Biology subjects

Mistry, S.

Publications and source records attributed to Mistry, S..

7 recordsLinked to original sources

bioRxiv2026

Can the Human Plastisphere Account for the Rise of Type 1 Diabetes: A Computational Molecular Mimicry Study

An increased incidence of childhood type 1 diabetes mellitus (T1DM) has been widely documented, but its pathophysiological origins are poorly understood. The post-World War II expansion of the plastics industry in the United States and elsewhere coincides with a marked increase in T1DM incidence; however, no pathophysiological mechanism has been proposed that could justify such a temporal correlation. Here, we leverage recent advances in artificial intelligence and protein structure prediction and binding to show that molecular mimicry is a plausible pathophysiological mechanism for plastic fragments to induce onset of T1DM for individuals with certain HLA haplotypes.

immunology↗

bioRxiv2026

IgG sequencing maps systemic antibody binding to oral commensals and pathobionts in health and periodontitis

The oral cavity harbors one of the body's most diverse microbial communities, which continuously seeds the bloodstream and gastrointestinal tract, particularly in periodontitis, a disease in which both barrier permeability and microbial burden increase. Despite this constant systemic exposure, overt bacteremia from oral organisms is rare, suggesting an active surveillance system that contains this reservoir. Here, we apply IgG-sequencing to comprehensively map mucosal and systemic antibody recognition of the oral microbiome across paired oral fluid and serum from healthy individuals and patients with periodontitis. We find that IgG-binding is only weakly predicted by microbial abundance, suggesting taxon-specific and largely conserved IgG-binding of commensals, many of them streptococci which dominate antibody recognition irrespective of disease state. Periodontitis broadens the repertoire of IgG-bound taxa to include particular disease-associated pathobionts while preserving robust targeting of health-associated symbionts. Comparison of salivary and serum antibody profiles further uncovers a subset of commensal streptococci, including species implicated in infective endocarditis, that acquire disproportionate systemic IgG binding in periodontitis. Together, these findings establish a taxon-level atlas of humoral immunosurveillance at a major mucosal-microbial interface and reveal how periodontal disease reshapes systemic antibody recognition of both pathobionts and commensals.

immunology↗

bioRxiv2026

Neutrophil remodeling is associated with human meibomian gland dysfunction and enables IFN-γ- and PAD4-dependent gland obstruction in mice

Meibomian gland dysfunction (MGD), a disorder of the eyelid's modified sebaceous glands, is the leading cause of dry eye disease and ocular surface morbidity, yet the immune mechanisms driving gland obstruction remain poorly defined. In a cross-sectional study of 66 patients with ocular surface inflammation, we used meibography and spectral flow cytometry of tear washes to identify a disease-associated, remodeled neutrophil state whose abundance is associated with gland atrophy. Using single-cell transcriptomics in a murine model of immune-mediated MGD, we revealed a disease-associated neutrophil state that exhibited ocular surface-enrichment, CD14 and ICAM-1 expression, and elevated IFN-{gamma} response and inflammatory signatures. Spatial transcriptomics localized IFN-{gamma} signaling and neutrophil migration signatures to the periglandular compartment. The remodeled neutrophils exhibited PAD4-dependent histone citrullination, with Padi4 deletion reducing NET-associated obstructive plugging, thus identifying PAD4-dependent NETotic activity as their disease-producing output. Inhibition of IFN-{gamma} signaling phenocopied Padi4 deficiency, yet combined disruption of these pathways provided no additive protection, indicating that IFN-{gamma} and PAD4 function as separable required inputs. Remodeled neutrophils accumulated under both conditions, uncoupling disease severity from cell abundance alone. Our findings support immune-mediated obstructive MGD as a mechanistic endotype driven by the IFN-{gamma}- and PAD4-dependent effector output of a remodeled neutrophil state.

immunology↗

bioRxiv2025

Structural Homology and Electrostatic Potential Comparisons of Epitope Pair Candidates for Molecular Mimicry Triggering of Type 1 Diabetes Mellitus

BackgroundMolecular mimicry, where foreign and self-peptides contain similar epitopes, can induce autoimmune responses. Identifying potential molecular mimics and studying their properties is key to understanding the onset of autoimmune diseases such as type 1 diabetes mellitus (T1DM). Previous work identified pairs of infectious epitopes (EINF) and T1DM epitopes (ET1D) that demonstrated sequence homology; however, structural homology was not considered. Correlating sequence homology with structural properties is important for translational investigation of potential molecular mimics. This work compares sequence homology with structural homology by calculating the structures and electrostatic potential surfaces of the epitope pairs identified in previous work from our laboratory. ResultsFor each pair of EINF and ET1D, the root mean square deviations (RMSD) were calculated between their predicted structures and their electrostatic potentials. Structures were predicted using the AlphaFold software program. Of the 53 epitope pairs considered here, only 10 did not exhibit any matching (i.e. less than 3 residues overlap). When considering all residues the RMSD ranges from 0.33 [A] to 11.66 [A] with an average of 2.68 [A]. Twenty-two pairs (42%) have RMSD of less than 1.5 [A] and 30 (58%) less than 3 [A]. ConclusionsMost of the EINF/ET1D pairs selected by sequence homology show similar structural and electrostatic distributions, indicating that the EINF may also bind to the same protein targets, i.e. the major histocompatibility complex molecules, for T1DM, leading to molecular mimicry onset of the disease. These findings suggest that searching for epitope pairs using sequence homology, a much less computationally demanding approach, leads to strong candidates for molecular mimicry that should be considered for further study. But structure homology, electrostatic potential calculations and full docking calculations may be necessary to advance the in-silico molecular mimicry predictions, which may be useful to select the most promising candidates for experimental studies.

immunology↗

bioRxiv2025

The Plasma Membrane may Serve as a Drug Depot to Drive the Extreme Potency of Fentanyl

Fentanyl is a leading cause of drug overdose deaths in the United States, yet the mechanisms underlying its extreme in vivo potency remain poorly understood. Recently, new synthetic opioids nitazene derivatives have emerged, among which isotonitazene is 50 times more potent than fentanyl. Here we used state-of-the-art molecular dynamics (MD) simulations and experiments to investigate the membrane-dependent pharmacology of fentanyl, isotonitazene, morphine, and naloxone. Using the weighted-ensemble continuous constant pH MD, we estimated the effective permeability of fentanyl at pH 7.5 to be on the order of 10-7 cm/s, which is about two orders of magnitude faster than the simulation estimate for morphine. In contrast, isotonitazene and naloxone effectively do not partition into the membrane under the same conditions. The simulations captured the protoncoupled permeation processes, challenging as well as refining the long-standing pH-partition hypothesis. Subsequent BRET reporter cell experiments demonstrated that cells exposed to fentanyl, but not morphine, reactivated the receptor after washout and in competition with naloxone. Immobilized affinity membrane chromatography confirmed fentanyls high affinity for phospholipids. Our findings strongly support the hypothesis that fentanyls extreme in vivo potency may be driven by its accumulation within the plasma membrane or intracellularly, enabling it to repartition into the extracellular space to rebind the receptor, or potentially access it via a lipid-mediated route. This highlights the importance of membrane-dependent pharmacology for understanding opioid toxicity and guiding the design of more effective antagonists. Our simulation methodology enables accurate prediction and analysis of membrane permeation of ionizable molecules, providing a valuable tool for ADME optimization in drug development.

biophysics↗

bioRxiv2025

Sulfide is a keystone metabolite for gut homeostasis and immunity

Hydrogen sulfide is a gaseous, reactive molecule specifically enriched in the gastrointestinal tract. Here, we uncover a non-redundant role for sulfide in the control of both microbial and immune homeostasis of the gut. Notably, depletion of sulfide via both pharmaceutical and dietary interventions led to a profound collapse of CD4 T cells in the ileum of the small intestine lamina propria and significant impact on microbial ecology. As a result, mice with reduced sulfide within the gut were deficient in their ability to mount T cell dependent antibody responses to oral vaccine. Mechanistically, our results support the idea that sulfide could act directly on CD4 T cells via enhanced AP-1 activation, leading to heightened proliferation and cytokine production. This study uncovers sulfides as keystone components in gut ecology and provides mechanistic insight between diet, gut sulfide production and mucosal immunity.

immunology↗

bioRxiv2021

Systemic IgG repertoire as a biomarker for translocating gut microbiota members

While the microbiota has been associated with diseases states, how specific alterations in composition, function, or localization contribute to pathologies remains unclear. The ability of defined microbes to translocate has been linked to diseases including inflammatory bowel disease (IBD) and was shown to promote responses to immune checkpoint therapy. However, scalable and unbiased tools to uncover microbes with enhanced ability to translocate are limited. Herein, we developed an approach to utilize systemic IgG in an unbiased, culture-independent, and high-throughput fashion as a biomarker to identify gut microbiota members that are capable of translocation across the gastrointestinal barrier. We validate these findings in a cohort of human subjects, and highlight a number of microbial taxa against which elevated IgG responses are unique to subjects with IBD including Collinsella, Bifidobacterium, Faecalibacterium, and Blautia spp. Collinsella and Bifidobacterium taxa identified as translocators and targets of immunity in IBD also exhibited heightened bacterial activity and growth rates in Crohns disease subjects. Our approach may represent a complementary tool to illuminate privileged interactions between host and its microbiota, and may provide an additional lens by which to uncover microbes linked to disease processes. One Sentence SummaryCirculating microbiota-specific IgG can identify gut microbiota constituents capable of crossing the gut barrier.

immunology↗