Biology subjects

Misra, V.

Publications and source records attributed to Misra, V..

4 recordsLinked to original sources

bioRxiv2025

Transglutaminase 2 predicts parasitic worm-mediated protection against hepatic steatosis in obese mice

Parasitic worm infection can mitigate high fat diet-induced chronic inflammation in obese mice by reducing hepatic fat accumulation and improving insulin sensitivity. However, the molecular alterations during infection-mediated regulation of hepatic steatotic events in obesity remain poorly understood. Here, we integrated proteomic and metabolomic analyses of infected obese mice, a functional deworming and interleukin-4c (IL-4c) treated animal model, and an obese patient cohort before and after bariatric surgery to uncover molecular targets/pathways indicative of the regulation of hepatic steatosis by gut Heligmosomoides polygyrus bakeri (H. p. bakeri) helminth infection. Proteomic analysis identified alterations in several molecules related to metabolism and showed elevated levels of transglutaminase 2 (TGM2) proportionate with an infection-regulated lipid load in diet-induced obese (DIO) mice. The role of TGM2 as a reliable predictor of hepatic steatosis was validated using deworming experiments which revealed a decrease in the liver tissue levels of Tgm2 following removal of H. p. bakeri. Further validation showing increase in Tgm2 levels in IL-4c treated mice confirmed its relevance as a general response indicator of type 2 immune response induced by helminth infection. Assessment of circulating TGM2 levels in matched obese patients before and after bariatric surgery revealed no change, indicating that differential expression of TGM2 is a unique functional response to regulation of hepatic steatosis by H. p. bakeri infection. Together, our data show that TGM2 is a unique predictive marker of improvement in hepatic lipid profile and provides additional evidence that parasitic worm infection protects against hepatic steatosis in DIO mice. These findings pave the way for novel therapeutic opportunities to resolve hepatic steatosis and prevent its progression to severe forms of metabolic dysfunction-associated steatotic liver disease, based on TGM2 coupled with mimetics of H. p. bakeri-derived products. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/689654v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1cae718org.highwire.dtl.DTLVardef@9ec0aorg.highwire.dtl.DTLVardef@1679b1corg.highwire.dtl.DTLVardef@f86bc9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

The ER stress transcription factor Luman/CREB3 is a novel regulator of Schwann cell survival and myelinating capacity through the activation of the unfolded protein response and cholesterol biosynthesis pathways

Misfolded protein accumulation in demyelinating disorders or injury can trigger internal endoplasmic reticulum (ER) stress alleviation mechanisms, namely the unfolded protein response (UPR) and cholesterol biosynthesis pathways. Here we demonstrate that the ER stress-associated transcription factor Luman/CREB3, herein called Luman, shown to drive axon regeneration by UPR-dependent regulation of adaptive low-level stress, also positively regulates rat Schwann cell (SC) survival, myelination, the UPR, and cholesterol production in vitro. siRNA knockdown of SC Luman expression decreased SC viability and increased apoptosis 48 hours post-transfection. Dorsal root ganglion (DRG) neuron/SC co-cultures where SCs overexpressed Luman exhibited increased myelination. Simulation of unstressed, mild and moderate ER stress by tunicamycin-mediated UPR induction in SCs, allowed examination of Luman on expression of known UPR regulators, including Xbp1, Xbp1s, CHOP, and pIRE1. They collectively demonstrate a cytoprotective role for Luman under manageable ER stress. Total cholesterol levels and sterol precursor Srebf1 expression, key to myelination, also decreased following Luman knockdown. Finally, levels of mature brain-derived neurotrophic factor (mBDNF), a positive regulator of myelination and also regulated by the UPR, decreased with Luman knockdown. In contrast, pro-apoptotic BDNF precursor (proBDNF) levels increased in Luman-deficient SCs at higher ER stress levels, indicating that any protection Luman confers at moderate ER stress levels is lost upon its reduced expression. In conclusion, a connection between Luman and adaptive beneficial ER stress pathways linked to survival and myelination capacity in SCs exists. These Luman-driven cytoprotective mechanisms including survival and myelination open avenues for targeting this pathway in nerve trauma and myelinating disorders.

neuroscience↗

bioRxiv2020

Proteogenomic analysis unveils the HLA Class I presented immunopeptidome in melanoma and EGFR mutant lung adenocarcinoma

Immune checkpoint inhibitor and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential for cancers with high tumor mutation burden (TMB). Here, we employed mass spectrometry (MS)-based proteogenomic large-scale profiling to identify potential immunogenic human leukocyte antigen (HLA) Class I-presented peptides in both melanoma, a "hot tumor" with high TMB, and EGFR mutant lung adenocarcinoma, a "cold tumor" with low TMB. We identified several classes of neopeptides, including mutated neoantigens and more than 1000 post-translationally modified peptides representing 58 different PTMs. We constructed a cancer germline (CG) antigen database with 285 antigens and identified 42 Class I-presented CG antigens. Finally, we developed a non-canonical peptide discovery pipeline to identify 44 lncRNA-derived peptides and validated Class I binding for select neopeptides. We provide direct evidence of HLA Class I presentation of a large number of neopeptides for potential vaccine or adoptive cell therapy in melanoma and mutant EGFR lung cancer.

immunology↗

bioRxiv2017

Fungus causing White-Nose Syndrome in bats accumulates genetic variability in North America and shows no sign of recombination

Emerging fungal diseases of wildlife are on the rise worldwide (3) and the best lens on the evolution of the fungal pathogens is population genomics. Our genome-wide analysis shows that the newly introduced North American population of Pseudogymnoascus destructans, the causal agent of White-Nose Syndrome (WNS) in bats, has expanded in size, has begun to accumulate variation through mutation, and presents no evidence as yet for genetic exchange and recombination among individuals.

evolutionary biology↗