Spatial transcriptomics technologies can be used to align transcriptomes with histopathological morphology, presenting exciting new opportunities for biomolecular discovery. Using spatial transcriptomic gene expression and corresponding histology data, we construct a novel framework, GeneFlow, to map single- and multi-cell gene expression onto paired cellular images. By combining an attention-based RNA encoder with a conditional UNet guided by rectified flow, we generate high-resolution images with different staining methods (e.g., H\&E, DAPI) to highlight various cellular/ tissue structures. Rectified flow with high-order ODE solvers creates a continuous, bijective mapping between expression and image manifolds, addressing the many-to-one relationship inherent in this problem. Our method enables the generation of realistic cellular morphology features and spatially resolved intercellular interactions under genetic or chemical perturbations. This enables minimally invasive disease diagnosis by revealing dysregulated patterns in imaging phenotypes. Our rectified flow based method outperforms diffusion methods and baselines in all experiments. Code is available at https://github.com/wangmengbo/GeneFlow.

Causal discovery from observational data is a fundamental task in artificial intelligence, with far-reaching implications for decision-making, predictions, and interventions. Despite significant advances, existing methods can be broadly categorized as constraint-based or score-based approaches. Constraint-based methods offer rigorous causal discovery but are often hindered by small sample sizes, while score-based methods provide flexible optimization but typically forgo explicit conditional independence testing. This work explores a third avenue: developing differentiable $d$-separation scores, obtained through a percolation theory using soft logic. This enables the implementation of a new type of causal discovery method: gradient-based optimization of conditional independence constraints. Empirical evaluations demonstrate the robust performance of our approach in low-sample regimes, surpassing traditional constraint-based and score-based baselines on a real-world dataset. Code implementing the proposed method is publicly available at [https://github.com/PurdueMINDS/DAGPA](https://github.com/PurdueMINDS/DAGPA).

Single-cell transcriptomics has revolutionized our understanding of cellular heterogeneity and drug perturbation effects. However, its high cost and the vast chemical space of potential drugs present barriers to experimentally characterizing the effect of chemical perturbations in all the myriad cell types of the human body. To overcome these limitations, several groups have proposed using machine learning methods to directly predict the effect of chemical perturbations either across cell contexts or chemical space. However, advances in this field have been hindered by a lack of well-designed evaluation datasets and benchmarks. To drive innovation in perturbation modeling, the Open Problems Perturbation Prediction (OP3) benchmark introduces a framework for predicting the effects of small molecule perturbations on cell type-specific gene expression. OP3 leverages the Open Problems in Single-cell Analysis benchmarking infrastructure and is enabled by a new single-cell perturbation dataset, encompassing 146 compounds tested on human blood cells. The benchmark includes diverse data representations, evaluation metrics, and winning methods from our "Single-cell perturbation prediction: generalizing experimental interventions to unseen contexts" competition at NeurIPS 2023. We envision that the OP3 benchmark and competition will drive innovation in single-cell perturbation prediction by improving the accessibility, visibility, and feasibility of this challenge, thereby promoting the impact of machine learning in drug discovery.

The advances of single-cell DNA sequencing (scDNA-seq) enable us to characterize the genetic heterogeneity of cancer cells. However, the high noise and low coverage of scDNA-seq impede the estimation of copy number variations (CNVs). In addition, existing tools suffer from intensive execution time and often fail on large datasets. Here, we propose SeCNV, an efficient method that leverages structural entropy, to profile the copy numbers. SeCNV adopts a local Gaussian kernel to construct a matrix, depth congruent map (DCM), capturing the similarities between any two bins along the genome. Then, SeCNV partitions the genome into segments by minimizing the structural entropy from the DCM. With the partition, SeCNV estimates the copy numbers within each segment for cells. We simulate nine datasets with various breakpoint distributions and amplitudes of noise to benchmark SeCNV. SeCNV achieves a robust performance, i.e. the F1-scores are higher than 0.95 for breakpoint detections, significantly outperforming state-of-the-art methods. SeCNV successfully processes large datasets (>50 000 cells) within 4 min, while other tools fail to finish within the time limit, i.e. 120 h. We apply SeCNV to single-nucleus sequencing datasets from two breast cancer patients and acoustic cell tagmentation sequencing datasets from eight breast cancer patients. SeCNV successfully reproduces the distinct subclones and infers tumor heterogeneity. SeCNV is available at https://github.com/deepomicslab/SeCNV.