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Khinvasara, K.

Publications and source records attributed to Khinvasara, K..

2 recordsLinked to original sources

Bloom unifies brain cell representations across modalities and contexts

Multimodal genomic datasets now profile mammalian brain cells across anatomical regions, developmental stages, disease states, and species. Learning shared representations that capture cellular diversity across these heterogeneous observations remains a central challenge. Here, we introduce Bloom, a transformer-based model that represents cells using gene expression, chromatin accessibility, or both. Bloom is trained on 300,000 adult mouse brain cells with paired measurements, randomly sampled with broad-subclass balancing--approximately 100-fold fewer cells than used by comparable pre-trained models. By combining genomic sequence embeddings with randomly sampled multimodal cell views, Bloom outperforms unimodal cell models in resolving brain-wide cell types and in annotation, regression, and label-transfer tasks. Its attention patterns reveal cell-type-dependent associations among genomic loci, including pairs separated by millions of base pairs. These results establish Bloom as a data-efficient framework for integrating multimodal brain cell measurements and generating hypotheses about cell-type-specific genomic relationships.

bioinformatics↗

Mapping the immune landscape in small cell lung cancer unveils a distinct tumor-reactive CD8+ T cell molecular signature

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic advances. Unlike many other cancers, its immune landscape, particularly immune competence and T cell recognition, remains poorly characterized. Here, we generate a single-cell transcriptome atlas of the SCLC immune microenvironment with paired T cell receptor (TCR) sequencing. By linking T cell states with clonality and a multilayered functional screening, we identify 6 tumor-reactive TCRs that recognize and eradicate autologous SCLC cell lines. We delineate a novel SCLC-reactive CD8+ T cell signature (SCLC_TR), enabling the identification of 47 further SCLC-reactive TCRs. The SCLC_TR signature performs extremely well in pancreatic ductal adenocarcinoma (PDAC), another immune-cold tumor indication, and, most strikingly, patients with elevated SCLC_TR signature scores exhibited significantly improved survival, underlining its prognostic potential. Comparative cell-cell interaction analyses implicate several immunosuppressive mechanisms, with myeloid cells and CD4 regulatory T cells possibly acting as counterbalances to effector T cell activity in SCLC. In summary, our study challenges the prevailing notion of SCLC as an immune-cold tumor type by providing direct evidence of tumor-reactive T cell responses and introduces the SCLC_TR signature as a tool to identify tumor-specific T cells and their microenvironmental restraints and escape mechanisms, ultimately shaping next-generation immunotherapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/735200v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1c25f2eorg.highwire.dtl.DTLVardef@1f6f519org.highwire.dtl.DTLVardef@553e57org.highwire.dtl.DTLVardef@6fe7e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗