Biology subjects

Sharma, K.

Publications and source records attributed to Sharma, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Central Glucagon-Like Peptide-1 Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of obesity and type 2 diabetes (T2D). These drugs also have anti-inflammatory effects that have recently been extended to the treatment of inflammatory bowel disease (IBD). Whether the mechanism underlying this benefit involves a direct action on the intestine or instead is mediated via GLP-1Rs in the brain, however, is unknown. Based on evidence implicating the brain as the target for the anti-obesity and anti-inflammatory effects of GLP-1RAs, we sought to determine if central GLP-1R signaling is sufficient to explain its intestinal anti-inflammatory effects. To this end, we compared the efficacy of peripheral vs central administration of the GLP-1RA, semaglutide (SEMA), in diet-induced obese (DIO) mice with dextran sodium sulfate (DSS)-induced colitis. We report that compared to vehicle, both colitis severity and histopathological injury following DSS administration are reduced by peripheral administration of SEMA. We also report that this benefit is largely recapitulated by intracerebroventricular administration of SEMA at a low dose that, when administered peripherally, is below that needed to affect food intake and body weight. We conclude that in a mouse model of colitis, activation of GLP-1Rs in the brain is sufficient to explain the intestinal anti-inflammatory effect conferred by GLP-1R agonism.

neuroscience↗

bioRxiv2026

Targeted and bilateral blood flow monitoring in middle cerebral artery using diffuse correlation spectroscopy

Objective: To develop and validate a dual-probe Diffuse Correlation Spectroscopy (DCS) system for non-invasive and simultaneous, monitoring of cerebral blood flow (CBF) in the bilateral Middle Cerebral Artery (MCA) territories, and expanding the utility of conventional DCS limited to cortical-volume-based CBF measurements to vessel-specific cerebral perfusion monitoring. Methods: A dual-probe DCS system was designed for non-invasive monitoring of MCA-specific perfusion. Probe placement and protocol optimization study has been performed using anatomical landmarks, motor and speech activation tasks in healthy volunteers. System stability and repeatability were further evaluated in a pilot cohort of 30 healthy (age, 25{+/-}7 years) participants using optimized probe position and protocol. A bilateral MCA ischemic Lacunar Infract stroke case report also validated the feasibility of the system in clinical settings. Results: Measurements demonstrated superior sensitivity towards MCA-territory perfusion at targeted probe locations compared to off-MCA positions. In pilot cohort, significant increase of 30.34 {+/-} 21.56% and 36.48 {+/-} 21.22% in rCBF corresponding to hand squeeze and speech task respectively showed reproducible physiological responsiveness of the system (p<0.001). Measurement done on a patient with bilateral MCA ischemic Lacunar Infract stroke showed a significant change of 30% during speech for both the MCAs but no significant change is observed for hand squeeze tasks. Conclusion: The custom built dual-probe DCS system enables non-invasive, operator-independent, targeted and continuous monitoring of rCBF within bilateral MCA territories. Significance: This approach enables the potential use of DCS system for bilateral and vessel-specific monitoring of cerebral perfusion in the MCA territories.

bioengineering↗

bioRxiv2026

Orthogonal Chemical Proteomic Strategies Reveal the Cholesteryl Ester Interactome in Mammalian Cells

Cholesteryl esters (CEs) are widely regarded as inert storage forms of cholesterol, yet their potential to directly engage cellular proteins remains largely unexplored. Here, we establish an integrated chemical proteomic platform to systematically define CE-protein interactions in mammalian cells. We developed and comparatively deployed three orthogonal photoaffinity labeling strategies: (i) metabolic assembly of a bifunctional CE probe through endogenous acyl-CoA:cholesterol acyltransferase activity, (ii) direct delivery of a structurally defined diazirine-alkyne CE analog, and (iii) fragment-assisted subtraction using sterol and fatty acyl control probes to resolve interactions dependent on the intact esterified scaffold. Each probe system was rigorously validated by lipidomics and UV-dependent crosslinking prior to quantitative proteomic analysis. Integration of these complementary modalities identified 495 CE-associated proteins spanning enzymes, transporters, scaffolding proteins, and canonical sterol-binding families. The limited overlap across strategies reveals that lipid-protein engagement is strongly conditioned by biosynthetic origin, probe topology, and intracellular routing. Functional and database annotations further demonstrate enrichment of druggable and disease-linked proteins, connecting CE interactions to metabolic, neurological, and cardiovascular pathways. Collectively, this work provides the first systems-level map of CE-protein interactions and establishes a generalizable, multimodal framework for chemically resolving lipid-protein interactomes.

biochemistry↗

bioRxiv2026

Targeted measurement of blood flow in the Anterior Cerebral Artery using Diffuse Correlation Spectroscopy

SignificanceDiffuse Correlation Spectroscopy (DCS) is an established technique for non-invasive monitoring of Cerebral Blood Flow (CBF), but existing applications primarily measure CBF changes averaged over cortical tissue volumes. A method capable of targeting blood flow within a particular intracranial artery would expand the utility of DCS for vessel-specific cerebral perfusion monitoring and continuous bedside assessment. AimWe aim to investigate the feasibility of targeted, non-invasive monitoring of blood flow in the Anterior Cerebral Artery (ACA) using DCS through optimization of probe geometry and placement. ApproachA custom-built DCS system operating at 785 nm was used to probe ACA from the glabellar region. Source-detector (SD) separation, probe orientation, and probe location were systematically optimized using lower-limb motor tasks and a mental arithmetic task. The optimized configuration was evaluated using an ACA-mimicking multilayer phantom and validated in forty healthy volunteers during lower-limb activation tasks and postural changes. ResultsAn SD separation of 17 mm, vertical probe orientation, and glabellar placement provided the highest sensitivity to ACA-related blood flow changes. Phantom experiments demonstrated sensitivity to flow changes in a vessel located 45 mm beneath the scalp and showed that the frontal sinus, cerebrospinal fluid, and the absence of cortical tissue beneath the glabella along the longitudinal fissure together provide the best optical window for probing deep ACA flow. Using the optimized probe configuration, significant increases in relative CBF were observed during standing leg marching (66.4 {+/-} 38.6%) and supine leg crunches (39.4 {+/-} 32.2%) (p < 0.01), with consistent responses during supine-to-stand postural transitions. ConclusionThe proposed DCS approach enables targeted measurement of blood flow within the ACA territory. This technique provides a framework for continuous, non-invasive monitoring of ACA perfusion and has potential applications in cerebrovascular monitoring and stroke care.

bioengineering↗

bioRxiv2026

Targeting Autophagy Accelerates Intestinal Repair after Acute Ionizing Radiation

Radiation exposure induces systemic and cellular damage, contributing to acute radiation syndrome and long-term effects such as premature aging and carcinogenesis. At the cellular level, radiation triggers apoptosis, mutation, and transformation through oxidative damage and activation of pathways including ER stress-mediated autophagy. Autophagy plays a context-dependent dual role in stressed cells, but its contribution to intestinal recovery after acute radiation remains unclear. Here, we evaluated combinatorial radiomodification using gamma radiation (8 Gy) and autophagy modulators in whole-body irradiated C57BL/6 mice (8-10 weeks old, n = 10). Mice were treated with autophagy inducers or inhibitors and euthanized at 3-, 8-, and 30-day post-irradiation. The jejunal-ileal region was analyzed via antioxidant assays, immunoblotting, H&E staining, and immunohistochemistry. Radiation significantly altered oxidative stress and autophagy markers, including increased LC3-II and decreased SQSTM1/p62. Autophagy induction enhanced intestinal proliferation (as measured by Ki-67), whereas inhibition impaired regeneration. Rapamycin pretreatment improved survival and reduced markers of intestinal injury following 8 Gy total body irradiation (TBI), whereas chloroquine exacerbated several injury-associated parameters. Overall, our findings suggest that targeted modulation of autophagy is a promising strategy for alleviating radiation-induced gastrointestinal injury and provide mechanistic insights relevant to therapeutic development.

molecular biology↗

bioRxiv2026

EGFR INHIBITION PROMOTES ENTEROENDOCRINE CELL DIFFERENTIATION CONTRIBUTING TO TREATMENT-ASSOCIATED DIARRHEA

Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief SummaryInhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

cell biology↗

bioRxiv2026

Reduced Myocardial Serine Synthesis Impairs Functional, Metabolic, and Redox Adaptations to Cardiac Stress

BackgroundImpaired myocardial metabolism is a defining feature of heart failure, but many defective pathways and mechanisms remain to be identified. Prior studies find phosphoglycerate kinase and its synthesized product 3-phospho-glycerate required for the serine synthetic pathway (SSP) are reduced in human HFpEF myocardium. As serine is also provided exogenously, the impact of SSP reduction is uncertain. Here, we tested if and how SSP decline coupled to phosphoglycerate dehydrogenase (PHGDH) impacts cardiomyocyte (CM) and whole heart metabolic remodeling and stress responses. MethodsStudies were performed in isolated CMs and mice with CM-selective knock-down of PHGDH. Using pharmacological inhibition or genetic silencing of PHGDH, we tested their impact on CM one-carbon metabolism pathways, cell hypertrophic responses, mitochondrial respiration, and in vivo functional, structural, and metabolic adaptations to pressure-overload stress. ResultsIn CMs, PHGDH inhibition caused dose-dependent serine depletion linearly coupled with cytotoxicity, accompanied by NAD/NADH and GSH/GSSG imbalance, reduced ATP, and disruption of one-carbon and nucleotide metabolites. Stable-isotope tracing revealed distinct metabolic fates of glucose-derived (SSP) versus exogenous serine. Exogenous serine did not rescue PHGDH-deficient CMs, whereas combined ribose and an anti-oxidant (DTT) attenuated injury and reduced nucleotide pools. PHGDH suppression reduced amino acid abundance, impaired nascent protein synthesis, and blunted endothelin-1-induced hypertrophic and mitochondrial respiration. In vivo, cardiomyocyte-specific PHGDH heterozygous mice (PHGDH+/-) had no basal phenotype, but amplified chamber dilation, dysfunction, fibrosis, and mortality 4 weeks after transverse aortic constriction (TAC). Corresponding increases in amino acids, one-carbon metabolites, nucleotides, and TCA-cycle intermediates in wild-type TAC hearts were significantly blunted in PHGDH+/- hearts. ConclusionsCardiomyocyte SSP is a critical regulator of redox balance, one-carbon metabolism, purine synthesis, amino acid homeostasis, and growth-related pathways required for cardiac adaptation to pressure overload. It is non-redundant with exogenous serine by providing distinct influences on key metabolic pathways and is a potential therapeutic target.

molecular biology↗

bioRxiv2026

In silico characterization of unique fungal modular rhodopsin expands the horizon of novel optobiological and biomedical applications

Microbial modular rhodopsins, in which light-sensing rhodopsin domains are fused with effector modules, have emerged as promising tools for optogenetic regulation in algae and other systems. However, the diversity and potential regulatory roles of fungal modular rhodopsins remain largely unexplored. Here, we performed a comprehensive in-silico analysis to identify previously uncharacterized fungal modular-rhodopsins that pair a conserved light-sensing core with diverse effector domains, including RPEL-motif, NADP-binding Rossmann fold domain, MCM (Mini-Chromosome Maintenance) domain, and GC-cAT (Carnitine O-Acetyltransferase) modules. In Aureobasidium pullulans, the representative modular rhodopsin (ApRh-RPEL) contains RPEL-motif associated with actin-related and transcriptional regulatory processes, suggesting light-driven fungal signaling pathway involved in transcriptional and cellular regulation, respectively. Rhodopsins fused with NADP-binding Rossmann fold and MCM domains further indicate possible applications in light-programmable metabolic and cell-cycle signaling. Genome mining additionally revealed that A. pullulans harbours a diverse but underexplored array of biosynthetic gene clusters (BGCs), raising the intriguing possibility that light perception may regulate secondary metabolite pathways. Supporting this, multisource protein-protein interaction network analysis links ApRh-RPEL to enzymes involved in terpenoid and sphingolipid biosynthesis, indicating potential cross-talk between light-sensing module and metabolic regulation. These findings outline a computationally derived model in which fungal modular rhodopsins (ApRh-RPEL) function as opto-synthetic regulators of biosynthetic processes. Structural predictions confirmed conserved Schiff-base lysine and retinal-binding pocket, highlighting functional diversity across fungal rhodopsins. Together, these findings expand the optogenetic toolkit and provide a framework for engineering light-driven signaling in fungi, with applications in optobiological and biomedical applications.

bioinformatics↗

bioRxiv2026

Directional Gene-Level Concordance and Methodological Constraints in Blood Transcriptomic and DNA Methylation Studies of Parkinson's Disease

Assessing reproducibility across different molecular profiling studies is a persistent methodological challenge (Zhang et al., 2009; Sweeney et al., 2017; Ioannidis, 2005). Differences in platform technology, cohort composition, analytical pipelines, and feature definitions often make it difficult to interpret cross-study comparisons based solely on gene-identity overlap. In this study, we conducted a retrospective computational analysis of seven publicly available analytical datasets (including alternative analytical pipelines applied to the same cohort) derived from five biologically independent peripheral blood transcriptomic and DNA methylation cohorts, comprising 3,487 samples (1,824 Parkinsons disease cases and 1,663 controls). Reproducibility was evaluated using gene-identity overlap, enrichment-based comparisons, and a permutation-based framework to assess directional consistency of effect estimates across datasets. We also tested the robustness of results by varying false discovery rate thresholds and applying alternative probe-to-gene collapsing strategies. All analyses were performed using reproducible workflows implemented in R and Python with fixed random seeds. Across independent cohorts, gene-identity overlap was generally limited, with enrichment ratios close to one, especially when datasets were generated using different platforms. In several datasets, limited numbers of statistically significant features further constrained overlap-based comparisons. In contrast, directional consistency showed greater stability. High levels of directional consistency were observed across independent cohort comparisons when restricted to overlapping statistically significant features and remained stable across statistical thresholds (90.0% at FDR < 0.05 and 82.8% at FDR < 0.10). When evaluated across the full shared gene universe without conditioning on statistical significance, directional consistency was substantially lower ([~]30 to 32%) but remained significantly above permutation-based null expectations. Permutation testing confirmed that the observed directional consistency exceeded what would be expected by chance. A combined analysis including methodological replicates (n [≥] 3 datasets) showed 98.3% directional consistency; however, this estimate includes non-independent analytical pipelines applied to the same cohort and reflects analytical stability rather than independent biological replication. Rather than introducing a new statistical method, this study examines how commonly used reproducibility metrics behave under crossstudy heterogeneity and identifies their practical limitations and appropriate use boundaries.

neuroscience↗

bioRxiv2026

Inhibition in motion: Test-retest reliability of inhibitory kinematics in a go/no-go mouse tracking task

Response inhibition, the ability to suppress contextually inappropriate actions, is a cornerstone of cognitive control and is commonly assessed using paradigms such as the go/no-go task. However, traditional go/no-go paradigms rely on binary outcomes such as commission errors, which offer limited insight into the dynamic, graded behavioral adjustments underlying successful stopping. The present study developed a novel mouse-tracking go/no-go paradigm with a dynamic start to capture inhibitory processes during ongoing execution. Twenty-three healthy young adults completed the task in two sessions separated by approximately one week to evaluate the test-retest reliability of standard behavioral measures (error rates and reaction times), and three kinematic features: path length, mean velocity, and mean acceleration. Results revealed robust differences between go and no-go trials across all measures. Successful inhibition was characterized by significantly shorter path lengths and reduced mean velocity and acceleration compared to go trials. Critically, all measures demonstrated moderate-to-good test-retest reliability across sessions, with intraclass correlation coefficients ranging from .75 to .85 for go trials and from .59 to .83 for no-go trials. These findings establish construct validity and psychometric reliability of the current mouse-tracking go/no-go paradigm. The demonstrated stability of these measures provides the methodological foundation for their use in cross-sectional, longitudinal, and intervention research targeting inhibitory control.

neuroscience↗

bioRxiv2026

Time-Resolved Neuronal Network Dynamics Distinguish Pathological States in Organoid Models

Human brain assembloids offer a powerful platform for modeling neurological diseases, yet comprehensive methods for analyzing their complex network dynamics are lacking. Here, we developed a time-resolved network analysis pipeline that extracts quantitative biomarkers from two-photon calcium imaging, enabling the detection of subtle differences between disease and control models. We applied this pipeline to assembloids containing a pathogenic MAPT p.R406W variant--clinically associated with an Alzheimers disease-like phenotype--and their isogenic controls. Our analysis revealed that mutant networks exhibit significantly increased degree variance and clustering. This indicates a "hub-like", interconnected topology prone to hypersynchrony, a finding that parallels the network hyperexcitability and seizure-like features observed in in-vivo models of Alzheimers disease. Furthermore, a Random Forest classifier trained on these dynamic network features distinguished between diseased and control states with high accuracy (F1 score = 0.90). These results establish that dynamic network properties can serve as potent biomarkers for identifying pathological states in assembloid models, providing a quantitative framework to investigate disease mechanisms and potential therapeutic interventions.

neuroscience↗

bioRxiv2026

Tau regulates epithelial morphogenesis through vesicle trafficking dependent Notch activation

Tau is a conserved microtubule-associated protein best known for its roles in neuronal cytoskeletal stability and axonal transport. However, its functions in non-neuronal tissues remain poorly understood. Here we demonstrate that Drosophila Tau (dTau) regulates epithelial growth and tissue architecture in the Drosophila Malpighian tubules by controlling vesicular trafficking and Notch signaling. Loss of dTau results in pronounced epithelial hyperplasia, increased tubule diameter, and ectopic branching. Despite elevated Notch transcript levels, dTau-deficient tubules exhibit significantly reduced Notch intracellular domain (NICD), indicating impaired pathway activation. Proteomic and cellular analyses reveal widespread disruption of endocytic regulators and vesicle trafficking components, including reduced levels of the endocytic adaptor Liquid facets (Epsin) and altered distribution of Rab5, Rab7, and Rab11 endosomes. dTau loss also disrupts autophagic-lysosomal homeostasis and reduces endosome-lysosome fusion. These trafficking defects correlate with abnormal Delta localization and diminished Notch signaling. Together, our findings uncover a previously unrecognized role for dTau in maintaining epithelial signaling homeostasis by coordinating vesicular trafficking and receptor activation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/713835v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@d8e3b6org.highwire.dtl.DTLVardef@14de1f6org.highwire.dtl.DTLVardef@2de65aorg.highwire.dtl.DTLVardef@16e2702_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2026

Blautia wexlerae Transforms Dietary Fatty Acids to Activate Enteroendocrine Signaling and Improve Metabolic Health in Mice and Humans

Metabolites produced by the gut microbiome influence host metabolic health, but how this occurs remains incompletely defined. Here, we report that a common human gut commensal, Blautia wexlerae, converts dietary fats into bioactive metabolites that induce gut hormone production to affect glucose metabolism and suppress appetite. We found that colonization with Blautia wexlerae correlated with healthier eating behaviors in humans. Blautia wexlerae encodes a unique acyl transferase and is capable of producing acyl amines from nutrient substrates. These Blautia acyl amines stimulated human enteroendocrine cells to secrete GLP-1 and other gut peptide hormones more potently than endogenously produced acyl amines. When fed to mice, acyl amines improved glycemic control and decreased appetite. In humans, higher stool levels of Blautia DNA encoding acyl amine synthesis genes correlated with leanness and decreased dietary fat intake. These results define a mechanism of action for how Blautia wexlerae affects host metabolic control.

microbiology↗

bioRxiv2026

Hidden palette: Culturing the sauropsid gut microbiome reveals a high prevalence and diversity of bacteria that undergo carotenoid biosynthesis

Pigments play essential roles in communication, sexual signaling, and ecological adaptation in taxa across the tree of life and are especially important for animals, which often rely on carotenoid pigments for their coloration. One potentially important yet largely overlooked source of pigments is host-associated microbes. Microbial carotenoids may influence host coloration or other fitness-related traits, but the extent to which they occur or vary across associations with host species remains largely unknown. To begin to address this gap, we used culture-based techniques to isolate gut-associated bacteria from multiple wild sauropsid species. We cultured 157 morphologically distinct bacterial isolates from 25 individuals representing eight host species; 17% of isolates were yellow- or orange-pigmented, and 40% of isolates exhibited absorbance spectra consistent with the presence of carotenoids. Sequencing of the 16S rRNA gene revealed that isolates spanned four phyla and 35 genera. Isolates that were consistent with the presence of carotenoids were found across all four phyla, with Pantoea being the most frequently represented carotenoid-associated genus. These results demonstrate that carotenoid-capable bacteria are both taxonomically diverse and prevalent in the gut microbiomes of wild sauropsids. More broadly, our findings provide insight into a hidden dimension of host-microbe interactions and their potential function.

microbiology↗

bioRxiv2026

Friend, not Foe: Lowered Tissue Reactivity to Long-Term Polyimide Implants

One of the biggest challenges for neurotechnology is the design of devices that are tolerated well by brain tissue, without sacrificing functionality and implantability. This study examined which design choices mitigate tissue damage and improve longevity, by varying probe features implanted in the cerebral cortex of mice. We report on a systematic, quantitative analysis of neuronal and inflammation markers across cortical depth. We implanted a total of 103 stiff silicon or flexible polyimide probes in 32 mice, varying their thicknesses and widths, which were either attached to the skull or not. A new, automated workflow to quantify immunohistochemical data examines: 1) the tissue loss caused by the implant, 2) the cortical neuronal density, and 3) the immune response expressed by astrocytic and microglial reaction. Flexible polyimide probes exhibited a clear advantage, with fewer lesions and weaker immune responses than stiff silicon probes. Furthermore, we observed a weaker influence of the shank cross-section. A cortical depth profile of immune reactivity revealed focal reactions at the device entry points in the superficial cortex and at the cortex-white matter boundary. This study gives important insights on optimizing device design parameters as well as surgical insights for improved tissue integration of intracortical electrode arrays.

bioengineering↗

bioRxiv2026

Defects in tissue-resident macrophages lead to smaller eardrums and abnormal neurovascular networks with increased middle-ear infection

The tympanic membrane (TM), or eardrum, is essential for hearing. Macrophages, the primary innate immune cells, are densely distributed in the eardrum after birth, especially near blood vessels and nerve fibers. During postnatal development, neonatal tissue-resident macrophages (TRMs) gradually polarize, and their population declines. These dynamic changes closely parallel the maturation of neurovascular networks. What are the precursors of the early wave of TRMs? Are they critical for postnatal TM development? Using fate mapping, single-cell RNA sequencing, and macrophage depletion, this study reveals for the first time that postnatal eardrum TRMs are heterogeneous, originating mainly from embryonic myeloid lineages, with increasing input from postnatal monocyte progenitor-derived cells. Single-cell RNA sequencing identifies gene signatures vital for vascular and neuronal development. Depleting TRMs results in smaller eardrums, disrupted vascular-neuronal networks, and increased risk of middle-ear infection. This study offers new insight into how the innate immune system supports TM maturation and protects against middle-ear infection during a critical postnatal window. TeaserTissue-resident macrophages guide eardrum neurovascular maturation and help prevent middle-ear abnormalities.

immunology↗

bioRxiv2026

Root-Suppressed Phenotype of Tomato Rs Mutant is Seemingly Related to Expression of Root-Meristem-Specific Sulfotransferases

Root development and growth are governed by a complex interplay between a plants genetic makeup and its ambient environment. In this study, we characterised a radiation-induced root-suppressed (Rs) mutant mapped on chromosome 4 of tomato. Rs seedlings had a dwarf stature, and mature plants exhibited abnormalities in their leaves, flowers, and fruits. The partial rescue of seedling root elongation by H2S donors or L-cysteine hinted that its root defect is linked to disrupted sulfur metabolism. The metabolite profiling of organs revealed altered homeostasis, analogous to that of plants subjected to sulfur starvation. Whole-genome sequencing revealed that the Rs genome was replete with genetic lesions; therefore, the pleiotropic morphological abnormalities likely emanate from mutations in other genes, including those related to sulfur. Among S-related genes, two sulfotransferase genes (Solyc04g028380 and Solyc04g028390) localised on chromosome 4 showed mutations in their promoters. The expression of both sulfotransferases is confined to the root meristem, suggesting a causal connection with the suppression of root growth. These sulfotransferases belonged to a distinct subset exclusively expressed in the root meristem and were distinct from the tyrosine sulfotransferase involved in the sulfation of root growth factors. Our study suggests that a sulfur-related module, other than tyrosine sulfotransferase, may regulate root development.

plant biology↗

bioRxiv2025

Early disruption of neurogenesis and neural architecture by amyloid β and Tau during Drosophila development

Alzheimers disease is recognized as a late-onset neurodegenerative disorder; however, accumulating evidence suggests that disease-associated proteins may exert deleterious effects much earlier during neural development. Using a Drosophila model expressing human amyloid-{beta} and Tau, we investigated the impact of these proteins on embryonic neurodevelopment and neural stem cell dynamics. Embryos expressing amyloid-{beta} and Tau exhibited pronounced defects in axonal patterning and compromised neuronal cytoskeletal integrity, indicating early disruption of neural architecture. We observed aberrant elevation and mislocalization of the cell fate determinant Prospero, leading to premature neuronal differentiation and disruption of progenitor lineage progression. Consequently, larval brains displayed a reduced number of Prospero-positive ganglion mother cells, reflecting impaired neuroblast lineage maintenance. Cell-cycle analysis using the FUCCI system revealed altered neuroblast cell-cycle dynamics, characterized by depletion of proliferative populations and enrichment of G1-phase cells, indicative of stem cell exhaustion. In addition, increased apoptotic signaling was detected in larval neural tissues expressing amyloid-{beta} and Tau. Together, our findings demonstrate that amyloid-{beta} and Tau disrupt asymmetric division, differentiation, and self-renewal of neural stem cells during development, resulting in reduced neuronal output and defective brain organization. This study highlights that amyloid-{beta} and Tau exert neurotoxic effects early in development, providing mechanistic insight into how neurodevelopmental perturbations may contribute to later neurodegeneration.

developmental biology↗