Biology subjects

Devkota, R.

Publications and source records attributed to Devkota, R..

8 recordsLinked to original sources

bioRxiv2026

Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity

Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.

immunology↗

bioRxiv2026

Thermal adaptation crosstalk with azole response through lncRNA in Aspergillus fumigatus

Fungal pathogens are adapting to increased temperatures altering host-pathogen interactions, disease patterns, and response to the antimicrobial drugs. Here, we show that thermal adaptation to 42{degrees}C leads to reversible changes in fungal colony size and azole drug response in the human pathogenic fungus Aspergillus fumigatus. Importantly, this adaptation is mediated by the lncRNA, afu-182, whose RNA levels negatively correlate with temperature. Growth at a lower temperature or ectopic upregulation of afu-182 RNA levels reverses the temperature adaptation. Previously, we have shown that {Delta}afu-182 strains produce worse disease outcomes in a murine model of invasive pulmonary aspergillosis (IPA). Here, more importantly, we show that the overexpression of afu-182 in clinically azole-resistant isolates increased survival in a murine model of IPA. Taken together, fungal adaptation to increased temperature leads to a decrease in afu-182 RNA levels that is associated with worse disease outcomes upon azole treatment. This provides a framework to take temperature into account when analyzing the rise in azole MIC in environmental and clinical isolates.

microbiology↗

bioRxiv2026

A long non-coding RNA, afu-254, is required for the oxidative stress response, cell wall stress response, azole susceptibility and virulence in Aspergillus fumigatus

Long non-coding RNAs play an important role in stress response in all forms of life; however, a tight regulation of lncRNAs is required for normal function. Abnormal expression of lncRNA is associated with uncontrolled cell growth in many forms of cancer. Recent studies have highlighted the role of lncRNAs in Aspergillus fumigatus in azole stress response and virulence. Here, using a transcriptome dataset of A. fumigatus response to stress, we identified afu-254 as an 854bp lncRNA that plays a role in modulating oxidative stress, fungal sub-MIC azole response to posaconazole and itraconazole, cell wall stress, macrophage phagocytosis and killing ex vivo, and virulence in an invertebrate model of Aspergillus infection. Importantly, afu-254 does not produce cross-azole susceptible response and plays a role in fungal azole response against posaconazole and itraconazole but not voriconazole. Furthermore, we showed that stochiometric levels of afu-254 are important for its function, and ectopic overexpression of afu-254 in the WT strain leads to an antimorph. This phenotype may stem from a higher ordered structure that is denatured with heat, indicating the presence of a non-functional isoform. In conclusion, we characterized a novel lncRNA, afu-254, that is important for stress response and virulence in the pathogenic fungus A. fumigatus. ImportanceFailure of azole treatment for invasive Aspergillus infection by both drug-resistant and drug-sensitive isolates is an area of concern and global importance. Fungal stress response is multifaceted, and long non-coding RNAs have emerged as important players in mediating it, including regulating responses to azole antifungals. Here, we have identified a long non-coding RNA, afu-254, that plays a role in modulating fungal response to oxidative stress, cell wall stress, azole stress, immune cell stress and virulence in an invertebrate model of invasive Aspergillus infection.

microbiology↗

bioRxiv2023

Role of the osaA gene in Aspergillus fumigatus development, secondary metabolism and virulence.

Aspergillus fumigatus is the leading cause of aspergillosis, associated with high mortality rates, particularly in immunocompromised individuals. In search of novel genetic targets against aspergillosis, we studied the WOPR transcription factor OsaA. Deletion of the osaA gene resulted in colony growth reduction. Conidiation is also influenced by osaA; both osaA deletion and overexpression resulted in a decrease in spore production. Wild-type expression levels of osaA are necessary for expression of the conidiation regulatory genes brlA, abaA and wetA. In addition, osaA is necessary for normal cell wall integrity. Furthermore, deletion of osaA resulted in a reduction in the ability of A. fumigatus to adhere to surfaces, decreased thermotolerance, as well as increased sensitivity to oxidative stress. Metabolomics analysis indicated that osaA deletion or overexpression led to alterations in the production of multiple secondary metabolites, including gliotoxin. This was accompanied by changes in the expression of genes in the corresponding secondary metabolite gene clusters. These effects could be, at least in part, due to the observed reduction in the expression levels of the veA and laeA global regulators when the osaA locus was altered. Importantly, our study shows that osaA is indispensable for virulence in both the neutropenic and corticosteroid-immunosuppressed mouse models.

microbiology↗

bioRxiv2023

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism. HighlightsO_LIFALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effects C_LIO_LIFALCON is applicable to many and diverse cell types C_LIO_LIA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidity C_LIO_LINew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for disease C_LIO_LIC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling C_LI

cell biology↗

bioRxiv2021

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPAR{gamma} to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism achieve membrane homeostasis and adapt to a variable environment.

cell biology↗

bioRxiv2020

Genome wide identification of QTL associated with yield and yield components in two popular wheat cultivars TAM 111 and TAM 112

Two drought-tolerant wheat cultivars, TAM 111 and TAM 112, have been widely grown in the Southern Great Plains of the U.S. and used as parents in many wheat breeding programs worldwide. This study aimed to reveal genetic control of yield and yield components in the two cultivars under both dryland and irrigated conditions. A mapping population containing 124 F5:7 recombinant inbred lines (RILs) was developed from the cross of TAM 112/TAM 111. A set of 5,948 SNPs from the wheat 90K iSelect array and double digest restriction-site associated DNA sequencing was used to construct high-density genetic maps. Data for yield and yield components were obtained from 11 environments. QTL analyses were performed based on 11 individual environments, across all environments, within and across mega-environments. Thirty-six unique consistent QTL regions were distributed on 13 chromosomes including 1A, 1B, 1D, 2A, 2D, 3D, 4B, 4D, 6A, 6B, 6D, 7B, and 7D. Ten unique QTL with pleiotropic effects were identified on four chromosomes and eight were in common with the consistent QTL. These QTL increased dry biomass grain yield by 16.3 g m-2, plot yield by 28.1 g m-2, kernels spike-1 by 0.7, spikes m-2 by 14.8, thousand kernel weight by 0.9 g with favorable alleles from either parent. TAM 112 alleles mainly increased spikes m-2 and thousand kernel weight while TMA 111 alleles increased kernels spike-1, harvest index and grain yield. The saturated genetic map and markers linked to significant QTL from this study will be very useful in developing high throughput genotyping markers for tracking the desirable haplotypes of these important yield-related traits in popular parental cultivars.

genetics↗

bioRxiv2020

AdipoR2 is Essential for Membrane Lipid Homeostasis in Response to Dietary Saturated Fats

Membrane lipid composition influences vital processes in all types of cells. The mechanisms by which cells maintain membrane lipid homeostasis while obtaining most of their constituent fatty acids from a varied diet remain largely unknown. In an attempt to discover such mechanisms, we performed an unbiased forward genetic screen in Caenorhabditis elegans and conclude that the adiponectin receptor 2 (AdipoR2) pathway is essential to prevent saturated fat-mediated cellular toxicity. Transcriptomics, lipidomics and membrane property analyses in human HEK293 cells and primary human endothelial cells further support our conclusion that the essential function of AdipoR2 is to respond to membrane rigidification by promoting fatty acid desaturation. Our results demonstrate that AdipoR2-dependent regulation of membrane homeostasis is a fundamental mechanism conserved from nematodes to mammals that prevents saturated fat-mediated lipotoxicity. ONE SENTENCE SUMMARYThe AdipoR2 protein insures membrane homeostasis in response to dietary saturated fatty acids that promote membrane rigidification.

cell biology↗