GeneQuery: A General QA-based Framework for Spatial Gene Expression Predictions from Histology Images

Gene expression profiling provides profound insights into molecular mechanisms, but its time-consuming and costly nature often presents significant challenges. In contrast, whole-slide hematoxylin and eosin (H&E) stained histological images are readily accessible and allow for detailed examinations of tissue structure and composition at the microscopic level. Recent advancements have utilized these histological images to predict spatially resolved gene expression profiles. However, state-of-the-art works treat gene expression prediction as a multi-output regression problem, where each gene is learned independently with its own weights, failing to capture the shared dependencies and co-expression patterns between genes. Besides, existing works can only predict gene expression values for genes seen during training, limiting their ability to generalize to new, unseen genes. To address the above limitations, this paper presents GeneQuery, which aims to solve this gene expression prediction task in a question-answering (QA) manner for better generality and flexibility. Specifically, GeneQuery takes gene-related texts as queries and whole-slide images as contexts and then predicts the queried gene expression values. With such a transformation, GeneQuery can implicitly estimate the gene distribution by introducing the gene random variable. Besides, the proposed GeneQuery consists of two architecture implementations, i.e., spot-aware GeneQuery for capturing patterns between images and gene-aware GeneQuery for capturing patterns between genes. Comprehensive experiments on spatial transcriptomics datasets show that the proposed GeneQuery outperforms existing state-of-the-art methods on known and unseen genes. More results also demonstrate that GeneQuery can potentially analyze the tissue structure.

DiffDTM: A conditional structure-free framework for bioactive molecules generation targeted for dual proteins

Advances in deep generative models shed light on de novo molecule generation with desired properties. However, molecule generation targeted for dual protein targets still faces formidable challenges including protein 3D structure data requisition for model training, auto-regressive sampling, and model generalization for unseen targets. Here, we proposed DiffDTM, a novel conditional structure-free deep generative model based on a diffusion model for dual targets based molecule generation to address the above issues. Specifically, DiffDTM receives protein sequences and molecular graphs as inputs instead of protein and molecular conformations and incorporates an information fusion module to achieve conditional generation in a one-shot manner. We have conducted comprehensive multi-view experiments to demonstrate that DiffDTM can generate drug-like, synthesis-accessible, novel, and high-binding affinity molecules targeting specific dual proteins, outperforming the state-of-the-art (SOTA) models in terms of multiple evaluation metrics. Furthermore, we utilized DiffDTM to generate molecules towards dopamine receptor D2 and 5-hydroxytryptamine receptor 1A as new antipsychotics. The experimental results indicate that DiffDTM can be easily plugged into unseen dual targets to generate bioactive molecules, addressing the issues of requiring insufficient active molecule data for training as well as the need to retrain when encountering new targets.