Biology subjects

Regmi, B.

Publications and source records attributed to Regmi, B..

5 recordsLinked to original sources

bioRxiv2025

Dysregulation of U12-Type Splicing in Lupus Neutrophils

ObjectiveNeutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and post-transcriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing. MethodsLDGs and normal-density neutrophils (NDGs) were isolated from SLE patients and healthy controls (HCs). CYBA (P22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes. ResultsCYBA expression was reduced in SLE LDGs (n=11) compared to SLE NDGs and HCs (n=6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n=7 SLE, n=12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad downregulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-- including exon skipping and mutually exclusive exon use--in genes such as GBP5, MAEA and STX10. These abnormalities were validated in an independent long-read RNA-seq dataset from SLE PBMCs. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles. ConclusionImpaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.

immunology↗

bioRxiv2024

TGF-β expressed by M2 macrophages promotes wound healing by inhibiting TSG-6 expression by mesenchymal stem cells

Wound healing involves the collaboration of multiple cells, including macrophages and fibroblasts, and requires the coordination of cytokines, growth factors, and matrix proteins to regulate the repair response. In this study, we investigated how M2 macrophages regulate expression of the anti-fibrotic and anti-inflammatory regulator tumor necrosis factor- (TNF-)-stimulated gene 6 (TSG-6) secreted by adipose tissue-derived stem cells (ASCs) during wound healing. Interleukin (IL)-4/IL-13, which is used to differentiate macrophage M2 phenotypes, increases TSG-6 in ASCs; however, M2 macrophages significantly decrease TSG-6 in ASCs. Transforming growth factor (TGF)-{beta} expression was increased, and TNF- expression was decreased in M2 macrophages. TGF-{beta} inhibited IL-4/IL-13-induced ASC TSG-6 expression. In addition, TSG-6 suppressed TGF-{beta}-triggered wound closure and fibrogenic responses in LX-2 cells. Collectively, TSG-6 inhibited wound healing, but M2 macrophage-expressed TGF-{beta} prevented TSG-6 production from ASCs, which ultimately helped wound healing. Our results indicate that the balance of TNF- and TGF-{beta} levels during wound healing regulates TSG-6 production from ASCs, which may ultimately modulate the healing process. Our study findings could contribute to novel therapeutic strategies that manipulate the delicate balance between TNF- and TGF-{beta} to enhance wound repair and mitigate fibrosis.

cell biology↗

bioRxiv2023

RichPathR: a gene set enrichment analysis and visualization tool

Gene set enrichment analysis (GSEA) is an important step for disease and drug discovery. Genomic, transcriptomics, proteomics and epigenetic analysis of tissue or cells generates gene lists that need to be further investigated in the known biological context. The advent of high-throughput technologies generates the vast number of gene lists that are up or down regulated together. One way of getting meaningful insights of the relationship of these genes is utilizing existing knowledge bases linking them with biological functions or phenotypes. Multiple public databases with annotated gene sets are available for GSEA, and enrichR is the most popular web application still requiring custom tools for large-scale mining. richPathR package is a collection of R functions that helps researchers carry out exploratory analysis and visualization of gene set enrichment using EnrichR. AvailabilityThe package, test data and additional figures can be downloaded from https://github.com/niams-bdmds/richPathR.git. Contactsunh1@nih.gov

bioinformatics↗

bioRxiv2021

Parallel adaptations to an altitudinal gradient persist in tetraploid snowtrout (Cyprinidae: Schizothorax), despite extensive genomic exchange within adjacent Himalayan rivers

The recurrence of similar evolutionary patterns within different habitats often reflects parallel selective pressures acting upon either standing or independently occurring genetic variation to produce a convergence of phenotypes. This interpretation (i.e. parallel divergences within adjacent streams) has been hypothesized for drainage-specific morphological ecotypes observed in polyploid snowtrout (Cyprinidae: Schizothorax). However, parallel patterns of differential introgression during secondary contact is a viable alternative hypothesis. Here, we utilized ddRADseq (N=35,319 de-novo and N=10,884 transcriptome-aligned SNPs), as derived from Nepali/Bhutanese samples (N=48 each), to test these competing hypotheses. We first employed genome-wide allelic depths to derive appropriate ploidy models, then a Bayesian approach to yield genotypes statistically consistent under the inferred expectations. Elevational ecotypes were consistent in geometric-morphometric space, but with phylogenetic relationships at the drainage-level, sustaining an hypothesis of independent emergence. However, partitioned analyses of phylogeny and admixture identified subsets of loci under selection that retained genealogical concordance with morphology, suggesting instead that apparent patterns of morphological/phylogenetic discordance are driven by widespread genomic homogenization. Here, admixture occurring in secondary contact effectively masks previous isolation. Our results underscore two salient factors:1) Morphological adaptations are retained despite hybridization; and 2) The degree of admixture varies across tributaries, presumably concomitant with underlying environmental or anthropogenic factors.

evolutionary biology↗

bioRxiv2020

Did the Himalayan Uplift Drive Evolution of Aquatic Biodiversity Across Asia? Snowtrout (Cyprinidae: Schizothorax) as a Test Case

The Himalayan uplift, a tectonic event of global importance, seemingly disseminated aquatic biodiversity broadly across Asia. But surprisingly, this hypothesis has yet to be tested. We do so herein by sequencing 1,140 base-pair of mtDNA cytochrome-b for 72 tetraploid Nepalese/Bhutanese Snowtrout (Schizothorax spp.), combining those data with 67 GENBANK(R) sequences (59 ingroup/8 outgroup), then reconstructing phylogenetic relationships using maximum likelihood/ Bayesian analyses. Results indicate Snowtrout originated in Central Asia, dispersed across the Qinghai-Tibetan Plateau (QTP), then into Bhutan via south-flowing tributaries of the east-flowing Yarlung-Tsangpo River (YLTR). The headwaters of five large Asian rivers provided dispersal corridors into southeast Asia. South of the Himalaya, the YLTR transitions into a westward-flowing Brahmaputra River that facilitated successive colonization of Himalayan drainages: First Bhutan, then Nepal, followed by far-western drainages subsequently captured by the Indus River. We found greater species-divergences across rather than within-basins, implicating vicariant evolution as a driver. The Himalaya is a component of the "third-pole" [Earths largest (but rapidly shrinking) glacial reservoir outside the Arctic/Antarctic]. Its unique aquatic biodiversity must not only be recognized (as herein) but also conserved through broad, trans-national collaborations. Our results effectively contrast phylogeography with taxonomy as a necessary first step in this process. The Himalaya is the most extensive and recently evolved mountain system on Earth (length=2400km; width=240km; elevation=75-8800m), with a global significance underscored by its large-scale lithospheric, cryospheric, and atmospheric interactions [1]. These have not only driven global climate, but also defined the cultural and biological endemism of the region [2]. Massive, tectonically derived mountain chains such as the Alps and the Himalaya are hypothesized as being fundamental to the formation of global biodiversity gradients via vicariance and local adaptation, with a significantly stronger signal in terrestrial rather than aquatic systems [3]. Here we test how orogeny (the deformation and folding of Earths crust by lateral compression) has contributed to the diversification of freshwater fishes broadly across Asia. We do so by evaluating the phylogeography of an endemic high-elevation fish, the Snowtrout (Schizothorax: Cyprinidae).

evolutionary biology↗