Phosphorothioate antisense oligonucleotides induce the formation of nuclear bodies

Antisense oligonucleotides are powerful tools for the in vivo regulation of gene expression. We have characterized the intracellular distribution of fluorescently tagged phosphorothioate oligodeoxynucleotides (PS-ONs) at high resolution under conditions in which PS-ONs have the potential to display antisense activity. Under these conditions PS-ONs predominantly localized to the cell nucleus where they accumulated in 20-30 bright spherical foci designated phosphorothioate bodies (PS bodies), which were set against a diffuse nucleoplasmic population excluding nucleoli. PS bodies are nuclear structures that formed in cells after PS-ON delivery by transfection agents or microinjection but were observed irrespectively of antisense activity or sequence. Ultrastructurally, PS bodies corresponded to electron-dense structures of 150-300 nm diameter and resembled nuclear bodies that were found with lower frequency in cells lacking PS-ONs. The environment of a living cell was required for the de novo formation of PS bodies, which occurred within minutes after the introduction of PS-ONs. PS bodies were stable entities that underwent noticeable reorganization only during mitosis. Upon exit from mitosis, PS bodies were assembled de novo from diffuse PS-ON pools in the daughter nuclei. In situ fractionation demonstrated an association of PS-ONs with the nuclear matrix. Taken together, our data provide evidence for the formation of a nuclear body in cells after introduction of phosphorothioate oligodeoxynucleotides

IBDome: an integrated molecular, histopathological, and clinical atlas of inflammatory bowel diseases

Multi-omic and multimodal datasets with detailed clinical annotations offer significant potential to advance our understanding of inflammatory bowel diseases (IBD), refine diagnostics, and enable personalized therapeutic strategies. In this multi-cohort study, we performed an extensive multi-omic and multimodal analysis of 1,002 clinically annotated IBD patients and non-IBD controls, incorporating whole-exome and RNA sequencing of normal and inflamed gut tissues, serum proteomics, and histopathological assessments from images of H&E-stained tissue sections. Transcriptomic profiles of normal and inflamed tissues revealed distinct site-specific inflammatory signatures in Crohn’s disease (CD) and ulcerative colitis (UC). Leveraging serum proteomics, we developed an inflammatory protein severity signature that reflects underlying intestinal molecular inflammation. Furthermore, foundation model-based deep learning accurately predicted histologic disease activity scores from images of H&E-stained intestinal tissue sections, offering a robust tool for clinical evaluation. Our integrative analysis highlights the potential of combining multi-omics and advanced computational approaches to improve our understanding and management of IBD