretation. PertMind further generates biological profiles that support competitive gene, cell, and donor representations across multiscale downstream tasks. These results support the hypothesis that reinforcement on experimental endpoints can concentrate reusable biological strategies already accessible to pretrained models. More broadly, perturbation-derived reinforcement learning offers a scalable route for transforming expanding experimental atlases into training environments for general-purpose biological reasoning.

Next-generation sequencing technologies, including RNA-sequencing, provide genome-wide measurements of gene expression and enable broad explorations of biomarkers and mechanisms underlying disease and treatment response. Bioinformatics tools for processing this data, such as differential expression analysis, are largely univariate, linear, and rely on predefined pathway knowledge annotations, which limits their ability to capture nonlinear and multivariate gene interactions. This paper explores the application of causal discovery to characterizing transcriptional responses to radiation as a function of dose rate in human cells. By jointly modeling radiation perturbations and gene expression, we learn directed gene networks that capture important regulatory relationships beyond correlation and exhibit significant enrichment of known radiation response pathways compared to baseline approaches. We find that inferred causal graphs reveal structured network features such as high in-degree housekeeping genes and high out-degree transcription factors. Further analysis suggests a hierarchical organization of stress response pathways and triggered cell death pathways. This work highlights the potential of causal discovery in healthcare settings with applications to understanding response mechanisms, identifying regulatory targets, and improving interpretation of complex genomic data.

Jointly identifying a mixture of discrete and continuous factors of variability without supervision is a key problem in unraveling complex phenomena. Variational inference has emerged as a promising method to learn interpretable mixture representations. However, posterior approximation in high-dimensional latent spaces, particularly for discrete factors remains challenging. Here, we propose an unsupervised variational framework using multiple interacting networks called cpl-mixVAE that scales well to high-dimensional discrete settings. In this framework, the mixture representation of each network is regularized by imposing a consensus constraint on the discrete factor. We justify the use of this framework by providing both theoretical and experimental results. Finally, we use the proposed method to jointly uncover discrete and continuous factors of variability describing gene expression in a single-cell transcriptomic dataset profiling more than a hundred cortical neuron types.

Gene expression prediction, which predicts mRNA expression levels from DNA sequences, presents significant challenges. Previous works often focus on extending input sequence length to locate distal enhancers, which may influence target genes from hundreds of kilobases away. Our work first reveals that for current models, long sequence modeling can decrease performance. Even carefully designed algorithms only mitigate the performance degradation caused by long sequences. Instead, we find that proximal multimodal epigenomic signals near target genes prove more essential. Hence we focus on how to better integrate these signals, which has been overlooked. We find that different signal types serve distinct biological roles, with some directly marking active regulatory elements while others reflect background chromatin patterns that may introduce confounding effects. Simple concatenation may lead models to develop spurious associations with these background patterns. To address this challenge, we propose Prism, a framework that learns multiple combinations of high-dimensional epigenomic features to represent distinct background chromatin states and uses backdoor adjustment to mitigate confounding effects. Our experimental results demonstrate that proper modeling of multimodal epigenomic signals achieves state-of-the-art performance using only short sequences for gene expression prediction.

Predicting single-cell transcriptomic responses to genetic perturbations is central to functional genomics and virtual-cell modeling. Existing approaches, however, typically predict an entire expression profile as a whole, leaving the order in which individual gene responses are generated unmodeled. To address this problem, we introduce D^{2R^{2}} (Discrete Diffusion with Regulation Reinforcement), which reformulates perturbation prediction as regulation-guided gene-wise progressive generation. A Masked Discrete Diffusion Model represents expression as ordinal tokens and reconstructs a fully masked profile step by step, allowing generated gene responses to condition those that remain masked. A Regulatory Policy Module initializes the generation policy from a gene regulatory network inferred from control cells and adapts it to the perturbation and current partially generated state. Then, group-relative policy optimization refines only the ordering policy using final perturbation-effect agreement as reward. Across Norman19 and VCC-H1, D^{2}R^{2} achieves the best performance on all five metrics on Norman19 and remains competitive on H1. Controlled ablations holding the generator and generation budget fixed show that biological-prior ordering improves over random ordering and is more reliable than uncertainty-based heuristics, whereas reversing the biological-prior ordering degrades every metric. Biological analyses further show that the refined policy prioritizes regulatory genes early while promoting perturbation-specific transcription factors and responsive genes. These results establish gene generation order as an effective, controllable, and biologically interpretable dimension of single-cell perturbation prediction.

Gene regulatory network inference (GRNI) is a challenging problem, particularly owing to the presence of zeros in single-cell RNA sequencing data: some are biological zeros representing no gene expression, while some others are technical zeros arising from the sequencing procedure (aka dropouts), which may bias GRNI by distorting the joint distribution of the measured gene expressions. Existing approaches typically handle dropout error via imputation, which may introduce spurious relations as the true joint distribution is generally unidentifiable. To tackle this issue, we introduce a causal graphical model to characterize the dropout mechanism, namely, Causal Dropout Model. We provide a simple yet effective theoretical result: interestingly, the conditional independence (CI) relations in the data with dropouts, after deleting the samples with zero values (regardless if technical or not) for the conditioned variables, are asymptotically identical to the CI relations in the original data without dropouts. This particular test-wise deletion procedure, in which we perform CI tests on the samples without zeros for the conditioned variables, can be seamlessly integrated with existing structure learning approaches including constraint-based and greedy score-based methods, thus giving rise to a principled framework for GRNI in the presence of dropouts. We further show that the causal dropout model can be validated from data, and many existing statistical models to handle dropouts fit into our model as specific parametric instances. Empirical evaluation on synthetic, curated, and real-world experimental transcriptomic data comprehensively demonstrate the efficacy of our method.

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.

Optimal transport (OT) compares probability distributions by computing a meaningful alignment between their samples. CO-optimal transport (COOT) takes this comparison further by inferring an alignment between features as well. While this approach leads to better alignments and generalizes both OT and Gromov-Wasserstein distances, we provide a theoretical result showing that it is sensitive to outliers that are omnipresent in real-world data. This prompts us to propose unbalanced COOT for which we provably show its robustness to noise in the compared datasets. To the best of our knowledge, this is the first such result for OT methods in incomparable spaces. With this result in hand, we provide empirical evidence of this robustness for the challenging tasks of heterogeneous domain adaptation with and without varying proportions of classes and simultaneous alignment of samples and features across single-cell measurements.

Foundation models for single-cell RNA sequencing (scRNA-seq) have shown promising capabilities in capturing gene expression patterns. However, current approaches face critical limitations: they ignore biological prior knowledge encoded in gene regulatory relationships and fail to leverage multi-omics signals that could provide complementary regulatory insights. In this paper, we propose GRNFormer, a new framework that systematically integrates multi-scale Gene Regulatory Networks (GRNs) inferred from multi-omics data into RNA foundation model training. Our framework introduces two key innovations. First, we introduce a pipeline for constructing hierarchical GRNs that capture regulatory relationships at both cell-type-specific and cell-specific resolutions. Second, we design a structure-aware integration framework that addresses the information asymmetry in GRNs through two technical advances: (1) A graph topological adapter using multi-head cross-attention to weight regulatory relationships dynamically, and (2) a novel edge perturbation strategy that perturb GRNs with biologically-informed co-expression links to augment graph neural network training. Comprehensive experiments have been conducted on three representative downstream tasks across multiple model architectures to demonstrate the effectiveness of GRNFormer. It achieves consistent improvements over state-of-the-art (SoTA) baselines: 3.6% increase in drug response prediction correlation, 9.6% improvement in single-cell drug classification AUC, and 1.1% average gain in gene perturbation prediction accuracy.

Understanding how cellular morphology, gene expression, and spatial context jointly shape tissue function is a central challenge in biology. Image-based spatial transcriptomics technologies now provide high-resolution measurements of cell images and gene expression profiles, but existing methods typically analyze these modalities in isolation or at limited resolution. We address the problem by introducing SPATIA, a multi-level generative and predictive model that learns unified, spatially aware representations by fusing morphology, gene expression, and spatial context from the cell to the tissue level. SPATIA also incorporates a spatially conditioned generative framework with confidence-aware OT reweighting and morphology-profile alignment for modeling target-state morphology distributions. Specifically, we propose a confidence-aware flow matching objective that reweights weak optimal-transport pairs based on uncertainty. We further apply morphology-profile alignment to encourage biologically meaningful image generation, enabling the modeling of microenvironment-dependent phenotypic transitions. We assembled a multi-scale dataset consisting of 25.9 million cell-gene pairs across 17 tissues. We benchmark SPATIA against 18 models across 12 tasks, spanning categories such as phenotype generation, annotation, clustering, gene imputation, and cross-modal prediction. SPATIA achieves improved performance over state-of-the-art models, improving generative fidelity by 8% and predictive accuracy by up to 3%.

Gene perturbation models aim to predict transcriptional responses to unseen genetic interventions, but comparisons rely on heterogeneous evaluation metrics and differentially-expressed (DE) gene subsets. We investigate the consequences of these choices using eight methods across six single-gene perturbation datasets under a unified evaluation protocol. Varying the number of top DE genes reveals substantial instability in Precision-based rankings, with the winning method changing 86.7% of the time, while rankings based on the rest of the metrics remain comparatively stable. Investigating this discrepancy exposes that repeating a single predicted expression profile across cell-level rows, a standard practice for many methods, can inflate significance estimates and produce excessively large predicted significant-DE sets. Specifically we found that 67.1% of tested perturbation--gene pairs pass the significance threshold despite some of them having minuscule effects. We derive an inflation factor showing that replicated predictions can amplify the standardized Mann--Whitney statistic even after correction for tied ranks, without adding independent information. This artifact changes Precision mainly as the number of DE genes increases because for smaller cutoffs, most of the genes are already significant due to the effect-based ordering. Taking this pitfall into account in our benchmark comparison, we find that a random forest using Gene Ontology features achieves the best overall results.

Learning population dynamics from temporally sparse, unpaired distribution snapshots is a fundamental challenge in developmental biology. Recent approaches based on neural differential equations and flow matching can interpolate between observed population snapshots, but may struggle to extrapolate beyond the training horizon and often lack an explicit mechanism for modeling developmental branching. We propose KoopCell, a unified generative framework based on Koopman-Mori-Zwanzig theory that jointly learns representations and predictive linear latent dynamics. Theoretically, using the weak continuity equation, we derive a closed-form least-squares estimator for the Koopman generator from distribution snapshots and establish convergence guarantees under suitable assumptions. To model branching dynamics, we further develop KoopCell-M, which incorporates non-Markovian memory into the latent Koopman dynamics through a Markovian embedding. Experiments on synthetic systems and three scRNA-seq datasets demonstrate the ability of our framework to recover Koopman spectra, model branching through memory, and scale to predicting high-dimensional gene expression distributions, achieving state-of-the-art performance among the evaluated methods.

Spatial Transcriptomics (ST) technologies provide biologists with rich insights into single-cell biology by preserving spatial context of cells. Building foundational models for ST can significantly enhance the analysis of vast and complex data sources, unlocking new perspectives on the intricacies of biological tissues. However, modeling ST data is inherently challenging due to the need to extract multi-scale information from tissue slices containing vast numbers of cells. This process requires integrating macro-scale tissue morphology, micro-scale cellular microenvironment, and gene-scale gene expression profile. To address this challenge, we propose SToFM, a multi-scale Spatial Transcriptomics Foundation Model. SToFM first performs multi-scale information extraction on each ST slice, to construct a set of ST sub-slices that aggregate macro-, micro- and gene-scale information. Then an SE(2) Transformer is used to obtain high-quality cell representations from the sub-slices. Additionally, we construct SToCorpus-88M, the largest high-resolution spatial transcriptomics corpus for pretraining. SToFM achieves outstanding performance on a variety of downstream tasks, such as tissue region semantic segmentation and cell type annotation, demonstrating its comprehensive understanding of ST data through capturing and integrating multi-scale information.

The vast majority of biological sequences encode unknown functions and bear little resemblance to experimentally characterized proteins, limiting both our understanding of biology and our ability to harness functional potential for the bioeconomy. Predicting enzyme function from sequence remains a central challenge in computational biology, complicated by low sequence diversity and imbalanced label support in publicly available datasets. Models trained on these data can overestimate performance and fail to generalize. To address this, we introduce GRIMM (Genetic stRatification for Inference in Molecular Modeling), a benchmark for enzyme function prediction that employs genetic stratification: sequences are clustered by similarity and clusters are assigned exclusively to training, validation, or test sets. This ensures that sequences from the same cluster do not appear in multiple partitions. GRIMM produces multiple test sets: a closed-set test with the same label distribution as training (Test-1) and an open-set test containing novel labels (Test-2), serving as a realistic out-of-distribution proxy for discovering novel enzyme functions. While demonstrated on enzymes, this approach is generalizable to any sequence-based classification task where inputs can be clustered by similarity. By formalizing a splitting strategy often used implicitly, GRIMM provides a unified and reproducible framework for closed- and open-set evaluation. The method is lightweight, requiring only sequence clustering and label annotations, and can be adapted to different similarity thresholds, data scales, and biological tasks. GRIMM enables more realistic evaluation of functional prediction models on both familiar and unseen classes and establishes a benchmark that more faithfully assesses model performance and generalizability.

Spatial transcriptomics can resolve gene expression at single-cell resolution, but it is costly, limited to targeted panels of a few hundred to a few thousand genes, and applicable to only a small number of samples. H&E imaging, by contrast, is cheap and collected routinely at scale. This makes predicting single-cell expression directly from morphology a practical way to bring molecular analysis to large tissue archives. We therefore present VOICE, a multimodal foundation model that predicts single-cell gene expression from H&E images using paired Xenium data. VOICE first aligns cell centered H&E morphology from a pathology foundation model with single-cell expression embeddings from a transcriptome foundation model, trained using contrastive learning over 23 million cells. Next it predicts expression through two branches. One branch directly regresses expression from morphology. The other branch retrieves measured expression from similar reference cells, recovering genes that do not have morphological signal. Because genes vary in morphological predictability, VOICE fuses the two branches with a per-gene weight. After training, VOICE generalizes to heldout patients, slides, and partially overlapping gene panels from Xenium, and it consistently outperforms prior single-cell expression prediction methods on seven metrics.

Transcriptomic foundation models (TFMs) have recently emerged as powerful tools for analyzing gene expression in cells and tissues, supporting key tasks such as cell-type annotation, batch correction, and perturbation prediction. However, the diversity of model implementations and training strategies across recent TFMs, though promising, makes it challenging to isolate the contribution of individual design choices or evaluate their potential synergies. This hinders the field's ability to converge on best practices and limits the reproducibility of insights across studies. We present BMFM-RNA, an open-source, modular software package that unifies diverse TFM pretraining and fine-tuning objectives within a single framework. Leveraging this capability, we introduce a novel training objective, whole cell expression decoder (WCED), which captures global expression patterns using an autoencoder-like CLS bottleneck representation. In this paper, we describe the framework, supported input representations, and training objectives. We evaluated four model checkpoints pretrained on CELLxGENE using combinations of masked language modeling (MLM), WCED and multitask learning. Using the benchmarking capabilities of BMFM-RNA, we show that WCED-based models achieve performance that matches or exceeds state-of-the-art approaches like scGPT across more than a dozen datasets in both zero-shot and fine-tuning tasks. BMFM-RNA, available as part of the biomed-multi-omics project ( https://github.com/BiomedSciAI/biomed-multi-omic ), offers a reproducible foundation for systematic benchmarking and community-driven exploration of optimal TFM training strategies, enabling the development of more effective tools to leverage the latest advances in AI for understanding cell biology.

The push toward large language models for biology (BioLM) has created a need for training corpora that can endow models with a genuine understanding of biology. However, existing biological resources, such as molecular databases, protein repositories, genomic annotations, single-cell atlases, and pathway databases, are scattered across heterogeneous formats and remain unorganized into a cohesive corpus for language model training. We present TheBioCollection, a 52.6B-token pre-training-scale corpus that converts these disparate resources into a unified, training-ready form spanning small molecules, proteins, genomic sequences, cells, and pathways. Beyond consolidating existing data, TheBioCollection enriches each record with tool-computed biological properties and introduces new instruction tasks for capabilities that current corpora barely cover. We pair the corpus with TheBioCollection-Eval, a matched suite probing recognition, generation, and prediction across molecular, protein, genomic, cellular, and cross-domain settings. Holding the base Gravity-16B-A3B architecture fixed, training on TheBioCollection more than doubles its overall score on TheBioCollection-Eval with gains in every domain, while leaving general linguistic ability nearly intact.

Gene set analysis (GSA) is a foundational approach for interpreting genomic data of diseases by linking genes to biological processes. However, conventional GSA methods overlook clinical context of the analyses, often generating long lists of enriched pathways with redundant, nonspecific, or irrelevant results. Interpreting these requires extensive, ad-hoc manual effort, reducing both reliability and reproducibility. To address this limitation, we introduce cGSA, a novel AI-driven framework that enhances GSA by incorporating context-aware pathway prioritization. cGSA integrates gene cluster detection, enrichment analysis, and large language models to identify pathways that are not only statistically significant but also biologically meaningful. Benchmarking on 102 manually curated gene sets across 19 diseases and ten disease-related biological mechanisms shows that cGSA outperforms baseline methods by over 30%, with expert validation confirming its increased precision and interpretability. Two independent case studies in melanoma and breast cancer further demonstrate its potential to uncover context-specific insights and support targeted hypothesis generation.

Computational modeling of single-cell gene expression is crucial for understanding cellular processes, but generating realistic expression profiles remains a major challenge. This difficulty arises from the count nature of gene expression data and complex latent dependencies among genes. Existing generative models often impose artificial gene orderings or rely on shallow neural network architectures. We introduce a scalable latent diffusion model for single-cell gene expression data, which we refer to as scLDM, that respects the fundamental exchangeability property of the data. Our VAE uses fixed-size latent variables leveraging a unified Multi-head Cross-Attention Block (MCAB) architecture, which serves dual roles: permutation-invariant pooling in the encoder and permutation-equivariant unpooling in the decoder. We enhance this framework by replacing the Gaussian prior with a latent diffusion model using Diffusion Transformers and linear interpolants, enabling high-quality generation with multi-conditional classifier-free guidance. We show its superior performance in a variety of experiments for both observational and perturbational single-cell data, as well as downstream tasks like cell-level classification.

The practical utility of machine learning models in the sciences often hinges on their interpretability. It is common to assess a model's merit for scientific discovery, and thus novel insights, by how well it aligns with already available domain knowledge--a dimension that is currently largely disregarded in the comparison of neural network models. While pruning can simplify deep neural network architectures and excels in identifying sparse models, as we show in the context of gene regulatory network inference, state-of-the-art techniques struggle with biologically meaningful structure learning. To address this issue, we propose DASH, a generalizable framework that guides network pruning by using domain-specific structural information in model fitting and leads to sparser, better interpretable models that are more robust to noise. Using both synthetic data with ground truth information, as well as real-world gene expression data, we show that DASH, using knowledge about gene interaction partners within the putative regulatory network, outperforms general pruning methods by a large margin and yields deeper insights into the biological systems being studied.

Spatial transcriptomics (ST) provides high-resolution pathological images and whole-transcriptomic expression profiles at individual spots across whole-slide scales. This setting makes it an ideal data source to develop multimodal foundation models. Although recent studies attempted to fine-tune visual encoders with trainable gene encoders based on spot-level, the absence of a wider slide perspective and spatial intrinsic relationships limits their ability to capture ST-specific insights effectively. Here, we introduce ST-Align, the first foundation model designed for ST that deeply aligns image-gene pairs by incorporating spatial context, effectively bridging pathological imaging with genomic features. We design a novel pretraining framework with a three-target alignment strategy for ST-Align, enabling (1) multi-scale alignment across image-gene pairs, capturing both spot- and niche-level contexts for a comprehensive perspective, and (2) cross-level alignment of multimodal insights, connecting localized cellular characteristics and broader tissue architecture. Additionally, ST-Align employs specialized encoders tailored to distinct ST contexts, followed by an Attention-Based Fusion Network (ABFN) for enhanced multimodal fusion, effectively merging domain-shared knowledge with ST-specific insights from both pathological and genomic data. We pre-trained ST-Align on 1.3 million spot-niche pairs and evaluated its performance through two downstream tasks across six datasets, demonstrating superior zero-shot and few-shot capabilities. ST-Align highlights the potential for reducing the cost of ST and providing valuable insights into the distinction of critical compositions within human tissue.

This paper shows that latent-space predictive pretraining can provide a scalable route to foundation models for spatial transcriptomics. Existing spatial transcriptomics foundation models primarily reconstruct masked gene identities or expression values, potentially encouraging the reproduction of assay-specific technical variation and limiting representation transferability. To avoid directly reconstructing such variation, we shift the prediction target from observed gene measurements to latent cell representations and introduce CellWorld, which predicts the latent representations of masked cells from visible spatial context and a limited partial-expression hint. We pretrain four CellWorld variants, spanning 5.74M to 94.56M trainable parameters, on a corpus of 46 million human cells. Our controlled scaling experiments show that performance improves with model capacity, particularly on spatial tasks, while spatial transfer depends more on sufficient optimization and broad biological source diversity than on cell count alone. Across four held-out datasets, even CellWorld-Small, with 5.74M trainable parameters, outperforms every baseline on all 11 linear-probe benchmarks and all seven fine-tuned spatial benchmarks. Most notably, a frozen CellWorld-Large pretrained on only 5\% of the corpus with broad biological source coverage outperforms every fully fine-tuned baseline across all seven spatial benchmarks. Code is available at https://github.com/UoM-HealthAI/CellWorld.

Model customization necessitates high-quality and diverse datasets, but acquiring such data remains time-consuming and labor-intensive. Despite the great potential of large language models (LLMs) for data synthesis, current approaches are constrained by limited seed data, model biases, and low-variation prompts, resulting in limited diversity and biased distributions with the increase of data scales. To tackle this challenge, we introduce TREESYNTH, a tree-guided subspace-based data synthesis approach inspired by decision trees. It constructs a spatial partitioning tree to recursively divide a task-specific full data space (i.e., root node) into numerous atomic subspaces (i.e., leaf nodes) with mutually exclusive and exhaustive attributes to ensure both distinctiveness and comprehensiveness before synthesizing samples within each atomic subspace. This globally dividing-and-synthesizing method finally collects subspace samples into a comprehensive dataset, effectively circumventing repetition and space collapse to ensure the diversity of large-scale data synthesis. Furthermore, the spatial partitioning tree enables sample allocation into atomic subspaces, allowing the rebalancing of existing datasets for more balanced and comprehensive distributions. Empirically, extensive experiments across diverse benchmarks consistently demonstrate the superior data diversity, model performance, and robust scalability of TREESYNTH compared to both human-crafted datasets and peer data synthesis methods, with an average performance gain reaching 10%. Besides, the consistent improvements of TREESYNTH-balanced datasets highlight its efficacious application to redistribute existing datasets for more comprehensive coverage and the induced performance enhancement. The code is available at https://github.com/cpa2001/TreeSynth.

Gene expression analysis holds the key to many biomedical discoveries, yet extracting insights from raw transcriptomic data remains formidable due to the complexity of multiple large, semi-structured files and the need for extensive domain expertise. Current automation approaches are often limited by either inflexible workflows that break down in edge cases or by fully autonomous agents that lack the necessary precision for rigorous scientific inquiry. GenoMAS charts a different course by presenting a team of LLM-based scientists that integrates the reliability of structured workflows with the adaptability of autonomous agents. GenoMAS orchestrates six specialized LLM agents through typed message-passing protocols, each contributing complementary strengths to a shared analytic canvas. At the heart of GenoMAS lies a guided-planning framework: programming agents unfold high-level task guidelines into Action Units and, at each juncture, elect to advance, revise, bypass, or backtrack, thereby maintaining logical coherence while bending gracefully to the idiosyncrasies of genomic data. On the GenoTEX benchmark, GenoMAS reaches a Composite Similarity Correlation of 89.13% for data preprocessing and an F_1 of 60.48% for gene identification, surpassing the best prior art by 10.61% and 16.85% respectively. Beyond metrics, GenoMAS surfaces biologically plausible gene-phenotype associations corroborated by the literature, all while adjusting for latent confounders. Code is available at https://github.com/Liu-Hy/GenoMAS.

Inspired by the success of unsupervised pre-training paradigms, researchers have applied these approaches to DNA pre-training. However, we argue that these approaches alone yield suboptimal results because pure DNA sequences lack sufficient information, since their functions are regulated by genomic profiles like chromatin accessibility. Here, we demonstrate that supervised training for genomic profile prediction serves as a more effective alternative to pure sequence pre-training. Furthermore, considering the multi-species and multi-profile nature of genomic profile prediction, we introduce our Species-Profile Adaptive Collaborative Experts (SPACE) that leverages Mixture of Experts (MoE) to better capture the relationships between DNA sequences across different species and genomic profiles, thereby learning more effective DNA representations. Through extensive experiments across various tasks, our model achieves state-of-the-art performance, establishing that DNA models trained with supervised genomic profiles serve as powerful DNA representation learners. The code is available at https://github.com/ZhuJiwei111/SPACE.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology. However, in most existing medical image-text datasets, the text typically provides high-level summaries that may not sufficiently describe sub-tile regions within a large pathology image. For example, an image might cover an extensive tissue area containing cancerous and healthy regions, but the accompanying text might only specify that this image is a cancer slide, lacking the nuanced details needed for in-depth analysis. In this study, we introduce STimage-1K4M, a novel dataset designed to bridge this gap by providing genomic features for sub-tile images. STimage-1K4M contains 1,149 images derived from spatial transcriptomics data, which captures gene expression information at the level of individual spatial spots within a pathology image. Specifically, each image in the dataset is broken down into smaller sub-image tiles, with each tile paired with 15,000-30,000 dimensional gene expressions. With 4,293,195 pairs of sub-tile images and gene expressions, STimage-1K4M offers unprecedented granularity, paving the way for a wide range of advanced research in multi-modal data analysis an innovative applications in computational pathology, and beyond.

Predicting transcriptional responses to genetic perturbations is central to understanding gene function. Existing predictors primarily rely on transcriptomic measurements, although chromatin accessibility provides complementary information about the cellular context in which perturbations act. Using this information requires linking chromatin context to specific perturbations and accounting for baseline differences between independently sampled control and perturbed populations. We propose ChromaPert, a chromatin-informed framework for predicting state-dependent perturbation responses. ChromaPert combines molecular and DNA-informed locus priors with paired control RNA--ATAC features to jointly represent target identity and measured cellular context. Its Chromatin-Guided Response Router (CGRR) builds a source bank of control-derived expression offsets and retrieves relevant sources using perturbation/locus or control-ATAC similarity. These offsets account for baseline differences, while conditional transport flow learns the remaining response. Across three unseen-target and held-out-state settings on K562 CAT-ATAC and Perturb-Multiome, ChromaPert achieves the highest all-gene response correlation among evaluated methods. When transferring known perturbations to held-out states, it improves correlation by 23.2% across all genes and 46.2% for the twenty most responsive genes over the strongest respective baselines. Correct RNA--ATAC pairing improves recovery of chromatin-associated response slopes over shuffled pairing, while cross-state predictions retain state-specific responses to the same perturbation.

Human medical data can be challenging to obtain due to data privacy concerns, difficulties conducting certain types of experiments, or prohibitive associated costs. In many settings, data from animal models or in-vitro cell lines are available to help augment our understanding of human data. However, this data is known for having low etiological validity in comparison to human data. In this work, we augment small human medical datasets with in-vitro data and animal models. We use Invariant Risk Minimisation (IRM) to elucidate invariant features by considering cross-organism data as belonging to different data-generating environments. Our models identify genes of relevance to human cancer development. We observe a degree of consistency between varying the amounts of human and mouse data used, however, further work is required to obtain conclusive insights. As a secondary contribution, we enhance existing open source datasets and provide two uniformly processed, cross-organism, homologue gene-matched datasets to the community.

Recent benchmarks reveal that models for single-cell perturbation response are often outperformed by simply predicting the dataset mean. We trace this anomaly to a metric artifact: control-referenced deltas and unweighted error metrics reward mode collapse whenever the control is biased or the biological signal is sparse. Large-scale in silico simulations and analysis of two real-world perturbation datasets confirm that shared reference shifts, not genuine biological change, drives high performance in these evaluations. We introduce differentially expressed gene (DEG)-aware metrics, weighted mean-squared error (WMSE) and weighted delta R^{2} (R^{2}_{w}(Δ)) with respect to all perturbations, that measure error in niche signals with high sensitivity. We further introduce negative and positive performance baselines to calibrate these metrics. With these improvements, the mean baseline sinks to null performance while genuine predictors are correctly rewarded. Finally, we show that using WMSE as a loss function reduces mode collapse and improves model performance.

We consider the problem of predicting gene expressions from DNA sequences. A key challenge of this task is to find the regulatory elements that control gene expressions. Here, we introduce Seq2Exp, a Sequence to Expression network explicitly designed to discover and extract regulatory elements that drive target gene expression, enhancing the accuracy of the gene expression prediction. Our approach captures the causal relationship between epigenomic signals, DNA sequences and their associated regulatory elements. Specifically, we propose to decompose the epigenomic signals and the DNA sequence conditioned on the causal active regulatory elements, and apply an information bottleneck with the Beta distribution to combine their effects while filtering out non-causal components. Our experiments demonstrate that Seq2Exp outperforms existing baselines in gene expression prediction tasks and discovers influential regions compared to commonly used statistical methods for peak detection such as MACS3. The source code is released as part of the AIRS library (https://github.com/divelab/AIRS/).

Genomic alterations lead to cancer complexity and form a major hurdle for a comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe the recent advances in studying cancer-associated genes from a systems biological point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in the information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, the genes, which are involved in the regulation of cancer progression, can be picked up from these networks after which their functions can be further confirmed in the laboratory.

Learning the response of single-cells to various treatments offers great potential to enable targeted therapies. In this context, neural optimal transport (OT) has emerged as a principled methodological framework because it inherently accommodates the challenges of unpaired data induced by cell destruction during data acquisition. However, most existing OT approaches are incapable of conditioning on different treatment contexts (e.g., time, drug treatment, drug dosage, or cell type) and we still lack methods that unanimously show promising generalization performance to unseen treatments. Here, we propose the Conditional Monge Gap which learns OT maps conditionally on arbitrary covariates. We demonstrate its value in predicting single-cell perturbation responses conditional to one or multiple drugs, a drug dosage, or combinations thereof. We find that our conditional models achieve results comparable and sometimes even superior to the condition-specific state-of-the-art on scRNA-seq as well as multiplexed protein imaging data. Notably, by aggregating data across conditions we perform cross-task learning which unlocks remarkable generalization abilities to unseen drugs or drug dosages, widely outperforming other conditional models in capturing heterogeneity (i.e., higher moments) in the perturbed population. Finally, by scaling to hundreds of conditions and testing on unseen drugs, we narrow the gap between structure-based and effect-based drug representations, suggesting a promising path to the successful prediction of perturbation effects for unseen treatments.

The application of deep learning methods, particularly foundation models, in biological research has surged in recent years. These models can be text-based or trained on underlying biological data, especially omics data of various types. However, comparing the performance of these models consistently has proven to be a challenge due to differences in training data and downstream tasks. To tackle this problem, we developed an architecture-agnostic benchmarking approach that, instead of evaluating the models directly, leverages entity representation vectors from each model and trains simple predictive models for each benchmarking task. This ensures that all types of models are evaluated using the same input and output types. Here we focus on gene properties collected from professionally curated bioinformatics databases. These gene properties are categorized into five major groups: genomic properties, regulatory functions, localization, biological processes, and protein properties. Overall, we define hundreds of tasks based on these databases, which include binary, multi-label, and multi-class classification tasks. We apply these benchmark tasks to evaluate expression-based models, large language models, protein language models, DNA-based models, and traditional baselines. Our findings suggest that text-based models and protein language models generally outperform expression-based models in genomic properties and regulatory functions tasks, whereas expression-based models demonstrate superior performance in localization tasks. These results should aid in the development of more informed artificial intelligence strategies for biological understanding and therapeutic discovery. To ensure the reproducibility and transparency of our findings, we have made the source code and benchmark data publicly accessible for further investigation and expansion at github.com/BiomedSciAI/gene-benchmark.

Protein-protein interaction (PPI) databases do not faithfully reflect biological realities. Instead, they are influenced by study and technical biases that distort certain protein and interaction attributes. Machine learning models can exploit these as learning shortcuts if the negative dataset is not constructed with care. So far, the shortcuts introduced during PPI dataset construction have only been examined in isolation. Here, we systematically characterize both reported and, to our knowledge, previously unreported biases in PPI datasets that lead machine learning models to learn shortcuts instead of biological signal. We analyze HIPPIE, IntAct, and STRING, dedicated PPI databases, as well as two datasets derived from 3D-structural information in the Protein Data Bank (PDB). We show that random data splitting introduces strong topological shortcuts. When train-test protein overlap is removed, the resulting datasets still retain usable shortcuts stemming from self-interactions, taxonomic identity, and functional relatedness, whose prevalence interestingly depends on the data source. We further show that sampling negatives from a set of high-confidence non-interactors, an intuitively appealing choice, can amplify the shortcut stemming from functional relatedness. To detect and mitigate these biases, we provide an open Nextflow pipeline that combines similarity-aware, data-loss-minimizing dataset splitting with bias-minimizing negative sampling, both formulated as integer linear programs. Its key concept of quantifying biases to minimize them through optimization-based negative sampling can, in principle, be extended to any machine learning problem where the pool of negative candidates is much larger than the positives and is thus of interest also beyond PPI prediction.

Scientific discovery relies on scientists generating novel hypotheses that undergo rigorous experimental validation. To augment this process, we introduce an AI co-scientist, a multi-agent system built on Gemini 2.0. The AI co-scientist is intended to help uncover new, original knowledge and to formulate demonstrably novel research hypotheses and proposals, building upon prior evidence and aligned to scientist-provided research objectives and guidance. The system's design incorporates a generate, debate, and evolve approach to hypothesis generation, inspired by the scientific method and accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute, improving hypothesis quality. While general purpose, we focus development and validation in three biomedical areas: drug repurposing, novel target discovery, and explaining mechanisms of bacterial evolution and anti-microbial resistance. For drug repurposing, the system proposes candidates with promising validation findings, including candidates for acute myeloid leukemia that show tumor inhibition in vitro at clinically applicable concentrations. For novel target discovery, the AI co-scientist proposed new epigenetic targets for liver fibrosis, validated by anti-fibrotic activity and liver cell regeneration in human hepatic organoids. Finally, the AI co-scientist recapitulated unpublished experimental results via a parallel in silico discovery of a novel gene transfer mechanism in bacterial evolution. These results, detailed in separate, co-timed reports, demonstrate the potential to augment biomedical and scientific discovery and usher an era of AI empowered scientists.

Predicting the effects of perturbations in-silico on cell state can identify drivers of cell behavior at scale and accelerate drug discovery. However, modeling challenges remain due to the inherent heterogeneity of single cell gene expression and the complex, latent gene dependencies. Here, we present PRiMeFlow, an end-to-end flow matching based approach to directly model the effects of genetic and small molecule perturbations in the gene expression space. The distribution-fitting approach taken by PRiMeFlow enables it to accurately approximate the empirical distribution of single-cell gene expression, which we demonstrate through extensive benchmarking inside PerturBench. Through ablation studies, we also validate important model design choices such as operating in gene expression space and parameterizing the velocity field with a U-Net architecture. Finally, by scaling PRiMeFlow to a broad perturbation data atlas spanning multiple datasets and employing a carefully designed pretraining-finetuning strategy, we demonstrate its outstanding performance on the H1 human embryonic stem cells from the ARC Virtual Cell Challenge benchmark.

Gene expression is widely measured in biomedicine, yet clinical outcome prediction remains challenging due to high dimensionality, strong feature correlations, and limited labeled data. Large self-supervised transcriptomic foundation models often fail to outperform simple supervised baselines. Tabular foundation models offer an alternative through in-context learning, but are typically pretrained on generic synthetic data rather than transcriptomic structure. We ask whether transcriptomics-aware pretraining, rather than scale, is the missing ingredient. Towards this end, we introduce GeneICL, a 4.2M-parameter tabular foundation model combining a semi-synthetic pretraining prior built from measured bulk expression profiles with a parameter-efficient recurrent architecture. We further enable right-censored survival prediction via a training-free reduction to regression using Cox partial-likelihood residuals. We evaluate GeneICL on 80 clinical outcome-prediction tasks spanning classification, regression, and survival. Tabular foundation models consistently outperform self-supervised transcriptomic models, while GeneICL achieves the best overall rank among evaluated foundation models and tuned baselines. GeneICL does so with up to 387times fewer parameters, no gradient updates at inference, and predictions within seconds on a laptop CPU.

Genomic foundation models increasingly adopt large language model architectures, yet almost universally rely on fixed tokenization schemes such as k-mers, BPE, or single nucleotides, which impose arbitrary sequence boundaries that may obscure biologically relevant structure. We present LDARNet, a 120M-parameter hierarchical genomic foundation model that adapts H-Net-style dynamic chunking from autoregressive generation to masked language modeling, combining BiMamba-2 state-space layers with local attention, bidirectional routing, and a ratio-based regularizer to induce adaptive token boundaries without supervision. Fine-tuned on 27 tasks from the Nucleotide Transformer and Genomic Benchmarks suites, LDARNet achieves 11/18 wins among compact models (<300M parameters) and state-of-the-art results on 5 histone modification tasks, outperforming models up to 20times larger. A FLOPs-matched controlled experiment isolates learned routing as the source of these gains: learned boundaries beat fixed-grid boundaries by up to 14 percentage points on histone tasks at identical compute. Nucleotide-resolution analysis further shows that the learned boundaries align with canonical promoter motifs and splice junctions without supervision, providing a biological interpretation for adaptive tokenization in genomic foundation models.

Single-cell cancer datasets are predominantly cross-sectional and rarely provide paired or longitudinal observations linking individual healthy-like cells to tumor-associated states. We introduce CancerZigZag, a seed-initialized diffusion-based framework for exploratory generation of tumor-associated single-cell candidate clouds from unpaired epithelial cell populations. For each cancer context, a diffusion model is trained exclusively on tumor-derived epithelial cells and applied through repeated partial latent-space perturbation and reverse diffusion to held-out healthy-like seeds, generating stochastic candidate clouds without paired measurements or classifier guidance. We applied CancerZigZag to colorectal, breast, lung, and renal cell carcinoma contexts and explored parameter landscapes defined by perturbation depth and the number of ZigZag cycles. Across the reported operating configurations, candidate clouds contained outputs classified toward held-out tumor-derived reference populations for each evaluated seed. Residual seed-dependent organization varied across contexts, with the clearest structure in colorectal cancer, more modest organization in lung cancer, and limited cloud-level structure in breast and renal cell carcinoma. Representative candidates also showed directional concordance with transcriptional shifts observed between held-out healthy-like and tumor-derived reference populations. CancerZigZag is not interpreted as a model of deterministic healthy-to-tumor transformation or cellular progression. Instead, it provides a reference-informed framework for exploring tumor-associated candidate distributions from unpaired healthy-like seeds and quantifying the context-dependent relationship between tumor-associated displacement and residual seed dependence.

Spectral methods are central to high-dimensional statistics and machine learning, underlying procedures for covariance estimation, matrix denoising, representation learning, clustering, and latent variable modeling. In this work, we focus primarily on spectral estimators for high-dimensional factor models, where leading singular vectors of the data matrix are used to estimate latent structure and covariance parameters. In many modern applications, however, data are collected across related but heterogeneous tasks, studies, domains, or populations. Applying such estimators separately to each task can lead to unstable estimates when sample sizes are limited relative to dimension, while completely pooling the data can obscure meaningful task-specific structure. We introduce Hierarchical Spectral Shrinkage (HSS), a scalable empirical-Bayes framework for partially pooling task-specific spectral estimators. The method regularizes the leading spectral directions of each task toward a data-adaptivelylearned common basis, while allowing the amount of shrinkage to vary across tasks and spectral components. The proposed estimator arises as the posterior mean in a surrogate Bayesian regression formulation of the empirical singular vectors. For factor models, HSS yields partially pooled estimators of the group-specific loading spaces and covariance matrices and can be combined with different spectral estimators by replacing their empirical singular vectors with hierarchically regularized counterparts. More broadly, the same construction provides a mechanism for extending spectral estimators to collections of related but heterogeneous datasets. We demonstrate substantial improvements in estimation accuracy and out-of-sample performance over separate, fully pooled, and shared-subspace approaches in synthetic experiments and multi-study gene-expression data.

Pre-trained large language models(LLMs) have attracted increasing attention in biomedical domains due to their success in natural language processing. However, the complex traits and heterogeneity of multi-sources genomics data pose significant challenges when adapting these models to the bioinformatics and biomedical field. To address these challenges, we present GP-GPT, the first specialized large language model for genetic-phenotype knowledge representation and genomics relation analysis. Our model is fine-tuned in two stages on a comprehensive corpus composed of over 3,000,000 terms in genomics, proteomics, and medical genetics, derived from multiple large-scale validated datasets and scientific publications. GP-GPT demonstrates proficiency in accurately retrieving medical genetics information and performing common genomics analysis tasks, such as genomics information retrieval and relationship determination. Comparative experiments across domain-specific tasks reveal that GP-GPT outperforms state-of-the-art LLMs, including Llama2, Llama3 and GPT-4. These results highlight GP-GPT's potential to enhance genetic disease relation research and facilitate accurate and efficient analysis in the fields of genomics and medical genetics. Our investigation demonstrated the subtle changes of bio-factor entities' representations in the GP-GPT, which suggested the opportunities for the application of LLMs to advancing gene-phenotype research.

Histopathology and transcriptomics are fundamental modalities in oncology, encapsulating the morphological and molecular aspects of the disease. Multi-modal self-supervised learning has demonstrated remarkable potential in learning pathological representations by integrating diverse data sources. Conventional multi-modal integration methods primarily emphasize modality alignment, while paying insufficient attention to retaining the modality-specific structures. However, unlike conventional scenarios where multi-modal inputs share highly overlapping features, histopathology and transcriptomics exhibit pronounced heterogeneity, offering orthogonal yet complementary insights. Histopathology provides morphological and spatial context, elucidating tissue architecture and cellular topology, whereas transcriptomics delineates molecular signatures through gene expression patterns. This inherent disparity introduces a major challenge in aligning them while maintaining modality-specific fidelity. To address these challenges, we present MIRROR, a novel multi-modal representation learning method designed to foster both modality alignment and retention. MIRROR employs dedicated encoders to extract comprehensive features for each modality, which is further complemented by a modality alignment module to achieve seamless integration between phenotype patterns and molecular profiles. Furthermore, a modality retention module safeguards unique attributes from each modality, while a style clustering module mitigates redundancy and enhances disease-relevant information by modeling and aligning consistent pathological signatures within a clustering space. Extensive evaluations on TCGA cohorts for cancer subtyping and survival analysis highlight MIRROR's superior performance, demonstrating its effectiveness in constructing comprehensive oncological feature representations and benefiting the cancer diagnosis.

Gene regulatory network modeling often requires balancing predictive accuracy and mechanistic interpretability. In this work, we compare continuous surrogate models and a discrete mechanistic model on the same Arabidopsis thaliana induced systemic resistance (ISR) dataset, using both the raw continuous gene-expression measurements and their sign-binarized representation. The study considers eight defense-related genes measured over nine time points and evaluates two continuous predictors, Random Forest (RF) regression and a Multi-Layer Perceptron (MLP), against a threshold Boolean network (TBN). The models are assessed using rolling-origin one-step prediction, recursive multi-step rollout, and interpretability analysis. RF achieved the best average one-step numerical performance in the continuous domain, with an MAE of 1.910 and an RMSE of 2.836, compared with 2.089 and 3.106 for the MLP. In the binary domain, the TBN obtained the best average one-step qualitative performance, with a binary accuracy of 0.550 and a Hamming distance of 3.600, compared with 0.500 and 4.000 for RF, and 0.495 and 4.040 for the MLP. In recursive rollout, the TBN exactly reproduced the observed binarized trajectory, while the MLP also showed near-perfect fidelity, with a trajectory binary accuracy of 0.986, and RF accumulated substantially larger deviation, with a trajectory binary accuracy of 0.708. These results highlight that local numerical accuracy and global qualitative dynamical fidelity are not necessarily aligned, and suggest that continuous surrogates and threshold Boolean networks should be viewed as complementary tools for modeling biological regulation.

Gene set knowledge discovery is essential for advancing human functional genomics. Recent studies have shown promising performance by harnessing the power of Large Language Models (LLMs) on this task. Nonetheless, their results are subject to several limitations common in LLMs such as hallucinations. In response, we present GeneAgent, a first-of-its-kind language agent featuring self-verification capability. It autonomously interacts with various biological databases and leverages relevant domain knowledge to improve accuracy and reduce hallucination occurrences. Benchmarking on 1,106 gene sets from different sources, GeneAgent consistently outperforms standard GPT-4 by a significant margin. Moreover, a detailed manual review confirms the effectiveness of the self-verification module in minimizing hallucinations and generating more reliable analytical narratives. To demonstrate its practical utility, we apply GeneAgent to seven novel gene sets derived from mouse B2905 melanoma cell lines, with expert evaluations showing that GeneAgent offers novel insights into gene functions and subsequently expedites knowledge discovery.

Complex gene interactions play a significant role in cancer progression, driving cellular behaviors that contribute to tumor growth, invasion, and metastasis. Gene co-expression networks model the functional connectivity between genes under various biological conditions. Understanding the system-level evolution of these networks in cancer is critical for elucidating disease mechanisms and informing the development of targeted therapies. While previous studies have primarily focused on structural differences between cancer and normal cell co-expression networks, this study applies graph frequency analysis to cancer transcriptomic signals defined on gene co-expression networks, highlighting the graph spectral characteristics of cancer systems. Using a range of graph frequency filters, we showed that cancer cells display distinctive patterns in the graph frequency content of their gene transcriptomic signals, effectively distinguishing between cancer types and stages. The transformation of the original gene feature space into the graph spectral space captured more intricate cancer properties, as validated by significantly higher F-statistic scores for graph frequency-filtered gene features compared to those in the original space.

Single-cell RNA-seq representation learning is fundamentally label-free: cell identities, states, and contexts are not fixed training targets, so what constitutes signal or nuisance is analysis-dependent. A single representation must therefore preserve biological identity and state, remain robust to nuisance context, and retain the gene-level variation needed for expression analysis, three demands we call the representation trilemma. To tackle this problem, we introduce scTrilemma, a latent-bottleneck VAE that routes expression-derived variation to the embedding, the decoder, or the prior rather than forcing all of it through one embedding. It gates gene tokens by expression, routes the cell representation through the decoder, and conditions the prior on unlabeled pseudo-bulk context, under a single reconstruction objective and without target annotations or auxiliary representation losses. In release-based zero-shot evaluation on successive CZ CELLxGENE Census releases, scTrilemma leads all three demands at once and preserves biological-state, differential-expression, and pathway structure across multiple disease settings. Latent interventions further show that context can be removed at almost no cost to the other demands, leaving identity against fidelity as the remaining tension. Code is publicly available at https://github.com/yunhak0/scTrilemma.

Recent advancements in Spatial Transcriptomics (ST) technology have facilitated detailed gene expression analysis within tissue contexts. However, the high costs and methodological limitations of ST necessitate a more robust predictive model. In response, this paper introduces TRIPLEX, a novel deep learning framework designed to predict spatial gene expression from Whole Slide Images (WSIs). TRIPLEX uniquely harnesses multi-resolution features, capturing cellular morphology at individual spots, the local context around these spots, and the global tissue organization. By integrating these features through an effective fusion strategy, TRIPLEX achieves accurate gene expression prediction. Our comprehensive benchmark study, conducted on three public ST datasets and supplemented with Visium data from 10X Genomics, demonstrates that TRIPLEX outperforms current state-of-the-art models in Mean Squared Error (MSE), Mean Absolute Error (MAE), and Pearson Correlation Coefficient (PCC). The model's predictions align closely with ground truth gene expression profiles and tumor annotations, underscoring TRIPLEX's potential in advancing cancer diagnosis and treatment.

Virtual Screening (VS) of vast compound libraries guided by Artificial Intelligence (AI) models is a highly productive approach to early drug discovery. Data splitting is crucial for better benchmarking of such AI models. Traditional random data splits produce similar molecules between training and test sets, conflicting with the reality of VS libraries which mostly contain structurally distinct compounds. Scaffold split, grouping molecules by shared core structure, is widely considered to reflect this real-world scenario. However, here we show that the scaffold split also overestimates VS performance. The reason is that molecules with different chemical scaffolds are often similar, which hence introduces unrealistically high similarities between training molecules and test molecules following a scaffold split. Our study examined three representative AI models on 60 NCI-60 datasets, each with approximately 30,000 to 50,000 molecules tested on a different cancer cell line. Each dataset was split with three methods: scaffold, Butina clustering and the more accurate Uniform Manifold Approximation and Projection (UMAP) clustering. Regardless of the model, model performance is much worse with UMAP splits from the results of the 2100 models trained and evaluated for each algorithm and split. These robust results demonstrate the need for more realistic data splits to tune, compare, and select models for VS. For the same reason, avoiding the scaffold split is also recommended for other molecular property prediction problems. The code to reproduce these results is available at https://github.com/ScaffoldSplitsOverestimateVS

The transcriptional response to genetic perturbation reveals fundamental insights into complex cellular systems. While current approaches have made progress in predicting genetic perturbation responses, they provide limited biological understanding and cannot systematically refine existing knowledge. Overcoming these limitations requires an end-to-end integration of data-driven learning and existing knowledge. However, this integration is challenging due to inconsistencies between data and knowledge bases, such as noise, misannotation, and incompleteness. To address this challenge, we propose ALIGNED (Adaptive aLignment for Inconsistent Genetic kNowledgE and Data), a neuro-symbolic framework based on the Abductive Learning (ABL) paradigm. This end-to-end framework aligns neural and symbolic components and performs systematic knowledge refinement. We introduce a balanced consistency metric to evaluate the predictions' consistency against both data and knowledge. Our results show that ALIGNED outperforms state-of-the-art methods by achieving the highest balanced consistency, while also re-discovering biologically meaningful knowledge. Our work advances beyond existing methods to enable both the transparency and the evolution of mechanistic biological understanding.

We introduce a comprehensive framework for modeling single cell transcriptomic responses to perturbations, aimed at standardizing benchmarking in this rapidly evolving field. Our approach includes a modular and user-friendly model development and evaluation platform, a collection of diverse perturbational datasets, and a set of metrics designed to fairly compare models and dissect their performance. Through extensive evaluation of both published and baseline models across diverse datasets, we highlight the limitations of widely used models, such as mode collapse. We also demonstrate the importance of rank metrics which complement traditional model fit measures, such as RMSE, for validating model effectiveness. Notably, our results show that while no single model architecture clearly outperforms others, simpler architectures are generally competitive and scale well with larger datasets. Overall, this benchmarking exercise sets new standards for model evaluation, supports robust model development, and furthers the use of these models to simulate genetic and chemical screens for therapeutic discovery.

Cancer progression arises from interactions across multiple biological layers, especially beyond morphological and across molecular layers that remain invisible to image-only models. To capture this broader biological landscape, we present EXAONE Path 2.5, a pathology foundation model that jointly models histologic, genomic, epigenetic and transcriptomic modalities, producing an integrated patient representation that reflects tumor biology more comprehensively. Our approach incorporates three key components: (1) multimodal SigLIP loss enabling all-pairwise contrastive learning across heterogeneous modalities, (2) a fragment-aware rotary positional encoding (F-RoPE) module that preserves spatial structure and tissue-fragment topology in WSI, and (3) domain-specialized internal foundation models for both WSI and RNA-seq to provide biologically grounded embeddings for robust multimodal alignment. We evaluate EXAONE Path 2.5 against six leading pathology foundation models across two complementary benchmarks: an internal real-world clinical dataset and the Patho-Bench benchmark covering 80 tasks. Our framework demonstrates high data and parameter efficiency, achieving on-par performance with state-of-the-art foundation models on Patho-Bench while exhibiting the highest adaptability in the internal clinical setting. These results highlight the value of biologically informed multimodal design and underscore the potential of integrated genotype-to-phenotype modeling for next-generation precision oncology.

Over the past decade, the revolution in single-cell sequencing has enabled the simultaneous molecular profiling of various modalities across thousands of individual cells, allowing scientists to investigate the diverse functions of complex tissues and uncover underlying disease mechanisms. Among all the analytical steps, assigning individual cells to specific types is fundamental for understanding cellular heterogeneity. However, this process is usually labor-intensive and requires extensive expert knowledge. Recent advances in large language models (LLMs) have demonstrated their ability to efficiently process and synthesize vast corpora of text to automatically extract essential biological knowledge, such as marker genes, potentially promoting more efficient and automated cell type annotations. To thoroughly evaluate the capability of modern instruction-tuned LLMs in automating the cell type identification process, we introduce SOAR, a comprehensive benchmarking study of LLMs for cell type annotation tasks in single-cell genomics. Specifically, we assess the performance of 8 instruction-tuned LLMs across 11 datasets, spanning multiple cell types and species. Our study explores the potential of LLMs to accurately classify and annotate cell types in single-cell RNA sequencing (scRNA-seq) data, while extending their application to multiomics data through cross-modality translation. Additionally, we evaluate the effectiveness of chain-of-thought (CoT) prompting techniques in generating detailed biological insights during the annotation process. The results demonstrate that LLMs can provide robust interpretations of single-cell data without requiring additional fine-tuning, advancing the automation of cell type annotation in genomics research.

Predicting how cells respond to genetic perturbations is fundamental to understanding gene function, disease mechanisms, and therapeutic development. While recent deep learning approaches have shown promise in modeling single-cell perturbation responses, they struggle to generalize across cell types and perturbation contexts due to limited contextual information during generation. We introduce PT-RAG (Perturbation-aware Two-stage Retrieval-Augmented Generation), a novel framework that extends Retrieval-Augmented Generation beyond traditional language-model applications to cellular biology. Unlike standard RAG systems designed for text retrieval with pre-trained LLMs, perturbation retrieval lacks established similarity metrics and requires learning what constitutes relevant context, making differentiable retrieval essential. PT-RAG addresses this through a two-stage pipeline: first, retrieving candidate perturbations K using GenePT embeddings, then adaptively refining the selection through Gumbel-Softmax discrete sampling conditioned on both the cell state and the input perturbation. This cell-type-aware differentiable retrieval enables end-to-end optimization of the retrieval objective jointly with generation. On the Replogle-Nadig single-gene perturbation dataset, we demonstrate that PT-RAG outperforms both STATE and vanilla RAG under identical experimental conditions, with the strongest gains in distributional similarity metrics (W_1, W_2). Notably, vanilla RAG's dramatic failure is itself a key finding: it demonstrates that differentiable, cell-type-aware retrieval is essential in this domain, and that naive retrieval can actively harm performance. Our results establish retrieval-augmented generation as a promising paradigm for modelling cellular responses to gene perturbation. The code to reproduce our experiments is available at https://github.com/difra100/PT-RAG_ICLR.

The approval success rate of drug candidates is very low with the majority of failure due to safety and efficacy. Increasingly available high dimensional information on targets, drug molecules and indications provides an opportunity for ML methods to integrate multiple data modalities and better predict clinically promising drug targets. Notably, drug targets with human genetics evidence are shown to have better odds to succeed. However, a recent tensor factorization-based approach found that additional information on targets and indications might not necessarily improve the predictive accuracy. Here we revisit this approach by integrating different types of human genetics evidence collated from publicly available sources to support each target-indication pair. We use Bayesian tensor factorization to show that models incorporating all available human genetics evidence (rare disease, gene burden, common disease) modestly improves the clinical outcome prediction over models using single line of genetics evidence. We provide additional insight into the relative predictive power of different types of human genetics evidence for predicting the success of clinical outcomes.

Destructive single-cell measurements provide unpaired population snapshots rather than observations of the same cells across conditions. Local cell states and transition requests may also be insufficient to distinguish responses across source populations. We introduce TempoBridge, a common source-conditioned transport formulation for temporal, genetic, and chemical population transitions. Source cells initialize latent transport and provide a fixed empirical population summary. The velocity field receives this summary alongside the evolving cell state, flow time, and a structured transition descriptor. Minibatch optimal transport (OT) supplies couplings only for conditional flow-matching training paths; inference requires neither target expression nor OT computation. On held-out donors, TempoBridge achieves an Energy distance of 0.129 versus 0.144 for scGen. Genetic mean-expression L_2 error is 2.261 versus 3.156 for scGPT-scratch under Seen 2/2. On held-out compounds, condition-averaged drug-effect correlation is 0.598 versus 0.561 for the CellFlow adapter. Temporal ablations show higher mean distributional error after removing source context, replacing optimal transport with random pairing, or replacing flow matching with static residual regression. Together, these results demonstrate the predictive utility of a common source-conditioned transport formulation across held-out donors, gene combinations, and compounds.

Single-cell transcriptomics enabled the study of cellular heterogeneity in response to perturbations at the resolution of individual cells. However, scaling high-throughput screens (HTSs) to measure cellular responses for many drugs remains a challenge due to technical limitations and, more importantly, the cost of such multiplexed experiments. Thus, transferring information from routinely performed bulk RNA HTS is required to enrich single-cell data meaningfully. We introduce chemCPA, a new encoder-decoder architecture to study the perturbational effects of unseen drugs. We combine the model with an architecture surgery for transfer learning and demonstrate how training on existing bulk RNA HTS datasets can improve generalisation performance. Better generalisation reduces the need for extensive and costly screens at single-cell resolution. We envision that our proposed method will facilitate more efficient experiment designs through its ability to generate in-silico hypotheses, ultimately accelerating drug discovery.

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.

A central goal in systems biology and drug discovery is to predict the transcriptional response of cells to perturbations. This task is challenging due to the noisy and sparse nature of single-cell measurements, as well as the fact that perturbations often induce population-level shifts rather than changes in individual cells. Existing deep learning methods typically assume cell-level correspondences, limiting their ability to capture such global effects. We present scDFM, a generative framework based on conditional flow matching that models the full distribution of perturbed cells conditioned on control states. By incorporating a maximum mean discrepancy (MMD) objective, our method aligns perturbed and control populations beyond cell-level correspondences. To further improve robustness to sparsity and noise, we introduce the Perturbation-Aware Differential Transformer (PAD-Transformer), a backbone architecture that leverages gene interaction graphs and differential attention to capture context-specific expression changes. Across multiple genetic and drug perturbation benchmarks, scDFM consistently outperforms prior methods, demonstrating strong generalization in both unseen and combinatorial settings. In the combinatorial setting, it reduces mean squared error by 19.6% relative to the strongest baseline. These results highlight the importance of distribution-level generative modeling for robust in silico perturbation prediction. The code is available at https://github.com/AI4Science-WestlakeU/scDFM

Multimodal data is a precious asset enabling a variety of downstream tasks in machine learning. However, real-world data collected across different modalities is often not paired, which is a significant challenge to learn a joint distribution. A prominent approach to address the modality coupling problem is Minimum Entropy Coupling (MEC), which seeks to minimize the joint Entropy, while satisfying constraints on the marginals. Existing approaches to the MEC problem focus on finite, discrete distributions, limiting their application for cases involving continuous data. In this work, we propose a novel method to solve the continuous MEC problem, using well-known generative diffusion models that learn to approximate and minimize the joint Entropy through a cooperative scheme, while satisfying a relaxed version of the marginal constraints. We empirically demonstrate that our method, DDMEC, is general and can be easily used to address challenging tasks, including unsupervised single-cell multi-omics data alignment and unpaired image translation, outperforming specialized methods.

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, K learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype times pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.

We introduce a novel score-based diffusion framework named Twigs that incorporates multiple co-evolving flows for enriching conditional generation tasks. Specifically, a central or trunk diffusion process is associated with a primary variable (e.g., graph structure), and additional offshoot or stem processes are dedicated to dependent variables (e.g., graph properties or labels). A new strategy, which we call loop guidance, effectively orchestrates the flow of information between the trunk and the stem processes during sampling. This approach allows us to uncover intricate interactions and dependencies, and unlock new generative capabilities. We provide extensive experiments to demonstrate strong performance gains of the proposed method over contemporary baselines in the context of conditional graph generation, underscoring the potential of Twigs in challenging generative tasks such as inverse molecular design and molecular optimization.

VGL-stGen is a multimodal large language model adapted from a pretrained medical vision-language model using paired lung H&E and spatial transcriptomics with single-cell references. Training integrates image-expression and expression-cell-type pairs, and gene-conditioned pseudo-labels transfer transcriptomic cell-type supervision to histology images. One deployed checkpoint supports thirteen evaluated tasks spanning tissue and cell-type classification, gene prediction and conditional expression completion from combinations of histology, cell identity and observed gene expression. Task-specific decoding produces categorical labels, gene lists and structured expression levels. For conditional completion, fixing queried gene identities and predicting their levels autoregressively improves structured prediction. Controlled adaptation shows that restricting supervision to requested expression-level tokens can further improve image-conditioned completion. Image-permutation experiments indicate that correctly paired histology adds information beyond observed expression. External classification relies partly on computational references with shared annotation lineage, and some H&E sources were exposed during cancer training or model development. Within these conditions, VGL-stGen demonstrates how a medical vision-language backbone can learn from spatial transcriptomics and histology to connect tissue morphology and molecular states through shared generative modeling.

We study a self-supervised generation task for single-cell gene expression vectors: given a set of vectors from a cell type, we aim to generate additional gene expression vectors of that cell type. For this task we characterize both the biological fidelity of the generated gene expression vectors and the scaling behavior of the pretraining loss. The model is a causal transformer paired with a learned quantized VAE tokenizer, trained with a cross-entropy loss. To evaluate the model, we condition it on held-out gene expression vectors of a cell type and generate vectors of gene expression, comparing the resulting distribution over gene expression vectors to the ground truth distribution of that cell type. We study the scaling properties of the proposed architecture by varying the number of trained parameters and the amount of training data. To our knowledge, we find the first jointly-fit two-exponent scaling law and compute-optimal frontier for a single-cell foundation model. Finally, we discuss how this pretrained model could be finetuned for perturbation response prediction.

Biomedical research increasingly relies on integrating diverse data modalities, including gene expression profiles, medical images, and clinical metadata. While medical images and clinical metadata are routinely collected in clinical practice, gene expression data presents unique challenges for widespread research use, mainly due to stringent privacy regulations and costly laboratory experiments. To address these limitations, we present GeMM-GAN, a novel Generative Adversarial Network conditioned on histopathology tissue slides and clinical metadata, designed to synthesize realistic gene expression profiles. GeMM-GAN combines a Transformer Encoder for image patches with a final Cross Attention mechanism between patches and text tokens, producing a conditioning vector to guide a generative model in generating biologically coherent gene expression profiles. We evaluate our approach on the TCGA dataset and demonstrate that our framework outperforms standard generative models and generates more realistic and functionally meaningful gene expression profiles, improving by more than 11\% the accuracy on downstream disease type prediction compared to current state-of-the-art generative models. Code will be available at: https://github.com/francescapia/GeMM-GAN

Comprehensively characterizing cellular diversity is critical for understanding tissue development, identifying disease-associated populations and investigating gene programmes linked to specialized functions. Advances in single-cell profiling reveal additional cell-specific transcripts and molecular associations, yet many foundation models represent only a restricted portion of this increasingly rich molecular information. Here we present CellNet, which enables panoramic modelling of single-cell transcriptomes by integrating DNA-derived gene identities and measured RNA expression in a shared image representation. Pretrained on 231 million cell profiles spanning 40 species, CellNet improves rare-population and condition-associated state recognition in evaluated cohorts while retaining competitive general cell representations. It predicts withheld coding-gene expression and selected non-coding targets in total-RNA data, and recovers lineage-specific expression patterns in spatial measurements. Prediction also extends across species, including to targets without expression-pretraining exposure. Its gene representations retrieve known non-coding modules and developmental or neural programmes, including from sparsely detected RNA queries. Together, these results establish CellNet as a scalable framework for interpreting cellular diversity through increasingly comprehensive transcriptomic measurements.

Medical image analysis is critical yet challenged by the need of jointly segmenting organs or tissues, and numerous instances for anatomical structures and tumor microenvironment analysis. Existing studies typically formulated different segmentation tasks in isolation, which overlooks the fundamental interdependencies between these tasks, leading to suboptimal segmentation performance and insufficient medical image understanding. To address this issue, we propose a Co-Seg++ framework for versatile medical segmentation. Specifically, we introduce a novel co-segmentation paradigm, allowing semantic and instance segmentation tasks to mutually enhance each other. We first devise a spatio-temporal prompt encoder (STP-Encoder) to capture long-range spatial and temporal relationships between segmentation regions and image embeddings as prior spatial constraints. Moreover, we devise a multi-task collaborative decoder (MTC-Decoder) that leverages cross-guidance to strengthen the contextual consistency of both tasks, jointly computing semantic and instance segmentation masks. Extensive experiments on diverse CT and histopathology datasets demonstrate that the proposed Co-Seg++ outperforms state-of-the-arts in the semantic, instance, and panoptic segmentation of dental anatomical structures, histopathology tissues, and nuclei instances. The source code is available at https://github.com/xq141839/Co-Seg-Plus.

Large language models (LLMs) and emerging agentic frameworks are beginning to transform single-cell biology by enabling natural-language reasoning, generative annotation, and multimodal data integration. However, progress remains fragmented across data modalities, architectures, and evaluation standards. LLM4Cell presents the first unified survey of 58 foundation and agentic models developed for single-cell research, spanning RNA, ATAC, multi-omic, and spatial modalities. We categorize these methods into five families-foundation, text-bridge, spatial, multimodal, epigenomic, and agentic-and map them to eight key analytical tasks including annotation, trajectory and perturbation modeling, and drug-response prediction. Drawing on over 40 public datasets, we analyze benchmark suitability, data diversity, and ethical or scalability constraints, and evaluate models across 10 domain dimensions covering biological grounding, multi-omics alignment, fairness, privacy, and explainability. By linking datasets, models, and evaluation domains, LLM4Cell provides the first integrated view of language-driven single-cell intelligence and outlines open challenges in interpretability, standardization, and trustworthy model development.

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired. Existing methods either attempt to forcibly pair unpaired data using random sampling, or neglect the inherent relationship between unperturbed and perturbed cells during the modeling. In this work, we propose a framework based on Dual Diffusion Implicit Bridges (DDIB) to learn the mapping between different data distributions, effectively addressing the challenge of unpaired data. We further interpret this framework as a form of data augmentation. We integrate gene regulatory network (GRN) information to propagate perturbation signals in a biologically meaningful way, and further incorporate a masking mechanism to predict silent genes, improving the quality of generated profiles. Moreover, gene expression under the same perturbation often varies significantly across cells, frequently exhibiting a bimodal distribution that reflects intrinsic heterogeneity. To capture this, we introduce a more suitable evaluation metric. We propose Unlasting, dual conditional diffusion models that overcome the problem of unpaired single-cell perturbation data and strengthen the model's insight into perturbations under the guidance of the GRN, with a dedicated mask model designed to improve generation quality by predicting silent genes. In addition, we introduce a biologically grounded evaluation metric that better reflects the inherent heterogeneity in single-cell responses.

In domains ranging from computer vision to natural language processing, machine learning models have been shown to exhibit stark disparities, often performing worse for members of traditionally underserved groups. One factor contributing to these performance gaps is a lack of representation in the data the models are trained on. It is often unclear, however, how to operationalize representativeness in specific applications. Here we formalize the problem of creating equitable training datasets, and propose a statistical framework for addressing this problem. We consider a setting where a model builder must decide how to allocate a fixed data collection budget to gather training data from different subgroups. We then frame dataset creation as a constrained optimization problem, in which one maximizes a function of group-specific performance metrics based on (estimated) group-specific learning rates and costs per sample. This flexible approach incorporates preferences of model-builders and other stakeholders, as well as the statistical properties of the learning task. When data collection decisions are made sequentially, we show that under certain conditions this optimization problem can be efficiently solved even without prior knowledge of the learning rates. To illustrate our approach, we conduct a simulation study of polygenic risk scores on synthetic genomic data -- an application domain that often suffers from non-representative data collection. We find that our adaptive sampling strategy outperforms several common data collection heuristics, including equal and proportional sampling, demonstrating the value of strategic dataset design for building equitable models.

Progress in genomic foundation models is difficult to assess due to fragmented benchmarks, incompatible evaluation protocols, and task-specific reporting. As a result, claims of superiority or generality across models are often not directly comparable. We introduce GENEB, a large-scale diagnostic benchmark that evaluates frozen representations from 40 genomic foundation models across 100 tasks spanning 13 functional categories under a unified probing-based protocol, including few-shot regimes. GENEB enables controlled comparison across model scale, architecture, tokenization, and pretraining data while explicitly exposing task-level trade-offs. Our analysis shows that aggregate leaderboards are unstable: model rankings vary sharply across task categories, scale provides only modest and inconsistent gains, and architectural and pretraining alignment frequently outweigh parameter count. These results highlight limitations of current evaluation practices and position GENEB as a reference framework for principled comparison and category-aware model selection in genomic machine learning.

Cell-type-specific marker genes are fundamental to plant biology, yet existing resources primarily rely on curated databases or high-throughput studies without explicitly modeling the supporting evidence found in scientific literature. We introduce PlantMarkerBench, a multi-species benchmark for evaluating literature-grounded plant marker evidence interpretation from full-text biological papers. PlantMarkerBench is constructed using a modular curation pipeline integrating large-scale literature retrieval, hybrid search, species-aware biological grounding, structured evidence extraction, and targeted human review. The benchmark spans four plant species -- Arabidopsis, maize, rice, and tomato -- and contains 5,550 sentence-level evidence instances annotated for marker-evidence validity, evidence type, and support strength. We define two benchmark tasks: determining whether a candidate sentence provides valid marker evidence for a gene-cell-type pair, and classifying the evidence into expression, localization, function, indirect, or negative categories. We benchmark diverse open-weight and closed-source language models across species and prompting strategies. Although frontier models achieve relatively strong performance on direct expression evidence, performance drops substantially on functional, indirect, and weak-support evidence, with evidence-type confusion emerging as a dominant failure mode. Open-weight models additionally exhibit elevated false-positive rates under ambiguous biological contexts. PlantMarkerBench provides a challenging and reproducible evaluation framework for literature-grounded biological evidence attribution and supports future research on trustworthy scientific information extraction and AI-assisted plant biology.

We introduce InVirtuoGen, a discrete flow generative model for fragmented SMILES for de novo and fragment-constrained generation, and target-property/lead optimization of small molecules. The model learns to transform a uniform source over all possible tokens into the data distribution. Unlike masked models, its training loss accounts for predictions on all sequence positions at every denoising step, shifting the generation paradigm from completion to refinement, and decoupling the number of sampling steps from the sequence length. For de novo generation, InVirtuoGen achieves a stronger quality-diversity pareto frontier than prior fragment-based models and competitive performance on fragment-constrained tasks. For property and lead optimization, we propose a hybrid scheme that combines a genetic algorithm with a Proximal Property Optimization fine-tuning strategy adapted to discrete flows. Our approach sets a new state-of-the-art on the Practical Molecular Optimization benchmark, measured by top-10 AUC across tasks, and yields higher docking scores in lead optimization than previous baselines. InVirtuoGen thus establishes a versatile generative foundation for drug discovery, from early hit finding to multi-objective lead optimization. We further contribute to open science by releasing pretrained checkpoints and code, making our results fully reproduciblehttps://github.com/invirtuolabs/InVirtuoGen_results.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Attributed bipartite graphs (ABGs) are an expressive data model for describing the interactions between two sets of heterogeneous nodes that are associated with rich attributes, such as customer-product purchase networks and author-paper authorship graphs. Partitioning the target node set in such graphs into k disjoint clusters (referred to as k-ABGC) finds widespread use in various domains, including social network analysis, recommendation systems, information retrieval, and bioinformatics. However, the majority of existing solutions towards k-ABGC either overlook attribute information or fail to capture bipartite graph structures accurately, engendering severely compromised result quality. The severity of these issues is accentuated in real ABGs, which often encompass millions of nodes and a sheer volume of attribute data, rendering effective k-ABGC over such graphs highly challenging. In this paper, we propose TPO, an effective and efficient approach to k-ABGC that achieves superb clustering performance on multiple real datasets. TPO obtains high clustering quality through two major contributions: (i) a novel formulation and transformation of the k-ABGC problem based on multi-scale attribute affinity specialized for capturing attribute affinities between nodes with the consideration of their multi-hop connections in ABGs, and (ii) a highly efficient solver that includes a suite of carefully-crafted optimizations for sidestepping explicit affinity matrix construction and facilitating faster convergence. Extensive experiments, comparing TPO against 19 baselines over 5 real ABGs, showcase the superior clustering quality of TPO measured against ground-truth labels. Moreover, compared to the state of the arts, TPO is often more than 40x faster over both small and large ABGs.

Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ breast cancer, which is costly, tissue destructive, requires specialized platforms and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA-sequencing techniques to predict the expression of 138 genes (incorporated from six commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E) stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n=335). We demonstrate successful gene prediction on a held-out test set (n = 160, corr = 0.82 across patients, corr = 0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n = 498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index = 0.56, hazard ratio = 2.16 (95% CI 1.12-3.06), p < 5 x 10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index = 0.65, hazard ratio = 1.85 (95% CI 1.30-2.68), p < 5 x 10-3).

The integration of multi-omics single-cell data remains challenging due to high-dimensionality and complex inter-modality relationships. To address this, we introduce MoRE-GNN (Multi-omics Relational Edge Graph Neural Network), a heterogeneous graph autoencoder that combines graph convolution and attention mechanisms to dynamically construct relational graphs directly from data. Evaluations on six publicly available datasets demonstrate that MoRE-GNN captures biologically meaningful relationships and outperforms existing methods, particularly in settings with strong inter-modality correlations. Furthermore, the learned representations allow for accurate downstream cross-modal predictions. While performance may vary with dataset complexity, MoRE-GNN offers an adaptive, scalable and interpretable framework for advancing multi-omics integration.

Learning a transport model that maps a source distribution to a target distribution is a canonical problem in machine learning, but scientific applications increasingly require models that can generalize to source and target distributions unseen during training. We introduce distribution-conditioned transport (DCT), a framework that conditions transport maps on learned embeddings of source and target distributions, enabling generalization to unseen distribution pairs. DCT also allows semi-supervised learning for distributional forecasting problems: because it learns from arbitrary distribution pairs, it can leverage distributions observed at only one condition to improve transport prediction. DCT is agnostic to the underlying transport mechanism, supporting models ranging from flow matching to distributional divergence-based models (e.g. Wasserstein, MMD). We demonstrate the practical performance benefits of DCT on synthetic benchmarks and four applications in biology: batch effect transfer in single-cell genomics, perturbation prediction from mass cytometry data, learning clonal transcriptional dynamics in hematopoiesis, and modeling T-cell receptor sequence evolution.

Principal component analysis (PCA) is a tool to capture factors that explain variation in data. Across domains, data are now collected across multiple contexts (for example, individuals with different diseases, cells of different types, or words across texts). While the factors explaining variation in data are undoubtedly shared across subsets of contexts, no tools currently exist to systematically recover such factors. We develop multi-context principal component analysis (MCPCA), a theoretical and algorithmic framework that decomposes data into factors shared across subsets of contexts. Applied to gene expression, MCPCA reveals axes of variation shared across subsets of cancer types and an axis whose variability in tumor cells, but not mean, is associated with lung cancer progression. Applied to contextualized word embeddings from language models, MCPCA maps stages of a debate on human nature, revealing a discussion between science and fiction over decades. These axes are not found by combining data across contexts or by restricting to individual contexts. MCPCA is a principled generalization of PCA to address the challenge of understanding factors underlying data across contexts.

The identification of heterogeneous treatment effects (HTE) across subgroups is of significant interest in clinical trial analysis. Several state-of-the-art HTE estimation methods, including causal forests, apply recursive partitioning for non-parametric identification of relevant covariates and interactions. However, the partitioning criterion is typically based on differences in absolute risk. This can dilute statistical power by masking variation in the relative risk, which is often a more appropriate quantity of clinical interest. In this work, we propose and implement a methodology for modifying causal forests to target relative risk, using a novel node-splitting procedure based on exhaustive generalized linear model comparison. We present results from simulated data that suggest relative risk causal forests can capture otherwise undetected sources of heterogeneity. We implement our method on real-world trial data to explore HTEs for liraglutide in patients with type 2 diabetes.

Genetic pathways usually encode molecular mechanisms that can inform targeted interventions. It is often challenging for existing machine learning approaches to jointly model genetic pathways (higher-order features) and variants (atomic features), and present to clinicians interpretable models. In order to build more accurate and better interpretable machine learning models for genetic medicine, we introduce Pathway Augmented Nonnegative Tensor factorization for HighER-order feature learning (PANTHER). PANTHER selects informative genetic pathways that directly encode molecular mechanisms. We apply genetically motivated constrained tensor factorization to group pathways in a way that reflects molecular mechanism interactions. We then train a softmax classifier for disease types using the identified pathway groups. We evaluated PANTHER against multiple state-of-the-art constrained tensor/matrix factorization models, as well as group guided and Bayesian hierarchical models. PANTHER outperforms all state-of-the-art comparison models significantly (p<0.05). Our experiments on large scale Next Generation Sequencing (NGS) and whole-genome genotyping datasets also demonstrated wide applicability of PANTHER. We performed feature analysis in predicting disease types, which suggested insights and benefits of the identified pathway groups.

Integrating molecular, morphological, and clinical data is essential for basic and translational biomedical research, yet systematic frameworks for jointly modeling these modalities remain limited. Here we present Haiku, a tri-modal contrastive learning model trained on multiplexed immunofluorescence (mIF). It comprises 26.7 million spatial proteomics patches from 3,218 tissue sections across 1,606 patients spanning 11 organ types, with matched hematoxylin and eosin (H&E) histology and clinical metadata aligned in a shared embedding space. Haiku enables three-way cross-modal retrieval, improves downstream classification and clinical prediction tasks over unimodal baselines, and supports zero-shot biomarker inference through fusion retrieval conditioned on clinical metadata-only text descriptions. Across tasks, Haiku outperforms competing approaches, achieving cross-modal retrieval (Recall@50 up to 0.611 versus near-zero baseline), survival prediction (C-index 0.737, +7.91% relative improvement), and zero-shot biomarker inference (mean Pearson correlation 0.718 across 52 biomarkers). Furthermore, we introduce a counterfactual prediction framework in which modifying only clinical metadata while fixing tissue morphology surfaces niche-specific molecular shifts associated with breast cancer stage progression and lung cancer survival outcomes. In a lung adenocarcinoma case study, the counterfactual analysis recovers niche-specific shifts characterized by increased CD8 and granzyme B, reduced PD-L1, and decreased Ki67, broadly consistent with patterns reported for favorable outcomes. We present these counterfactual results as exploratory, hypothesis-generating signals rather than mechanistic claims. These capabilities demonstrate that tri-modal alignment via Haiku enables integrative analysis of spatial biology, bridging molecular measurements with clinical context for biological exploration.

Understanding cellular mechanisms requires integrating information across DNA, RNA, and protein - the three molecular systems linked by the Central Dogma of molecular biology. While domain-specific foundation models have achieved success for each modality individually, they remain isolated, limiting our ability to model integrated cellular processes. Here we present the Central Dogma Transformer (CDT), an architecture that integrates pre-trained language models for DNA, RNA, and protein following the directional logic of the Central Dogma. CDT employs directional cross-attention mechanisms - DNA-to-RNA attention models transcriptional regulation, while RNA-to-Protein attention models translational relationships - producing a unified Virtual Cell Embedding that integrates all three modalities. We validate CDT v1 - a proof-of-concept implementation using fixed (non-cell-specific) RNA and protein embeddings - on CRISPRi enhancer perturbation data from K562 cells, achieving a Pearson correlation of 0.503, representing 63% of the theoretical ceiling set by cross-experiment variability (r = 0.797). Attention and gradient analyses provide complementary interpretive windows: in detailed case studies, these approaches highlight largely distinct genomic regions, with gradient analysis identifying a CTCF binding site that Hi-C data showed as physically contacting both enhancer and target gene. These results suggest that AI architectures aligned with biological information flow can achieve both predictive accuracy and mechanistic interpretability.

Recent advances in general-purpose foundation models have stimulated the development of large biological sequence models. While natural language shows symbolic granularity (characters, words, sentences), biological sequences exhibit hierarchical granularity whose levels (nucleotides, amino acids, protein domains, genes) further encode biologically functional information. In this paper, we investigate the integration of cross-granularity knowledge from models through a case study of BiGCARP, a Pfam domain-level model for biosynthetic gene clusters, and ESM, an amino acid-level protein language model. Using representation analysis tools and a set of probe tasks, we first explain why a straightforward cross-model embedding initialization fails to improve downstream performance in BiGCARP, and show that deeper-layer embeddings capture a more contextual and faithful representation of the model's learned knowledge. Furthermore, we demonstrate that representations at different granularities encode complementary biological knowledge, and that combining them yields measurable performance gains in intermediate-level prediction tasks. Our findings highlight cross-granularity integration as a promising strategy for improving both the performance and interpretability of biological foundation models.

We propose a graph clustering formulation based on multicut (a.k.a. weighted correlation clustering) on the complete graph. Our formulation does not need specification of the graph topology as in the original sparse formulation of multicut, making our approach simpler and potentially better performing. In contrast to unweighted correlation clustering we allow for a more expressive weighted cost structure. In dense multicut, the clustering objective is given in a factorized form as inner products of node feature vectors. This allows for an efficient formulation and inference in contrast to multicut/weighted correlation clustering, which has at least quadratic representation and computation complexity when working on the complete graph. We show how to rewrite classical greedy algorithms for multicut in our dense setting and how to modify them for greater efficiency and solution quality. In particular, our algorithms scale to graphs with tens of thousands of nodes. Empirical evidence on instance segmentation on Cityscapes and clustering of ImageNet datasets shows the merits of our approach.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

Cancer is known as a disease mainly caused by gene alterations. Discovery of mutated driver pathways or gene sets is becoming an important step to understand molecular mechanisms of carcinogenesis. However, systematically investigating commonalities and specificities of driver gene sets among multiple cancer types is still a great challenge, but this investigation will undoubtedly benefit deciphering cancers and will be helpful for personalized therapy and precision medicine in cancer treatment. In this study, we propose two optimization models to de novo discover common driver gene sets among multiple cancer types (ComMDP) and specific driver gene sets of one certain or multiple cancer types to other cancers (SpeMDP), respectively. We first apply ComMDP and SpeMDP to simulated data to validate their efficiency. Then, we further apply these methods to 12 cancer types from The Cancer Genome Atlas (TCGA) and obtain several biologically meaningful driver pathways. As examples, we construct a common cancer pathway model for BRCA and OV, infer a complex driver pathway model for BRCA carcinogenesis based on common driver gene sets of BRCA with eight cancer types, and investigate specific driver pathways of the liquid cancer lymphoblastic acute myeloid leukemia (LAML) versus other solid cancer types. In these processes more candidate cancer genes are also found.

Survival prediction is a complicated ordinal regression task that aims to predict the ranking risk of death, which generally benefits from the integration of histology and genomic data. Despite the progress in joint learning from pathology and genomics, existing methods still suffer from challenging issues: 1) Due to the large size of pathological images, it is difficult to effectively represent the gigapixel whole slide images (WSIs). 2) Interactions within tumor microenvironment (TME) in histology are essential for survival analysis. Although current approaches attempt to model these interactions via co-attention between histology and genomic data, they focus on only dense local similarity across modalities, which fails to capture global consistency between potential structures, i.e. TME-related interactions of histology and co-expression of genomic data. To address these challenges, we propose a Multimodal Optimal Transport-based Co-Attention Transformer framework with global structure consistency, in which optimal transport (OT) is applied to match patches of a WSI and genes embeddings for selecting informative patches to represent the gigapixel WSI. More importantly, OT-based co-attention provides a global awareness to effectively capture structural interactions within TME for survival prediction. To overcome high computational complexity of OT, we propose a robust and efficient implementation over micro-batch of WSI patches by approximating the original OT with unbalanced mini-batch OT. Extensive experiments show the superiority of our method on five benchmark datasets compared to the state-of-the-art methods. The code is released.

The rapid advancement of high-throughput sequencing has led to large, high-dimensional omics datasets. Deep unsupervised learning architectures, particularly Autoencoders (AEs), are increasingly used for dimensionality reduction and representation learning in this domain. However, AEs are highly sensitive to architectural choices and hyperparameters, and unsupervised optimization typically relies on reconstruction loss, which may be a poor proxy for downstream utility. Exhaustive hyperparameter optimization (HPO) is computationally expensive, leading researchers to frequently rely on suboptimal default configurations. To democratize access to large-scale unsupervised HPO research, we introduce BBOmix, the first open-source tabular benchmark for unsupervised representation learning on real-world biological data. Our benchmark includes 105,000 evaluations across four AE architectures and seven multi-omics modalities from the TCGA and SCHC datasets. We quantify the correlation between reconstruction loss and downstream task performance and provide an extensive evaluation of state-of-the-art single-fidelity, multi-fidelity, and transfer learning HPO methods, establishing a rigorous baseline for future research in unsupervised biological representation learning.

Genome-wide association studies are pivotal in understanding the genetic underpinnings of complex traits and diseases. Collaborative, multi-site GWAS aim to enhance statistical power but face obstacles due to the sensitive nature of genomic data sharing. Current state-of-the-art methods provide a privacy-focused approach utilizing computationally expensive methods such as Secure Multi-Party Computation and Homomorphic Encryption. In this context, we present a novel algorithm PP-GWAS designed to improve upon existing standards in terms of computational efficiency and scalability without sacrificing data privacy. This algorithm employs randomized encoding within a distributed architecture to perform stacked ridge regression on a Linear Mixed Model to ensure rigorous analysis. Experimental evaluation with real world and synthetic data indicates that PP-GWAS can achieve computational speeds twice as fast as similar state-of-the-art algorithms while using lesser computational resources, all while adhering to a robust security model that caters to an all-but-one semi-honest adversary setting. We have assessed its performance using various datasets, emphasizing its potential in facilitating more efficient and private genomic analyses.