Biology subjects

Shah, A. A.

Publications and source records attributed to Shah, A. A..

15 recordsLinked to original sources

bioRxiv2026

A mast cell receptor is associated with fibrosis and itch in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by symmetric fibrosis of the skin and multiple internal organs. The mechanisms that trigger early fibrotic changes remain unclear. Mast cells are known to infiltrate human SSc lesional skin in early disease stages, yet the role of mast cells in initiating fibrosis and pruritus in SSc remains debated, in part due to unclear pathways of mast cell activation. Here, we show that mast cells, via the receptor Mrgprb2, contribute to fibrosis in the bleomycin (BLM)-induced skin fibrosis mouse model. Mast cells accumulate in the skin of BLM-treated wild-type (WT) but not Mrgprb2-knockout (Mrgprb2-/-) mice. Mrgprb2-/- mice show attenuated disease severity, with reduced collagen deposition and lower expression of matrix metalloproteinases and inflammatory markers associated with fibrosis. BLM treatment also increases pruritus in WT mice in the early stages of the model; an effect reduced in Mrgprb2-/- mice. This is the first report of itch in this model of skin fibrosis, further linking it to clinical SSc, where pruritus is an early and prevalent symptom affecting nearly half of patients. In a parallel human cohort, lesional SSc skin harbors significantly more mast cells than paired non-lesional skin from the same patients, demonstrating that mast cell accumulation is specific to affected tissue. Lesional mast cell counts also track with skin disease severity, correlating with modified Rodnan skin score and patient-reported skin tightness. Together, these findings implicate Mrgprb2-mediated mast cell activity in both fibrosis and pruritus in SSc, highlighting mast cells as a candidate therapeutic target in this understudied disease process.

immunology↗

bioRxiv2026

Proteome wide serology reveals immune defined subtypes of gastrointestinal disease in systemic sclerosis

BackgroundGastrointestinal (GI) involvement in systemic sclerosis (SSc) affects up to 90% of patients and is a major driver of morbidity and mortality. Despite its clinical importance, GI disease in SSc is highly heterogeneous, with upper and lower GI manifestations representing distinct phenotypic extremes whose underlying immunologic basis remains poorly defined. MethodsWe performed unbiased, proteome-wide autoantibody profiling using a human protein microarray comprising >21,000 full-length proteins (>80% of the human proteome). Sera from patients with SSc and isolated upper GI dysmotility (n=23), isolated lower GI dysmotility (n=17), and non-SSc controls (n=20) were analyzed. Enriched autoantibodies were identified using Fishers exact test, and unsupervised clustering was applied to define serology-based patient subsets and relate immune signatures to clinical phenotypes. ResultsDistinct autoantibody profiles differentiated patients with upper versus lower GI disease. Upper GI-predominant SSc was characterized by enrichment of previously unreported autoantibodies, including those targeting TiSSc1/2 (newly identified proteins encoded within the MIRLET7BHG locus), FAM9C, SPATA20, FAM110D, EMILIN1, CARD14, SMN1, KCTD7, and PHYHD1, whereas lower GI disease was associated with antibodies against HAO2, KLHL7, SUFU, APPL1, BNIP2, UCHL3, ZNF385A, LIMD1, MAGEA9, and PPP2R3C. Serology-driven clustering identified four reproducible subgroups with distinct patterns of GI, pulmonary, vascular, and autonomic involvement, defining clinically meaningful disease phenotypes that extend beyond traditional anatomic classification. ConclusionsProteome-scale serological profiling reveals previously unrecognized autoimmune signatures underlying GI heterogeneity in SSc. These findings support a shift from anatomy-based to serology-defined classification of SSc GI disease and provide a foundation for biomarker development, patient stratification, and precision medicine approaches in this population.

immunology↗

bioRxiv2026

Global synthesis of aquatic insect heat tolerance reveals oxygen availability as a key driver of climate vulnerability

Accurately predicting species responses to climate change requires an understanding of the drivers of their thermal limits. Despite rapid warming of freshwater ecosystems worldwide, we still lack a global perspective on how upper thermal limits (UTLs) vary among aquatic insects, what constrains these limits, and how they contribute to species vulnerability. Here, we compiled a global dataset encompassing 423 aquatic insect species to test the effects of environmental conditions, organismal traits, acclimation history, and phylogenic relationships on patterns of heat tolerance. Maximum habitat temperatures were positively correlated with UTLs supporting the Climate Extremes Hypothesis, and insects relying exclusively on dissolved oxygen had the lowest UTLs supporting the Oxygen- and Capacity-Limited Thermal Tolerance hypothesis. Functional traits also explained substantial variation in UTLs; those that feed via scraping and shredding exhibited some of the lowest UTLs. Laboratory acclimation methods further influenced UTL estimates. Short-term exposure to higher acclimation temperatures increased UTLs, but longer exposure led to decreased heat tolerance. Finally, warming tolerance, i.e., the difference between UTL and the maximum habitat temperature) varied with breathing mode. Across latitude, warming tolerances were lowest for obligate dissolved oxygen-breathers but increased more rapidly in insects that can access terrestrial air. Collectively, these patterns indicate that oxygen is a key mechanism shaping thermal vulnerability in aquatic insects.

ecology↗

bioRxiv2025

Autoantibody hotspots reveal origin and impact of immunogenic XIST ribonucleoprotein complex

Four out of five patients with autoimmune diseases are women. The XIST ribonucleoprotein (RNP) complex, comprising the female-specific long noncoding RNA XIST and over 100 associated proteins, may drive several autoimmune diseases that disproportionately affect women, who have elevated levels of autoantibodies against the XIST RNP. However, the structural distribution, potential origin, and clinical significance of XIST RNP autoantibodies remained unexplored. Here, we find that XIST RNP is associated with autoantigens associated with six female-biased autoimmune conditions. Mapping autoantibody targets to their occupancy sites on XIST shows that these autoantigens are concentrated at discrete "hotspots" along the XIST lncRNA, notably the A-repeat. Cell type-specific protein expression data nominated neutrophils as a predominant source of hotspot antigens, and we confirmed the presence of both XIST and hotspot antigens in neutrophil extracellular traps during NETosis, an immunogenic programmed cell death pathway triggered by neutrophil activation upon which neutrophils extrude their nuclear content. Furthermore, we found that levels of autoantibodies against a top hotspot antigen, SPEN, that binds the A-repeat, correlate with severe digital ischemia in systemic sclerosis in two independent cohorts. Together, these data show a plausible mechanism for the origin of AXA, guided by RNA structure and RNA-protein interactions, and show that antibodies to XIST RNP holds promise for disease endotyping and prognostication in female-biased autoimmune conditions. One Sentence SummaryNovel autoantibodies target hotspots on XIST ribonucleoprotein complex in female-biased autoimmune diseases.

immunology↗

bioRxiv2025

Two Transport Routes for Fetuin-A-based Mineral Complexes in Osteogenic Matrix Mineralization

Living organisms must transport calcium and phosphate at high concentrations to enable bone formation without triggering uncontrolled mineral precipitation. Fetuin-A binds calcium phosphate to form soluble calciprotein complexes, but how these complexes contribute to physiological mineralization has remained unclear. Here we show that Fetuin-A-based mineral complexes exist in functionally distinct states that determine mineral bioavailability. Using cryogenic and liquid-phase electron microscopy, biochemical analysis, and osteoblast cell cultures, we demonstrate that small, chemically labile calciprotein monomers directly mineralize collagen fibrils, whereas larger, chemically matured primary calciprotein particles cannot. Instead, these particles require cellular uptake and lysosomal processing to release mineral for matrix deposition. This functional divergence arises from a irreversible chemical transformation of the mineral phase that drives the primary CPP assembly. Together, our findings establish nanoscale chemical maturation as a key control point that separates mineral transport from mineralization, reframing our understanding both physiological bone formation and pathological calcification.

biochemistry↗

bioRxiv2024

Nucleic Acid Aptamers Protect Against Lead (Pb(II)) Toxicity

Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies. Here we show that DNA and RNA aptamers protect C. elegans from toxic phenotypes caused by lead. Reproductive toxicity, as measured by brood size assays, is prevented by co-feeding of animals with DNA or RNA aptamers. Similarly, lead-induced behavioral anomalies are also normalized by aptamer feeding. Further, cultured human HEK293 and primary murine osteoblasts are protected from lead toxicity by transfection with DNA aptamers. The osteogenic development, which is decreased by lead exposure, is maintained by prior transfection of lead-binding DNA aptamers. Aptamers may be an effective strategy for the protection of human health in the face of increasing environmental toxicants. SYNOPSISLead remains a pervasive environmental contaminant with significant human health implications. This study investigates an entirely novel intervention for the problem of lead toxicity, using nucleic acid aptamers.

pharmacology and toxicology↗

bioRxiv2022

XIST ribonucleoproteins promote female sex-biased autoimmunity

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of numerous autoantigenic components, is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity. HIGHLIGHTSO_LITransgenic mouse models inducibly express Xist in male animals. C_LIO_LIXist expression in males induce autoantibodies and autoimmune pathology. C_LIO_LIXist in males reprograms T and B cell populations to female-like patterns. C_LIO_LIAutoantibodies to Xist RNP characterize female-biased autoimmune diseases. C_LI

molecular biology↗

bioRxiv2022

Warming undermines emergence success in a threatened alpine stonefly: a multi-trait perspective on vulnerability to climate change

Species vulnerability to global warming is often assessed using short-term metrics such as the critical thermal maximum (CTmax), which represents an organisms ability to survive extreme heat. However, an understanding of the long-term effects of sub-lethal warming is an essential link to fitness in the wild, and these effects are not adequately captured by metrics like CTmax. The meltwater stonefly, Lednia tumana, is endemic to high-elevation streams of Glacier National Park, MT, USA, and has long been considered acutely vulnerable to climate change-associated stream warming. In 2019, it was listed as Threatened under the U.S. Endangered Species Act. This presumed vulnerability to warming was challenged by a recent study showing that nymphs can withstand short-term exposure to temperatures as high as ~27 {degrees}C. But how this short-term tolerance relates to chronic, long-term warming has remained unclear. By measuring fitness-related traits at several ecologically relevant temperatures over several weeks, we show that L. tumana cannot complete its life-cycle at temperatures well below the CTmax values measured for its nymphs. Although warmer temperatures maximized growth rates, they appear to have a detrimental impact on other key traits (survival, emergence success, and wing development), thus extending our understanding of L. tumanas vulnerability to climate change. Our results call into question the use of CTmax as a measure of thermal sensitivity, while highlighting the power and complexity of multi-trait approaches to assessing climate vulnerability.

ecology↗

bioRxiv2021

Sesamol and its derivative investigated as antiandrogen - A potential prevention to prostate cancer in rats

Androgen signaling is essential for the development of prostate cancer (PCa) initiated from prostatic basal cells with collocation of androgen receptor gene mutations. Phytoestrogens, the naturally occurring compounds are AR antagonist. These compounds downregulate prostate-specific antigen (PSA) expression and cell proliferation. Thus, this gives a track to research these compounds as a possible treatment for PCa. In this work, STITCH and molecular docking predict the conformation of ligands inside the suitable target binding site. Therefore, a study was planned to know the interactions among SM and its derivatives with AR. It was further, evaluated for in vitro evaluation on LNCaP, PC-3, and DU-145 using MTT studies. The two lead compounds shortlisted from MTT studies were further analyzed for androgen-regulated genes by using RT-PCR, western blot studies and an animal model of prostate cancer. We found that SM and its derivative (3-MA) may prevent the development of PCa by androgen pathway.

cancer biology↗

bioRxiv2020

Cold tolerance of mountain stoneflies (Plecoptera: Nemouridae) from the high Rocky Mountains

ABSTRACTHow aquatic insects cope with cold temperatures is poorly understood. This is particularly true for high-elevation species that often experience a seasonal risk of freezing. In the Rocky Mountains, nemourid stoneflies (Plecoptera: Nemouridae) are a major component of mountain stream biodiversity and are typically found in streams fed by glaciers and snowfields, which due to climate change, are rapidly receding. Predicting the effects of climate change on mountain stoneflies is difficult because their thermal physiology is largely unknown. We investigated cold tolerance of several alpine stoneflies (Lednia tumana, Lednia tetonica, and Zapada spp.) from the Rocky Mountains, USA. We measured the supercooling point (SCP) and tolerance to ice enclosure of late-instar nymphs collected from a range of thermal regimes. SCPs varied among species and populations, with the lowest SCP measured for nymphs from an alpine pond, which is much more likely to freeze solid in winter than flowing streams. We also show that L. tumana cannot survive being enclosed in ice, even for short periods of time (less than three hours) at relatively mild temperatures (−0.5 °C). Our results indicate that high-elevation stoneflies at greater risk of freezing may have correspondingly lower SCPs, and despite their common association with glacial meltwater, they appear to be living near their lower thermal limits.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

Temperature-dependence of metabolic rate in tropical and temperate aquatic insects: support for the Climate Variability Hypothesis in mayflies but not stoneflies.

A fundamental gap in climate change vulnerability research is an understanding of the relative thermal sensitivity of ectotherms. Aquatic insects are vital to stream ecosystem function and biodiversity but insufficiently studied with respect to their thermal physiology. With global temperatures rising at an unprecedented rate, it is imperative that we know how aquatic insects respond to increasing temperature and whether these responses vary among taxa, latitudes, and elevations. We evaluated the thermal sensitivity of standard metabolic rate in stream-dwelling baetid mayflies and perlid stoneflies across a ~2,000 m elevation gradient in the temperate Rocky Mountains in Colorado, U.S.A., and the tropical Andes in Napo, Ecuador. We used temperature-controlled water baths and microrespirometry to estimate changes in oxygen consumption. Tropical mayflies generally exhibited greater thermal sensitivity in metabolism compared to temperate mayflies; tropical mayfly metabolic rates increased more rapidly with temperature and the insects more frequently exhibited behavioral signs of thermal stress. By contrast, temperate and tropical stoneflies did not clearly differ. Varied responses to temperature among baetid mayflies and perlid stoneflies may reflect differences in evolutionary history or ecological roles as herbivores and predators, respectively. Our results show that there is physiological variation across elevations and species and that low elevation tropical mayflies may be especially imperiled by climate warming. Given such variation among species, broad generalizations about the vulnerability of tropical ectotherms should be made more cautiously.

ecology↗

bioRxiv2019

Mountain stoneflies may tolerate warming streams: evidence from organismal physiology and gene expression

Rapid glacier recession is altering the physical conditions of headwater streams. Stream temperatures are predicted to rise and become increasingly variable, putting entire meltwater-associated biological communities at risk of extinction. Thus, there is a pressing need to understand how thermal stress affects mountain stream insects, particularly where glaciers are likely to vanish on contemporary timescales. In this study, we tested the critical thermal maximum (CTMAX) of stonefly nymphs representing multiple species and a range of thermal regimes in the high Rocky Mountains, USA. We then collected RNA-sequencing data to assess how organismal thermal stress translated to the cellular level. Our focal species included the meltwater stonefly, Lednia tumana, which was recently listed under the U.S. Endangered Species Act due to climate-induced habitat loss. For all study species, critical thermal maxima (CTMAX > 20{degrees}C) far exceeded the stream temperatures mountain stoneflies experience (< 10{degrees}C). Moreover, while evidence for a cellular stress response was present, we also observed constitutive expression of genes encoding proteins known to underlie thermal stress (i.e., heat shock proteins) even at low temperatures that reflected natural conditions. We show that high-elevation aquatic insects may not be physiologically threatened by short-term exposure to warm temperatures and that longer term physiological responses or biotic factors (e.g., competition) may better explain their extreme distributions.

physiology↗

bioRxiv2019

Definition of naturally processed peptides reveals convergent presentation of autoantigenic topoisomerase-I epitopes in scleroderma

Disease-associated HLA-DRB1 alleles are thought to confer risk of developing autoimmunity by favoring the presentation of select autoantigenic epitopes. However, identification of these epitopes and the principles governing their presentation has been hindered by the imprecision of currently available methods, which cannot fully recapitulate the complexity of human pathophysiology. We present a natural antigen processing assay (NAPA), which overcomes these limitations by studying the presentation of autoantigenic CD4+ T cell epitopes by monocyte-derived dendritic cells (mo-DCs) from patients. We applied this strategy to study the processing and presentation of topoisomerase-1 (TOP1), a prevalent autoantigen in scleroderma that is associated with lung fibrosis and high mortality. We found that a common set of 10 epitopes was presented by mo-DCs from patients with diverse HLA-DR variants, including those not previously associated with the disease. Sequence analysis revealed a shared peptide-binding motif within the HLA-DR peptide binding grooves of patients who developed anti-TOP1 autoantibodies. In addition, a subset of naturally presented TOP1 peptides were characterized by immunological promiscuity, as they could bind to diverse HLA-DR peptide binding grooves. NAPA epitopes were immunorelevant: they could stimulate autoreactive CD4+ T cells in patients, and the number of epitopes recognized correlated with lung disease severity. These findings mechanistically implicate presentation of a convergent set of TOP1 epitopes in the development of scleroderma lung disease. Precise identification of autoantigenic epitopes is key to understanding the primordial mechanisms for the loss of tolerance, studying disease-propagating autoreactive T cells, and developing antigen-specific immunotherapy.\n\nOne Sentence SummaryUse of a novel natural antigen processing assay reveals a mechanism for the presentation of shared CD4+ T cell epitopes of topoisomerase-I in immunogenetically diverse patients with scleroderma.

immunology↗

bioRxiv2019

Genome annotation of Poly(lactic acid) degrading Pseudomonas aeruginosa and Sphingobacterium sp.

Pseudomonas aeruginosa and Sphinogobacterium sp. are well known for their ability to decontaminate many environmental pollutants like PAHs, dyes, pesticides and plastics. The present study reports the annotation of genomes from P. aeruginosa and Sphinogobacterium sp. that were isolated from compost, based on their ability to degrade poly(lactic acid), PLA, at mesophillic temperatures (~30{degrees}C). Draft genomes of both the strains were assembled from Illumina reads, annotated and viewed with an aim of gaining insight into the genetic elements involved in degradation of PLA. The draft-assembled genome of strain Sphinogobacterium strain S2 was 5,604,691 bp in length with 435 contigs (maximum length of 434,971 bp) and an average G+C content of 43.5%. The assembled genome of P. aeruginosa strain S3 was 6,631,638 bp long with 303 contigs (maximum contig length of 659,181 bp) and an average G+C content 66.17 %. A total of 5,385 (60% with annotation) and 6,437 (80% with annotation) protein-coding genes were predicted for strains S2 and S3 respectively. Catabolic genes for biodegradation of xenobiotic and aromatic compounds were identified on both draft genomes. Both strains were found to have the genes attributable to the establishment and regulation of biofilm, with more extensive annotation for this in S3. The genome of P. aeruginosa S3 had the complete cascade of genes involved in the transport and utilization of lactate while Sphinogobacterium strain S2 lacked lactate permease, consistent with its inability to grow on lactate. As a whole, our results reveal and predict the genetic elements providing both strains with the ability to degrade PLA at mesophilic temperature.

microbiology↗

bioRxiv2017

Estimating Autoantibody Signatures To Detect Autoimmune Disease Patient Subsets

Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre-filtering step to define subgroups with similar specificities based on migration of radiolabeled, immunoprecipitated proteins on sodium dodecyl sulfate (SDS) gels and autoradiography [Gel Electrophoresis and band detection on Autoradiograms (GEA)]. Human recognition of patterns is not optimal when the patterns are complex or scattered across many samples. Multiple sources of errors - including irrelevant intensity differences and warping of gels - have challenged automation of pattern discovery from autoradiograms.\n\nIn this paper, we address these limitations using a Bayesian hierarchical model with shrinkage priors for pattern alignment and spatial dewarping. The Bayesian model combines information from multiple gel sets and corrects spatial warping for coherent estimation of autoantibody signatures defined by presence or absence of a grid of landmark proteins. We show the pre-processing creates more clearly separated clusters and improves the accuracy of autoantibody subset detection via hierarchical clustering. Finally, we demonstrate the utility of the proposed methods with GEA data from scleroderma patients.

cancer biology↗