Biology subjects

Khan, S.

Publications and source records attributed to Khan, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Integrative Genomic and Structure-Based Prioritization of Molecular Targets in Multidrug-Resistant Salmonella enterica from Brazilian Poultry

Salmonella spp. remains one of the leading foodborne pathogens worldwide, and the circulation of multidrug-resistant strains in the poultry industry poses a significant challenge. In this study, five isolates from poultry litter swabs (commercial broiler chickens) belonging to the Salmonella Heidelberg and Salmonella Minnesota serovars were characterized using an integrated approach involving phenotypic resistance profiling, whole-genome sequencing, structural prioritization of molecular targets, and in silico screening of ligands. All isolates exhibited multidrug resistance phenotypes and genetic repertoires consistent with resistance to {beta}-lactams, sulfonamides, and tetracyclines, as well as determinants linked to efflux systems, virulence, and persistence. Genomic analysis allowed for the prioritization of five proteins for structural investigation: CTX-M-2, CMY-2, Sul2, AcrB, and SpvC. Sequence-structure validation revealed high correspondence between the proteins of the isolates and the experimental structures selected for CMY-2, Sul2, AcrB, and SpvC, while CTX-M-2 was modeled with high structural confidence. Molecular docking analyses with GNINA revealed distinct behaviors among the targets. Sul2 showed biological relevance but a more conservative structural response, with no significant gain after analog generation. In contrast, AcrB stood out as the most promising target, with analogs generated by BRICS yielding better scores and, in some cases, coherent international networks identified by PLIP. The results demonstrate that the integration of phenotype, comparative genomics, and structural prioritization constitutes a rational strategy for selecting targets and molecular candidates in multidrug-resistant avian strains of S. Heidelberg and S. Minnesota.

microbiology↗

bioRxiv2026

Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity

Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient-derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand-receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1-positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1-regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high-risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.

cancer biology↗

bioRxiv2026

Histone modifications analysis reveals enhancers reprogramming during maternal-to-zygotic transition

Enhancers are important epigenetic regulatory components that coordinate spatiotemporal gene expression and play a crucial role in mammalian development, gene regulation, and illness. During early mammalian embryogenesis, histone modifications including H3K4me1, a canonical enhancer mark, and H3K27ac, which identifies active enhancers, are still poorly understood. This study profiles the genome-wide H3K4me1 and H3K27ac patterns in mouse oocytes and pre-implantation embryos using low-input CUT&RUN (cleavage under targets and release using nuclease) with input as low as 50 cells. Both markers are enriched in distal regions and exhibit distinct sequence preferences and reprogramming dynamics in pre-implantation embryos. H3K27ac, a mark of active enhancers, is reprogrammed at the 2-cell stage, whereas H3K4me1 is remodeled at the 4-cell stage and overlaps with H3K27ac, coinciding with accessible chromatin regions. Interestingly, H3K4me1 and H3K27ac are co-localized in promoter regions, where they are mutually exclusive to H3K4me3. Enhancers are dynamically remodeled during maternal-to-zygotic transition (MZT). there are three enhancer types: active enhancers (H3K4me1/H3K27ac), primed enhancers (H3K4me1), and poised enhancers (H3K4me1/H3K27me3). Active enhancers increase significantly after zygotic genome activation. Further, super-enhancers are present across the genome and are mainly enriched in promoters. The specific motifs enriched by super-enhancers may be associated with the variations of gene expressions at different stages.

developmental biology↗

bioRxiv2026

Acquired resistance to immune checkpoint inhibitors is associated with hypoxia and ECM remodeling in colorectal cancer

Acquired resistance to immune checkpoint inhibitors (ICIs) limits the durability of therapeutic responses across multiple cancer types, yet the underlying mechanisms remain poorly defined. Using the murine MC38 colorectal cancer model, we established an in vivo model recapitulating clinical response patterns, including complete regression, primary resistance, and acquired resistance. Tumors with acquired resistance progressed after initial benefit from combined anti-PD-1 and anti-CTLA-4 therapy and maintained resistance upon retransplantation into naive hosts, indicating a cancer cell-intrinsic driver of resistance. Whole-genome sequencing showed no mutations in antigen presentation or IFN-{gamma} signaling pathways previously described in single clinical cases of acquired resistance, and functional assays confirmed preserved antigenicity and IFN-{gamma} responsiveness. Transcriptomic and metabolic profiling of resistant cancer cells instead revealed metabolic reprogramming characterized by enhanced mitochondrial respiration and enrichment of hypoxia-related gene signatures, suggesting cancer cell-intrinsic adaptations that reshape the tumor microenvironment. Tumors with acquired resistance exhibited an increase in tumor-associated macrophages, and these macrophages displayed enriched transcriptional signatures of hypoxia, angiogenesis, and extracellular matrix (ECM) remodeling. Proteomic analysis of ECM-enriched tumor fragments showed accumulation of proteoglycans and enzymes such as lysyl oxidase, consistent with active matrix-remodeling. These changes coincided with altered T cell activation characterized by reduced cytotoxic gene expression and decreased CD44 expression on tumor-infiltrating T cells, suggesting impaired effector functions within the resistant microenvironment. This study identifies non-genetic mechanisms of acquired resistance to ICIs and highlights metabolic and ECM remodeling programs as promising therapeutic targets to prevent or reverse acquired resistance to ICIs.

cancer biology↗

bioRxiv2026

Unveiling Common Molecular Signatures and Pathways in Psychiatric Disorders and Alcohol Use Disorder through Integrated Transcriptome Analysis

Research studies have demonstrated that persons who have Alcohol Use Disorder (AUD) exhibit a more severe progression of psychiatric disorders, indicating potential causal connections between AUD and psychiatric disorders. Identifying underlying risk variables between AUD and psychiatric problems continues to be challenging. To address these issues, we created a bioinformatics pipeline and employed network-based methods to discover genes that exhibit improper expression in both AUD and psychiatric disorders. The objective of our study was to identify common molecular pathways that may elucidate the relationship between AUD and psychiatric disorders. We identified 49 genes that were expressed differently in tissue samples of patients with both AUD and psychiatric disorders. The DAVID online platform was used to discover the most significant Gene Ontology (GO) keywords and metabolic pathways. It detected the involvement of immune response, chemokine activity, TNF signaling, IL-17 signaling, and prostaglandin signaling pathways among the common DEGs. In addition, eleven topological algorithms identified a single hub protein, specifically TTR, from the protein-protein interaction (PPI) network. Through regulatory network analysis, we identified four crucial transcription factors (TFs)--YY1, FOXC1, JUND, and GATA2--and seven miRNAs (e.g., hsa-mir-146a-5p, hsa-mir-20a-5p) that play vital roles in regulating the development of AUD and psychiatric disorders. These miRNAs may serve as potential therapeutic targets. Validation of the hub gene using ROC analysis indicated acceptable predictive performance. Our approach revealed several potential biomarkers and signaling pathways linking AUD with psychiatric disorders, offering new insights for diagnosis and treatment. HighlightsO_LIIntegration of genome-scale transcriptomic datasets with biomolecular networks identified key hub genes (TTR, SOCS3, CXCL10, MMP9, and C4A). C_LIO_LICommon transcription factors, including YY1, FOXC1, JUND, and GATA2, were uncovered as potential regulatory elements. C_LIO_LICritical miRNAs (hsa-miR-146a-5p, hsa-miR-20a-5p, hsa-miR-107, hsa-miR-124-3p, hsa-miR-138-5p, and hsa-miR-330-3p) were identified as key post-transcriptional regulators. C_LIO_LIHistone modification profiling revealed multiple modification sites in hub genes and transcription factors, linking them to Intellectual Disability, Bipolar Disorder, Schizophrenia, and Alcohol Use Disorder. C_LIO_LIProtein-drug interaction analysis highlighted 10 candidate compounds with potential therapeutic relevance for the identified markers across ID, Bipolar Disorder, Schizophrenia, and AUD. C_LI

bioinformatics↗

bioRxiv2026

Uromodulin promotes immune zonation and inhibits alternative inflammasome-mediated activation of immune-to-collecting duct inflammatory signaling in early acute kidney injury

Uromodulin, a protein made uniquely by the kidney, is protective against acute kidney injury. An integrated transcriptomic and multiplexed spatial protein imaging was used to uncover early cellular and molecular pathophysiological mechanisms following murine kidney ischemia and reperfusion injury (IRI) and better define the role of Uromodulin at the early stage of injury. Six hours following IRI, there was a pan-nephronal transcriptomic response with activation of common pathways but also unique gene expression signatures for each nephron segment. Cell-cell communications and epithelial-immune spatial interactions most prominently involved thick ascending limbs and distal nephron segments with distinct immune zonation in the inner stripe of the outer medulla. Uromodulin deficiency swayed the tubular transcriptomic signatures towards more severe injury and inflammation with altered macrophage communication. Uromodulin deficiency also caused partial loss of immune zonation and a shift towards broader epithelial-immune interactions in the outer stripe and cortex. Uromodulin inhibited activation of the Nlrc4-dependent alternative inflammasome pathway in macrophages, where the production of IL-1{beta} predominantly targets other immune and collecting duct (CD) cells. Indeed, Uromodulin deficiency induced the expression of CD8 in CD cells which acquire a proinflammatory phenotype linked to spatial niches containing immune cells. The presence of CD8+ CD cells was validated in human kidney biopsies. In conclusion, our findings support a role for Uromodulin in spatially confining the immune system around TAL cells in the inner stripe away from the vulnerable outer stripe in early injury. Uromodulin also inhibits the inflammasome-mediated macrophage-epithelial crosstalk that could induce collecting duct cells towards more inflammatory signaling.

physiology↗

bioRxiv2026

TAZ (Wwtr1) deficiency leads to ER stress and mitochondrial dysfunction in a mouse model of Fuchs' endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD) impacts over 300 million individuals worldwide with corneal transplantation as the primary treatment. There is a dire need to establish non-surgical alternatives which are dependent on mouse models. Transcriptional co-activator with PDZ-binding motif (TAZ, encoded by Wwtr1) is a mechanotransducer implicated in maintaining homeostasis of corneal endothelial cells (CEnC). Wwtr1-/- (TAZ KO) mice serve as an animal model for late-onset FECD. We combined single-cell transcriptomics, transmission electron microscopy, and immunofluorescence staining to elucidate the mechanisms driving pathogenesis in young (2-month-old) and geriatric (11-month-old) mice. A progressive stress response was observed in TAZ KOs defined by endoplasmic reticulum (ER) stress, mitochondrial structural and functional abnormalities, and impaired Na+/K+ ATPase localization. These changes were accompanied by an altered expression of genes involved in extracellular matrix (ECM) organization, oxidative phosphorylation, macroautophagy and response to oxidative stress. Additionally, we noted age-related differences in cellular response with young TAZ KO CEnCs upregulating macroautophagy and downregulating ECM organization while geriatric TAZ KO CEnCs downregulated macroautophagy, and ECM organization. Both TAZ KO groups downregulated response to oxidative stress and cell-substrate adhesion. Together, these findings establish a mechanistic link between disrupted mechanotransduction and organelle stress in CEnC degeneration, further elaborating on potential mechanisms driving FECD pathogenesis. This positions TAZ KO mice as a translational platform for evaluating non-surgical therapeutic strategies targeting FECD. Significance statementFuchs endothelial corneal dystrophy (FECD) is a common, age-related cause of vision loss involving a depletion of corneal endothelial cells (CEnC) that necessitates corneal transplantation. Understanding why corneal endothelial cells progressively fail in this disease is essential for developing non-surgical therapies. Using transcriptomics, electron microscopy and immunofluorescence staining, we demonstrate that loss of the mechanotransducer TAZ disrupts cellular homeostasis by inducing endoplasmic reticulum stress, mitochondrial dysfunction and improper extracellular matrix and functional protein organization in CEnCs. By linking altered mechanotransduction to organelle stress and endothelial cell loss, these findings provide insight into fundamental disease mechanisms and identify pathways that may be targeted to preserve corneal endothelial function in FECD.

pathology↗

bioRxiv2026

Estradiol modulates neuronal network hyperexcitability in select NDD risk genes

Sex hormone signaling during neurodevelopment may act as a modulator of risk for neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs). By conducting a systematic and multi-modal evaluation of estradiol effects across loss-of-function deletions in 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell-derived neurons and larval zebrafish, we uncover convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Whereas estradiol partially ameliorates dysregulated expression signatures across all ASD/NDD gene knockouts examined, it selectively and rapidly dampens network hyperexcitability phenotypes in only a subset of ASD/NDD gene knockouts. Two genes, ASH1L and SCN2A, are particularly responsive to estradiol treatment, with dramatic rescue of molecular and cellular effects in human knockout neurons, coupled with behavioral phenotypes in larval zebrafish mutants. The seven most estradiol responsive genes show enhanced protein-protein interaction network connectivity, strong co-expression in specific postnatal time periods, and enrichment in upper-layer mature excitatory neurons. Altogether, we describe distinct estradiol rescue in different modalities, elucidating shared transcriptomic effects as well as gene-specific cellular and behavioral rescue in the context of loss of function mutations of select ASD/NDD genes.

genomics↗

bioRxiv2026

A Multi-Organ Single-Cell Atlas Maps Allergen and Organ-Specific Cellular Dynamics in the Progression from Food Allergy to Anaphylactic Shock

The transition from food allergic sensitization to life-threatening anaphylactic shock (AS) with complex multi-organ cellular interactions has been poorly understood. We herein conducted a multi-organ single-cell sequencing of heart, lung, and intestinal tissues from mouse models of food allergy, sensitized to bovine serum albumin (BSA) or ovalbumin (OVA), across both sensitization (Phase I) and anaphylactic shock (Phase II). We found that organ-specific pathologies included cardiac vascular dysfunction with pericyte loss and cardiomyocyte adaptation, distinct lung responses (Th2/B-cell predominance with BSA vs. neutrophilia with OVA), and profound intestinal remodeling featuring Paneth cell expansion. We also identified conserved inflammatory pathways (e.g., NOD-like receptor, NF-{kappa}B, JAK-STAT signaling) and unique organ specific signatures. Notably, phase-dependent reprogramming showed NLRP3 inflammasome activation and suppressed anti-inflammatory responses during AS. Cell-cell communication networks shifted from stromal-immune crosstalk in Phase I to dominant myeloid-vascular/neuroimmune interactions in Phase II. We further linked early extracellular matrix remodeling to late-stage neuromodulatory responses in Schwann and smooth muscle cells. This multi-organ atlas elucidates the coordinated, organ-selective immune cascade driving FA to AS progression, providing a foundational resource for developing targeted therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/703914v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@19ffd9forg.highwire.dtl.DTLVardef@c3fda3org.highwire.dtl.DTLVardef@141174corg.highwire.dtl.DTLVardef@60ac5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Developing Potent and Selective TBK1 Molecular Glue Degraders for Cancer Immunotherapy

Immune checkpoint blockade (ICB) has transformed cancer therapy across multiple tumour types, yet primary and acquired resistance remain major barriers to durable benefit. TANK-binding kinase 1 (TBK1) has emerged as an attractive target to enhance anti-tumour immunity, acting as a serine/threonine kinase that restrains immunogenic cell death and downstream immune activation. Here we report the discovery of a first-in-class TBK1 molecular glue degrader (MGD), CCT412020, identified through high-throughput proteomics screening of a next-generation molecular glue library. CCT412020 induces rapid, potent and selective TBK1 degradation across a panel of breast cancer cell lines. A cryo-EM structure of CCT412020 in complex with CRBN/{Delta}BPB-DDB1 and TBK1-homodimer reveals an unexpected binding mode that bypasses the canonical G-loop and instead engages an unconventional site at the TBK1 homodimer interface. Functionally, TBK1 loss via CCT412020 sensitises tumour cells to TNF- and interferon-driven responses and reduced viability across a broad range of cancer cell lines. Together, these findings establish CCT412020 as a mechanistically distinct TBK1 degrader and provide a framework for developing TBK1-targeted degraders as immunomodulatory anti-cancer agents to overcome ICB resistance.

cancer biology↗

bioRxiv2026

CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis

Targeted immunotherapies have revolutionized outcomes for lymphoid malignancies, but success in myeloid neoplasms is limited by the lack of amenable targets and immunologically hostile tumor microenvironment (TME). Myeloproliferative neoplasms are chronic myeloid blood cancers, a third of which are driven by mutations in calreticulin (mutCALR). This yields a common neoepitope that binds to, and activates, the thrombopoietin receptor and results in display of the oncoprotein on the extracellular membrane of disease-driving cells, exposing a therapeutic vulnerability. Here, we present a first-in-class chimeric antigen receptor (CAR) T-cell therapy that specifically targets mutCALR+ cells, both in vitro and in vivo. The CAR T-cell therapy selectively depleted mutCALR+ stem cells from patients with myelofibrosis while sparing healthy stem cells, and improved survival in mutCALR leukemia xenografts. To mimic myelofibrotic marrow, we developed a bespoke human chimeroid model and showed no decrease in the potency of CAR T cell-mediated target cell killing even in a fibrotic tumor microenvironment. We also devised a method to boost cell surface expression of mutCALR in CD34+ cells isolated from patients with accelerated/blast phase MPN (defined as >10 % blasts in peripheral blood or bone marrow), enhancing CAR T targeting. This study presents a therapeutic with potential to eradicate mutCALR-driven malignancies and highlights an innovative strategy to evaluate blood cancer-targeting immunotherapies in a relevant TME. One Sentence SummaryA first-in-class CAR T-cell therapy targeting mutant calreticulin selectively depletes malignant stem cells in vivo and in fibrotic human organoids.

cancer biology↗

bioRxiv2026

Localisation of corticosteroids in male mouse kidney by mass spectrometry imaging

Renal sodium balance is important for blood pressure homeostasis and is regulated by corticosteroids, chiefly aldosterone but also glucocorticoids. Abundance of these hormones in functional subregions of the kidney is unknown, previous work being limited to measurements in plasma and urine, and in microdialysate from kidney medulla. Here mass spectrometry imaging (MSI) was applied to map corticosteroids in kidney to understand how their distribution overlays with functional targets. Male C57BL6 mice, aged 10 weeks, were fed diets containing 0.03%, 0.3% or 3% w:w sodium for two weeks and kidneys harvested at cull. Steroids were localised as Girard T derivatives on cryosections using Matrix assisted laser desorption ionisation Fourier transform ion cyclotron MSI, with confirmation by liquid extraction surface analysis. Co-registration was performed on sections stained with hematoxylin and eosin. Corticosterone localised along the papilla, medulla and inner cortex, whereas 11-dehydrocorticosterone was concentrated in the medulla. Higher amounts of aldosterone were present in medulla and outer cortex. Distribution patterns were unchanged by dietary salt, but amounts of corticosterone were elevated, particularly in outer cortex with low salt diet. MSI holds great promise to dissect corticosteroid signalling in functional zones of the kidney.

biochemistry↗

bioRxiv2026

Enhancing Lipid Detection and Spatial Accuracy in Carotid Plaques Using Mass Spectrometry Imaging Techniques

Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) is a powerful technique for studying lipid distribution in carotid plaques, key to understanding atherosclerosis. This study aimed to improve sample preparation for MALDI-MSI-based spatial lipidomics of carotid plaques by improving both matrix application and tissue handling. Human carotid plaques were collected from endarterectomy patients with ethical approval and sectioned at 10 {micro}m thickness for MALDI-MSI. We compared eight sample preparation methods, including hydroxypropyl methylcellulose-polyvinylpyrrolidone (HPMC-PVP) embedding media and Cryofilm-type IMS(R) to provide support and maintain tissue structural integrity during sectioning. Methods were assessed for signal intensity, lipid diffusion, lipid coverage, tissue morphology, and image co-registration which each criterion scored from 1-3. Cryofilm-based methods scored highest for preserving tissue morphology and minimising folding artifacts (2.9-3.0) but were limited in co-registration (2.0) due to reliance on adjacent sections. Sublimation methods generally produced greater lipid coverage with reduced lateral diffusion, while automated sprayer methods scored higher in signal intensity/sensitivity (3.0) but had increased lipid delocalisation, particularly for highly hydrophobic species such as triacylglycerols and sterols. The results highlight clear trade-offs between tissue structural preservation, lipid detection sensitivity, and spatial integrity in MALDI-MSI. Because spatial integrity cannot be compromised for imaging lipids in carotid atherosclerotic plaques, Cryofilm combined with sublimation offers a clear advantage. This work strengthens MALDI-MSI workflows enabling more precise spatial mapping and deeper biological interpretation of atherosclerotic lipid distributions.

molecular biology↗

bioRxiv2026

Hair promotion effect of Beta vulgaris L. fruit extracts; physicochemical, and analytical evaluation

Natural products are used frequently for medicinal purposes due to their lower toxicity effect and greater safety than synthetic products. Alopecia is becoming common due to inheritance, hormonal change and environmental factors. The current study evaluates the physicochemical, analytical and hair growth promotion activity of extracts of Beta vulgaris L. Extraction was done by using hexane, chloroform, methanol, ethanol and water in increasing order of their polarity. For the hair growth activity, five groups (positive, negative, untreated, test-group 1 and test-group 2) of albino mice were made and each group has five mice. The hair tonic formulation was applied on their dorsal surface. The analysis revealed that methanolic and ethanolic extracts showed the highest phytochemical content. The average length and diameter were noted. On day 14 and 21 length of different groups were: standard group (7.40{+/-}0.34, 8.15{+/-}0.56), negative group (3.05{+/-}0.65 and 5.65{+/-}0.78), untreated group (3.44{+/-}0.27 and 4.58{+/-}0.61), test group1 5% methanol (5.25{+/-}0.20 and 6.26{+/-}0.10), 10% methanol (5.23{+/-}0.07 and 6.35{+/-}0.33), test group2, 5% ethanol 5.28{+/-}0.50 and 6.30{+/-}0.84, 10% ethanol 5.50{+/-}0.50 and 6.72{+/-}0.75 and the diameter of groups were; standard (3.5{+/-}0.42 and 4{+/-}0.86), negative (1.5{+/-}0.33 and 2{+/-}0.22), untreated (2{+/-}0.34 and 2{+/-}0.24), test group1 5% (2{+/-}0.41 and 2.5{+/-}0.65), 10%(2{+/-}0.65 and 2.5{+/-}0.34), test group2 5%(1.5{+/-}0.67 and 2.5{+/-}0.42), 10% (2{+/-}0.88 and 2.5{+/-}0.54). Both extracts showed significant results, but ethanolic extract is more effective than methanolic. The exact mechanism of hair growth is not known yet, but it might be due to its strong antioxidant and anti-inflammatory effect. hence, this study is useful in treating baldness.

pharmacology and toxicology↗

bioRxiv2025

DYT1 mutation alters gut microbiome composition and gut-brain axis dynamics in a mouse model

Dystonia is a neurological movement disorder characterized by involuntary, sustained, or intermittent muscle contractions, that result in twisting movements, repetitive motor patterns, or abnormal postures. While genetic mutations such as Tor1a+/{Delta}GAG are known contributors, the environmental and peripheral factors influencing disease onset and progression remain poorly understood. Emerging evidence implicates the gut microbiome in shaping neurodevelopment and host behavioral function, yet its contribution to dystonia pathobiology is largely unexplored. Here, we longitudinally profiled the gut microbiome of Tor1a+/{Delta}GAG mouse model using 16S rRNA gene sequencing and uncovered early emerging, persistent disruptions in microbial diversity and community composition that track with progressive motor impairment. Mutant mice exhibited an alteration of key commensal taxa, and molecular signatures indicative of compromised gut-barrier integrity. Parallel transcriptomic profiling of colonic epithelium reveals coordinated dysregulation of pathways governing epithelial stress responses, endoplasmic reticulum homeostasis, lipid signaling, autophagy, and DNA damage and repair, pointing to a previously unrecognized epithelial stress state in Tor1a+/{Delta}GAG mouse model. Integrative microbial-host interaction correlation analyses uncovered robust associations between specific dysbiotic taxa and host signaling pathways. These peripheral perturbations coincide with longitudinal motor deficits, suggesting a mechanistic gut-brain axis linking intestinal dysfunction to central neuronal vulnerability. Together, our findings provide the first experimental framework connecting microbiome perturbations, gut-barrier disruption, and neuronal vulnerability in a genetic model of dystonia. This work positions the gut microbiome and its regulation of epithelial and neuronal homeostasis as a novel entry point for disease modification in individuals carrying deleterious dystonia-associated variants.

neuroscience↗

bioRxiv2025

Nutrient/TOR signaling controls Mitochondrial transcription factor A (TFAM) to regulate organismal growth in Drosophila

Animals must adapt their growth to fluctuations in nutrient availability to ensure proper development. While nutrient-sensing tissues coordinate organismal growth through inter-organ signaling, the metabolic changes within these tissues that mediate whole-body growth control remain poorly understood. Using Drosophila larvae, we show that TOR (Target-Of-Rapamycin), a conserved nutrient-sensing kinase, controls developmental growth through regulation of the mitochondrial genome transcription factor TFAM, which controls mitochondrial bioenergetic capacity and metabolic state. We find that nutrient/TOR signaling post-transcriptionally suppresses TFAM protein levels. Furthermore, we find that TOR regulation of TFAM in the larval fat body, a key nutrient-sensing tissue, controls developmental growth. These findings establish a molecular mechanism linking nutrient-sensing pathways to mitochondrial metabolic reprogramming, revealing how environmental nutrient availability coordinates organismal growth through tissue-specific metabolic control.

cell biology↗

bioRxiv2025

Arsenic Trioxide Underpins Delayed Neuroinflammation and Impaired Synaptic Integrity involving Integrative Stress Response Signaling

Arsenic trioxide (ATO), an industrial and environmental chemical with potential for accidental or intentional exposure, exerts profound neurotoxic effects. Its single acute exposure has been linked to delayed neurological and neurodegenerative outcomes. However, the molecular and cellular pathways driving these long-term manifestations remain poorly defined. In this study, combining human iPSC-derived neuronal and in vivo mouse model, we uncovered that the acute ATO exposure activates cellular stress pathway, which drives long-term neurotoxic and associated functional outcomes. We found that ATO induces integrated stress response (ISR) signaling in human iPSC-derived neurons. To model the impact of accidental ATO exposure in vivo, we administered a single high dose of ATO to C57BL/6J wild type mice. Four weeks post-treatment, ATO-exposed mice displayed neuropsychological symptoms and cognitive deficits. Brain analyses of ATO-challenged mice revealed elevated ISR activity marked by the increased phosphorylation of PERK and eIF2 and upregulation of the transcription factors, CHOP and ATF4. Transcriptomic profiling using bulk RNAseq revealed activation of pathways associated with stress and neuroinflammatory responses. Consistently, increased DNA damage and dysregulation of the STING-mediated innate immune response were also found in the brain of ATO-challenged mice. Pharmacological inhibition of the ISR with a small-molecule inhibitor, ISRIB mitigated ISR activation and preserved synaptic integrity in mouse hippocampal cells. In conclusion, our data identify ISR activation and DNA damage-driven immune dysregulation as key pathogenic drivers of ATO-induced delayed neurotoxicity and cognitive deficits and highlight ISR inhibitors as promising therapeutics to mitigate these effects.

neuroscience↗

bioRxiv2025

Tumors Located in the Brain Impair the Frequency and Phenotype of Dendritic Cells in Blood and Tumor

BackgroundProfessional antigen-presenting dendritic cells (DC) are critical for anti-tumor immune responses, yet patients with glioblastoma, an aggressive primary brain tumor that responds poorly to current investigational immunotherapies, appear to be deficient in DC. The extent of this deficiency, the specific DC subsets affected, and the causative mechanisms remain undefined. Furthermore, DCs in other brain tumors have not been systematically investigated. MethodsHigh-parameter flow cytometry was used to profile circulating and intra-tumoral DCs in patients with glioblastoma, low-grade gliomas, and brain metastases, and non-CNS cancers. Plasma DC growth factors were quantified using ELISA. We also evaluated single-cell RNA sequencing (scRNAseq) datasets to compare intra-tumoral DCs in brain and lung tumors, and quantified DC number and phenotype in three intracranial mouse brain tumor models. ResultsOur studies reveal a profound systemic reduction of multiple DC subsets in the blood of patients with diverse brain tumors, coupled with reduced DC activation marker expression and lower plasma levels of FLT3L and G-CSF. Furthermore, scRNAseq analyses revealed reduced intra-tumoral DCs in glioblastoma compared to lung tumors. Circulating DC numbers inversely correlated with perioperative corticosteroid dose in patients with or without a brain tumor. However, brain tumor patients not receiving corticosteroids also had reduced DCs, suggesting a direct effect of the brain tumor. This was supported by our observation of systemic DC defects in mouse brain tumor models. ConclusionsWe reveal profound DC defects in patients with brain tumors, which may contribute to current difficulties in developing effective immunotherapies for glioblastoma. SummaryWe demonstrate multiple DC defects in patients with brain tumors. This includes a profound reduction in circulating DC number, diminished activation marker expression and growth factor levels in cancer patients with brain tumors compared to those without, and reduced intra-tumoral DCs in brain compared to lung tumors. This is the first time DC subsets have been fully characterized in a range of brain tumor patients. We show that corticosteroid usage is closely associated with DC defects, highlighting the adverse effects of a standard symptomatic treatment on these critical immune cells. However, tumors located within the brain also directly contribute to DC defects. We identified several mouse brain tumor models that can be used to further the understanding of this endogenous DC deficiency and to develop approaches to restore DCs, ultimately leading to new combination immunotherapies for the treatment of brain cancers. HighlightsO_LIDCs are reduced in brain tumor patients and mice with intracranial tumors. C_LIO_LIDCs are rare within glioblastoma tumor tissue. C_LIO_LIThe presence of a brain tumor and corticosteroid use are both associated with DC defects. C_LI

immunology↗