Histology imaging is an important tool in medical diagnosis and research, enabling the examination of tissue structure and composition at the microscopic level. Understanding the underlying molecular mechanisms of tissue architecture is critical in uncovering disease mechanisms and developing effective treatments.Gene expression profiling provides insight into the molecular processes underlying tissue architecture, but the process can be time-consuming and expensive. We present BLEEP (Bi-modaL Embedding for Expression Prediction), a bi-modal embedding framework capable of generating spatially resolved gene expression profiles of whole-slide Hematoxylin and eosin (H&E) stained histology images. BLEEP uses contrastive learning to construct a low-dimensional joint embedding space from a reference dataset using paired image and expression profiles at micrometer resolution. With this approach, the gene expression of any query image patch can be imputed using the expression profiles from the reference dataset. We demonstrate BLEEP's effectiveness in gene expression prediction by benchmarking its performance on a human liver tissue dataset captured using the 10x Visium platform, where it achieves significant improvements over existing methods. Our results demonstrate the potential of BLEEP to provide insights into the molecular mechanisms underlying tissue architecture, with important implications in diagnosis and research of various diseases. The proposed approach can significantly reduce the time and cost associated with gene expression profiling, opening up new avenues for high-throughput analysis of histology images for both research and clinical applications.

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.

Identifying evolutionary correspondences between cell types across species is a fundamental challenge in comparative genomics and evolutionary biology. Existing approaches often rely on either reference-based matching, which imposes asymmetry by designating one species as the reference, or projection-based matching, which may increase computational complexity and obscure biological interpretability at the cell-type level. Here, we present OT-MESH, an unsupervised computational framework leveraging entropy-regularized optimal transport (OT) to systematically determine cross-species cell type homologies. Our method uniquely integrates the Minimize Entropy of Sinkhorn (MESH) technique to refine the OT plan, transforming diffuse transport matrices into sparse, interpretable correspondences. Through systematic evaluation on synthetic datasets, we demonstrate that OT-MESH achieves near-optimal matching accuracy with computational efficiency, while maintaining remarkable robustness to noise. Compared to other OT-based methods like RefCM, OT-MESH provides speedup while achieving comparable accuracy. Applied to retinal bipolar cells (BCs) and retinal ganglion cells (RGCs) from mouse and macaque, OT-MESH accurately recovers known evolutionary relationships and uncovers novel correspondences, one of which was independently validated experimentally. Thus, our framework offers a principled, scalable, and interpretable solution for evolutionary cell type mapping, facilitating deeper insights into cellular specialization and conservation across species.

We present BLEEP (Bi-modaL Embedding for Expression Prediction), a bi-modal embedding framework capable of generating spatially resolved gene expression profiles of whole-slide Hematoxylin and eosin (H&E) stained histology images.

Current molecular generative models primarily focus on improving drug-target binding affinity and specificity, often neglecting the system-level phenotypic effects elicited by compounds. Transcriptional profiles, as molecule-level readouts of drug-induced phenotypic shifts, offer a powerful opportunity to guide molecular design in a phenotype-aware manner. We present PhenoMoler, a phenotype-guided molecular generation framework that integrates a chemistry large language model with expression profiles to enable biologically informed drug design. By conditioning the generation on drug-induced differential expression signatures, PhenoMoler explicitly links transcriptional responses to chemical structure. By selectively masking and reconstructing specific substructures-scaffolds, side chains, or linkers-PhenoMoler supports fine-grained, controllable molecular optimization. Extensive experiments demonstrate that PhenoMoler generates chemically valid, novel, and diverse molecules aligned with desired phenotypic profiles. Compared to FDA-approved drugs, the generated compounds exhibit comparable or enhanced drug-likeness (QED), optimized physicochemical properties, and superior binding affinity to key cancer targets. These findings highlight PhenoMoler's potential for phenotype-guided and structure-controllable molecular optimization.

The generation of high-quality candidate molecules remains a central challenge in AI-driven drug design. Current phenotype-based and target-based strategies each suffer limitations, either incurring high experimental costs or overlook system-level cellular responses. To bridge this gap, we propose ExMoIRL, a novel generative framework that synergistically integrates phenotypic and target-specific cues for de novo molecular generation. The phenotype-guided generator is first pretrained on expansive drug-induced transcriptional profiles and subsequently fine-tuned via multi-objective reinforcement learning (RL). Crucially, the reward function fuses docking affinity and drug-likeness scores, augmented with ranking loss, prior-likelihood regularization, and entropy maximization. The multi-objective RL steers the model toward chemotypes that are simultaneously potent, diverse, and aligned with the specified phenotypic effects. Extensive experiments demonstrate ExMoIRL's superior performance over state-of-the-art phenotype-based and target-based models across multiple well-characterized targets. Our generated molecules exhibit favorable drug-like properties, high target affinity, and inhibitory potency (IC50) against cancer cells. This unified framework showcases the synergistic potential of combining phenotype-guided and target-aware strategies, offering a more effective solution for de novo drug discovery.