Integrating gene regulatory priors into Transformer attention with scTransformer for interpretable scRNA-seq analysis

Motivation: Transformer-based models are increasingly applied to large-scale single-cell transcriptomics, showing strong performance through self-supervised learning on millions of cells. However, most existing approaches treat genes as independent features, and largely ignore prior biological knowledge, which limits interpretability and robustness. In this paper, we explore whether explicitly incorporating gene regulatory information can improve both model performance and biological insight. Results: We present scTransformer, the first Transformer-based approach that builds a priori knowledge of biological mechanisms into the model's attention patterns. By constraining information flow according to known regulatory structures, the model learns representations that are more biologically meaningful. We evaluate scTransformer on a disease-relevant single-nucleus RNA-seq dataset using supervised cell-type classification. Compared to standard Transformers, our approach improves classification accuracy, enhances separation of cell types in embedding space, and produces attention patterns consistent with known regulatory programs. Overall, our results demonstrate that embedding biological structure into Transformer models can enhance interpretability without sacrificing performance, offering a principled step toward biologically grounded foundation models for single-cell omics.

Benchmarking and Explaining Deep Learning Cortical Lesion MRI Segmentation in Multiple Sclerosis

Cortical lesions (CLs) have emerged as valuable biomarkers in multiple sclerosis (MS), offering high diagnostic specificity and prognostic relevance. However, their routine clinical integration remains limited due to subtle magnetic resonance imaging (MRI) appearance, challenges in expert annotation, and a lack of standardized automated methods. We propose a comprehensive multi-centric benchmark of CL detection and segmentation in MRI. A total of 656 MRI scans, including clinical trial and research data from four institutions, were acquired at 3T and 7T using MP2RAGE and MPRAGE sequences with expert-consensus annotations. We rely on the self-configuring nnU-Net framework, designed for medical imaging segmentation, and propose adaptations tailored to the improved CL detection. We evaluated model generalization through out-of-distribution testing, demonstrating strong lesion detection capabilities with an F1-score of 0.64 and 0.5 in and out of the domain, respectively. We also analyze internal model features and model errors for a better understanding of AI decision-making. Our study examines how data variability, lesion ambiguity, and protocol differences impact model performance, offering future recommendations to address these barriers to clinical adoption. To reinforce the reproducibility, the implementation and models will be publicly accessible and ready to use at https://github.com/Medical-Image-Analysis-Laboratory/ and https://doi.org/10.5281/zenodo.15911797.