Biology subjects

Munshi, R.

Publications and source records attributed to Munshi, R..

6 recordsLinked to original sources

bioRxiv2026

Glycocalyx-Directed Enzymatic Hydrogels Unlocks Fibroblast Regeneration to Promote Diabetic Wound Healing

Chronic diabetic wounds remain a major clinical challenge because current therapies address infection or supplement growth factors without correcting the cellular dysfunction that prevents regeneration. We identify pathological glycocalyx thickening in diabetic dermal fibroblasts (DDFs) as a driver of elevated caspase 3, 8, and 9 expression and heightened apoptosis -- deficits that stall wound repair. Cleavage of sialic acid residues by neuraminidase (NMase) reverses this dysfunction, restoring fibroblast migration, proliferation, and contractility. We engineer a photo-crosslinked hybrid hydrogel combining methacrylated gelatin (GelMA) with high-molecular-weight methacrylated chitosan (HMW ChMA). ChMA increases storage modulus 8-12-fold, reduces pore size, and confers antibacterial activity against gram-positive and gram-negative bacteria, addressing infection susceptibility. The fortified HMW hybrid (HMWH) network enables sustained, localized NMase delivery that outperforms GelMA alone in resisting degradation and controlling release kinetics. NMase-loaded HMWH (N-HMWH) gels enhance DDF proliferation and migration in vitro, correlating with reduced focal adhesion size and increased turnover. In a diabetic rat model, N-HMWH patches achieve superior wound closure, outperforming EGF therapy, with robust epidermal regeneration, neovascularization, and collagen deposition. This work establishes glycocalyx-targeting hydrogels as a new class of wound therapeutics addressing the root cause of diabetic fibroblast failure, not just compensating with growth factors.

bioengineering↗

bioRxiv2022

Deep Brain Magnetothermal Silencing of Dopaminergic Neurons via Endogenous TREK1 Channels Abolishes Place Preference in Mice

Remote neuromodulation techniques have revolutionized our understanding of brain circuits and their role in behavior. The reversible silencing of specific neuronal populations has emerged as a powerful tool to investigate the necessity and sufficiency of these populations in behavioral responses. Here, we apply magnetothermal silencing using endogenous TREK-1 channels to selectively suppress dopaminergic reward in the ventral tegmental area (VTA) to prove that activation of this specific reward circuit is required for place preference in mice. Magnetothermal silencing entails the application of alternating magnetic fields that penetrate tissue, leading to the heating of superparamagnetic nanoparticles at the target cells, without causing any attenuation or adverse effects. The resultant slight, rapid, and reversible elevation in temperature effectively suppresses neuronal firing, without necessitating genetic modification of the neurons. We demonstrate that two-pore potassium channels, TREK-1, are responsible for this thermal neuronal silencing. Using fiber-based optogenetics we measured both the heating and neuronal silencing in the VTA brain of the animals. We show that in a place preference assay, magnetothermal neuronal silencing of the dopaminergic neurons in the VTA is sufficient to abolish the place preference. Notably, TREK1 knock-out mice exhibit immunity to magnetothermal silencing, behaving as if the magnetic field was not applied. These results underscore the critical role of dopaminergic neuronal activity in the VTA for the establishment of place preference and highlight the dependency on functional TREK1 channels in this magnetothermal silencing approach. HighlightsO_LITREK1 is a highly efficient, thermally activated neuronal silencer C_LIO_LIFirst magnetothermal neuronal silencing in behaving mice C_LIO_LIFiber photometry quantification of local heating and silencing of target neurons in the ventral tegmental area C_LIO_LIMagnetothermal suppression of dopaminergic reward response in the ventral tegmental area is sufficient to abolish place preference C_LI

neuroscience↗

bioRxiv2022

A genome-wide mutational constraint map quantified from variation in 76,156 human genomes

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders, but attempts to assess constraint for non-protein-coding regions have proven more difficult. Here we aggregate, process, and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD), the largest public open-access human genome reference dataset, and use this dataset to build a mutational constraint map for the whole genome. We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation across the genome. As expected, proteincoding sequences overall are under stronger constraint than non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association, and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, while non-coding constraint captures additional functional information underrecognized by gene constraint metrics. We demonstrate that this genome-wide constraint map provides an effective approach for characterizing the non-coding genome and improving the identification and interpretation of functional human genetic variation.

genetics↗

bioRxiv2021

LungMAP Portal Ecosystem: Systems-Level Exploration of the Lung

An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular, imaging and pathological datasets. To centralize and standardize information across broad lung research efforts we expanded the LungMAP.net website into a gateway portal. This portal connects a broad-spectrum of research networks, bulk and single-cell multi-omics data and a diverse collection of image data that span mammalian lung development and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, mouse), to enable consistent queries across technologies, cohorts, age, disease and drug treatment. These atlases are provided as independent and integrated queriable datasets, with an emphasis on dynamic visualization, figure generation and reference-based classification of user-provided datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, data portals and datasets from LungMAP and external research efforts.

systems biology↗

bioRxiv2019

An open resource of structural variation for medical and population genetics

Structural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large ([≥]1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.

genomics↗

bioRxiv2018

Transient Magnetothermal Neuronal Silencing using the Chloride Channel Anoctamin1 (TMEM16A)

The importance of specific neurons to a networks function is best studied by precisely timed, reversible silencing of these neurons. Previously, we showed that alternating magnetic field mediated heating of magnetic nanoparticles bound to neurons expressing temperature-sensitive cation channels TRPV1, stimulates these neurons to fire and affects animal behavior in vivo (Munshi et al., 2017). Here, we demonstrate how to apply magnetic nanoparticle mediated heating to silence target neurons. Rat hippocampal neuron cultures are transfected to express the temperature gated chloride Anoctamin1 (TMEM16A) channels. Within seconds the heating of the membrane opens the Anoctamin1 (TMEM16A) channels, suppressing action potential firing. Five seconds of magnetic field application leads to about 12 seconds of silencing, with a latency of about 2 seconds and an average suppression ratio of more than 80%. The method provides a promising avenue for tether free, remote, transient neuronal silencing in vivo for both scientific and therapeutic applications.

neuroscience↗