Biology subjects

Khandekar, N.

Publications and source records attributed to Khandekar, N..

3 recordsLinked to original sources

bioRxiv2025

Epithelial and stromal remodeling in murine Crohn's disease-like ileitis

Background and AimsInflammatory bowel disease is characterized by progressive epithelial, immune, and stromal dysfunction. Human datasets yield important insights yet are inherently descriptive, requiring animal models for in vivo mechanistic interrogation. The SAMP1/YitFc (SAMP) mouse model develops spontaneous Crohns disease (CD)-like ileitis while allowing controlled manipulation of pathophysiologic pathways. To understand cell-specific disease-associated transcriptional changes, we defined the single-nucleus transcriptomes of inflamed SAMP ilea using single-nucleus RNA-sequencing (snRNA-seq). MethodsWe performed whole-ileum snRNA-seq on SAMP (n=4) and control AKR/J (n=3) mice using the gut-optimized CitraPrep protocol, generating 58,349 high-quality nuclei across epithelial, immune, and stromal lineages. We corroborated SAMP-associated changes with immunofluorescent staining, Western blotting, spatial transcriptomic, and human single-cell RNA-sequencing data. ResultsWe observed a primary type 2 immune phenotype in SAMP compared to AKR mice, but most transcriptional changes occurred in stromal and epithelial, not immune, cells. Stromal remodeling included increased fibroblast-derived Igf1. In SAMP epithelium, expansion of tuft cells and emergence of SAMP-specific Pcsk6+ crypt enterocytes were observed and confirmed in human CD patients. Finally, we identified cross-compartmental changes in cell-cell signaling, including enterocyte-to-type 3 innate lymphoid cell (ILC3) communication and enhanced global Igf1 signaling. These features recapitulate known, as well as novel, characteristics of CD and extend our understanding of disease-associated multicellular networks. ConclusionThis atlas of ileitis-prone SAMP mice provides a high-resolution resource for dissecting conserved and novel mechanisms of inflammation and tissue remodeling. Herein, we uncover disease-associated transcriptional changes conserved in human CD, presenting a translational platform for future mechanistic and therapeutic studies.

molecular biology↗

bioRxiv2025

NoisyFlow: Differentially Private Optimal Transport Using Neural Networks for Secure Biomedical Data Sharing

MotivationAdvancing data sharing in biomedical research, particularly for sensitive genomic and clinical datasets, is crucial for improving model performance across diverse patient populations. However, stringent privacy concerns hinder collaboration and limit insights derived from multi-institutional datasets. Current approaches to privacy-preserving data sharing fail to address gaps between data distributions. ResultsWe introduce NoisyFlow, a differentially private neural network-based optimal transport framework designed to enable secure and unbiased biomedical data sharing. By integrating optimal transport theory with neural networks and differential privacy mechanisms, our framework aligns data distributions across institutions while preserving individual privacy. NoisyFlow eliminates the need for direct data sharing and reduces distribution shifts caused by covariate and batch effects. Empirical evaluations demonstrate the frameworks effectiveness in handling high-dimensional single-cell genomic data and histopathology images, achieving superior privacy guarantees while maintaining high utility in downstream tasks such as disease classification. Availability and implementationThe implementation of NoisyFlow is available at https://github.com/liyy2/NoisyFlow. Contactmark@gersteinlab.org. Supplementary informationSupplementary data are available online.

bioinformatics↗

bioRxiv2024

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma(R), utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with some antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with an antibody escape phenotype, with the potential to expand the patient cohort treatable with AAV9 vectors to include those that were previously excluded due to their pre-existing neutralizing antibodies, and possibly also to those requiring redosing.

immunology↗