Biology subjects

Chopra, K.

Publications and source records attributed to Chopra, K..

8 recordsLinked to original sources

bioRxiv2026

A Spatio-Temporal Analysis Framework for Characterizing Radiation-Induced Genomic Instability

Chronic low-dose ionizing radiation induces complex genomic instability encompassing both structural variants and point mutations, yet these alterations are typically analyzed as independent events, limiting detection of mechanistic coupling between rearrangement formation and localized mutagenesis at breakpoint junctions. This gap is particularly consequential given the widespread occupational and environmental exposure contexts such as nuclear energy, medical imaging, and environmental contamination, where coupled genomic alterations may contribute to cancer risk through mechanisms invisible to type-agnostic analyses. We developed an integrated analytical framework combining temporal pattern tracking, breakpoint-proximal mutation enrichment analysis, and systematic testing across all structural variant types to resolve these coupled dynamics across dose and time. Applying this framework to whole-genome sequencing data from primary human endothelial cells (HUVEC) exposed to chronic low-dose gamma radiation (0.20-2.62 mGy/hr) over three weeks, we identified inversion-specific mutagenic coupling; doublet base substitutions (DBS) were 7.13-fold enriched within 10bp of inversion breakpoints, a signal absent from other structural variant types, with sharp distance-dependent decay indicating localized mutagenesis at these junctions. Temporal analysis further revealed divergent fates of co-occurring alterations: inversions appeared transiently while DBS mutations showed greater persistence. These results illustrate how systematic integration of dose, time, and variant-type dimensions can uncover coupled mutagenic mechanisms that remain invisible in static or type-agnostic analyses. The framework is broadly applicable to longitudinal sequencing studies of genotoxic exposures, with applications to cancer genomics, radiation risk assessment, and mechanistic studies of DNA repair fidelity.

bioinformatics↗

bioRxiv2026

Interpretable transcriptome-to-phenotype modeling of cell-painting nuclear morphology features from RNA-seq under low-dose radiation exposure

With rapid advancements in high-throughput multi-modal profiling techniques across molecular, cellular to tissue scales, translating such multi-modal data into knowledge discovery for foundational understanding of cellular mechanisms is central in modern biomedical sciences. In this study, we focus on understanding how low-dose radiation exposure perturbs cellular morphology by linking high-dimensional transcriptomic responses to quantitative cell-phenotype readouts over time. We present a time-resolved inverse modeling framework that associates gene expression changes via RNA-sequencing with nuclear morphology features obtained from cell-painting imaging. Morphology responses were defined as treated-control differences for multiple nuclear features including size, shape, intensity, and textures, indexed by radiation dose and week. To capture time-dependent associations while maintaining interpretability, both RNA-sequencing and cell-painting data were stratified into four temporal phases (weeks 1-2, 3-4, 5-6, 7-9) and phase-dependent effects are encoded via gene-phase interaction predictors. To reduce confounding by dose trends and to evaluate generalization across time, we used a two-stage leave-one-week-out procedure: (i) a dose-only baseline model produced out-of-week residuals for each morphology feature, and (ii) elastic-net regression on phase-aware predictors modeled residual variation not explained by dose. Hyperparameters were selected via an exhaustive grid search scored by the correlation between observed residuals and out-of-week residual predictions, with additional sparsity diagnostics based on nonzero coefficient counts per fold. Stable predictors were identified by selection frequency and sign consistency across folds, then pruned further for multicollinearity and parsimony. Final reduced models were fit using ordinary least squares with heteroskedasticity-consistent standard errors to report effect estimates robust to non-constant variance. This workflow yields a transparent, time-stratified set of transcriptomic predictors associated with longitudinal nuclear morphology changes and provides a reproducible foundation for downstream biological interpretation and validation.

bioinformatics↗

bioRxiv2026

Strain-specific response to pharmacological cold mimicking in aging mice

BackgroundAging impairs thermogenic and metabolic flexibility, increasing metabolic disease risk. We examined six aging male mouse strains for responses to chronic topical menthol, a pharmacological cold mimetic. Material and methodsMale (C57BL/6J, A/J, BALB/c, C3H/hej, DBA/2J, and FVB/NJ) mice were treated with 4g/kg of 10% menthol weight per volume cream once per day or vehicle as control using finger application for 15 days. After last application, core body temperature measurement, BAT thermography, Nesting behaviour, and metabolic tolerance test were performed, and gene expression was analysed in BAT. ResultsMenthol improved core temperature recovery via thermogenesis and enhanced insulin sensitivity across all strains. However, effects on BAT mass, nesting behaviour, and gluconeogenesis were strain-dependent. ConclusionCollectively, these findings highlight that genetic background modulates metabolic responses to cold mimetics, informing future precision strategies for age-related metabolic disorders.

pharmacology and toxicology↗

bioRxiv2026

Role of brown adipose tissue-specific sympathetic and sensory innervations in menthol-induced energy-expending phenotype

Menthol, a TRPM8 agonist and pharmacological cold mimic, activates brown adipose tissue (BAT) to increase adaptive thermogenesis and whole-body energy expenditure. BAT is highly innervated with sensory and sympathetic nerve fibers. There is existing literature that sympathetic nerves have a critical role in regulating menthols (or cold) effect on energy homeostasis, but there is minimal literature about the involvement of somatosensory innervations. Here, we ought to investigate whether short-term topical application (3 days) of menthol elicits sympathetic and sensory nerves. We used chemical denervation models of complete (100 mg/kg; 6-OHDA and 125 mg/kg; capsaicin, s.c.) and localized (in BAT, 20 {micro}L of 6-OHDA (20 mg/ml) and 20{micro}L of capsaicin (20{micro}g/{micro}L) in each BAT lobe) ablation of sympathetic (6-OHDA) and sensory (capsaicin) innervations to explore their roles in menthol induced BAT activation and energy expanding phenotype. In the present study we have shown that (i) short-term topical application of menthol (10 % menthol for 3 consecutive days) elicits sympathetic and sensory innervations, and induces thermogenesis, lipolysis and mitochondrial biogenesis in mice BAT; (ii) localized ablation of sympathetic innervation prevented menthol induced BAT activation and lipolysis (iii) localized ablation of sensory neurons augments sympathetic innervations induced BAT activation and modulated thermoregulation. Collectively, our results suggest that BAT activation following short-term topical application of menthol is dependent primarily but not exclusively on centrally mediated SNS activation. TRPV1-positive sensory neurons are partially necessary for thermoregulation and efficient BAT activation.

pharmacology and toxicology↗

bioRxiv2021

Colon Innervating TRPA1 Positive Nociceptors Influence Mucosal Health In Mice

IntroductionTransient receptor potential ankyrin-1 positive (TRPA1+ve) nociceptors, primarily present as peptidergic neuronal afferents in the colon are sensors of disturbance in lower gastrointestinal tract including pain induced by different pathologies. Their therapeutic role in the alleviation of chronic pain (receptor antagonism and receptor desensitization) associated with inflammatory bowel diseases (IBD) is reported. However, there is limited literature available about their role in formation and sustenance of the mucosal layer, and its interaction with host physiology as well as luminal microbial community. The aim of this study focuses on the effects of nociceptive TRPA1 channel desensitization on colonic mucus production and gut health. MethodsTRPA1+ve nociceptors were desensitized by rectal administration of capsazepine. Ileum, colon was harvested and cecum content was collected. We performed morphological/histological analysis, gut permeability alteration, gene expression changes, colon metabolite profiling, and gut microbial abundance in these animals. ResultsWe found that presence of TRPA1-positive nociceptors is required for mucus layer integrity, using an intra-rectal capsazepine-induced TRPA1 desensitization model. Desensitization of TRPA1 positive nociceptors resulted in damaged mucosal lining, resultant increase in gut permeability and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. ConclusionThese results suggest that caution may need to be exercised before employing TRPA1 desensitization as a therapeutic option to alleviate pain caused due to IBD.

pharmacology and toxicology↗

bioRxiv2021

The roles of NADPH oxidases during adult zebrafish fin regeneration

Sustained elevated levels of reactive oxygen species (ROS) have been shown to be essential for whole body, appendage and organ regeneration in various organisms, including planarians, Hydra, zebrafish, axolotl, Xenopus, geckos and mice. In the majority of cases these roles have been shown via the use of NADPH oxidase pharmacological inhibitors, which generally target all NAPDH oxidases (NOXes). To identify the specific NOX or NOXes essential for ROS production during adult fin regeneration in zebrafish, we generated nox mutants for duox, nox5 and cyba (a key subunit of NOXes 1-4). We also crossed these mutant lines to a transgenic line ubiquitously expressing HyPer, which permits the measurement of ROS levels in adult zebrafish fins. Using this approach, we found that homozygous duox mutants have significantly attenuated ROS levels following fin amputation, and this correlated with a significantly diminished rate of fin regeneration. While the other nox homozygous mutants (nox5 and cyba) showed less of an effect on ROS levels or adult fin regeneration, duox/cyba double mutants showed a more diminished rate of fin regeneration than duox mutants alone, suggesting that Nox1-4 do play a role during regeneration, but one that is secondary to that of Duox. This work also serendipitously found that ROS levels in amputated adult zebrafish fins oscillate during the day with a circadian rhythm.

developmental biology↗

bioRxiv2019

CoRNeA: A pipeline to decrypt the protein-protein interaction from amino acid sequence information

Computational methods have been devised in the past to predict the interface residues using amino acid sequence information but have been majorly applied to predict for prokaryotic protein complexes. Since the composition and rate of evolution of the primary sequence are different between prokaryotes and eukaryotes, it is important to develop a method specifically for eukaryotic complexes. Here we report a new hybrid pipeline for the prediction of protein-protein interaction interfaces from the amino acid sequence information alone based on the framework of Co-evolution, machine learning (Random forest) and Network Analysis named CoRNeA trained specifically on eukaryotic protein complexes. We incorporate the intra contact information of the individual proteins to eliminate false positives from the predictions as the amino acid sequence also holds information for its own folding along with the interface propensities. Our prediction on various case studies shows that CoRNeA can successfully identify minimal interacting regions of two partner proteins with higher precision and recall.

bioinformatics↗

bioRxiv2018

Zebrafish duox mutations provide a model for human congenital hypothyroidism

Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidase, DUOX1 and DUOX2. Indeed mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles of the single duox gene in zebrafish, sa9892 and sa13017. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine the external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from the early larval stage, when T4 levels are already noticeably absent in the mutants. Loss of T4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia / external goiter, and infertility. Remarkably all of these defects associated with chronic congenital hypothyroidism could be rescued with T4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advance stages of development.

developmental biology↗