Biology subjects

Mehta, H.

Publications and source records attributed to Mehta, H..

7 recordsLinked to original sources

bioRxiv2026

Hog1/p38 and ZAKα drive Shwachman-Diamond syndrome and provide targets to improve cell growth

Shwachman-Diamond syndrome (SDS) is a ribosomopathy characterized by neutropenia, pancreatic insufficiency, skeletal defects, and predisposition to leukemia. Most cases result from biallelic SBDS mutations that impairing 80S ribosome and polysome assembly. In yeast lacking SDO1 (the SBDS ortholog), growth slows dramatically and the p38 ortholog Hog1 signaling is elevated by multiple types of stress. SBDS-deficient HeLa cells exhibited reduced proliferation and slowed cell cycling. The p38 kinase was constitutively activated in SBDS mutants and SDS patient-derived blood cells. Because ZAK detects ribosome dysfunction, its activation links ribosomal defects to stress kinase pathways in SDS. Suppressing p38 or its upstream activator ZAK restored cell growth and reduced stress signaling. These findings reveal an evolutionarily conserved-independent mechanism via p38 drives SDS pathophysiology and identifies stress kinases as potential therapeutic targets for ribosomal dysfunction.

cell biology↗

bioRxiv2025

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs) - arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin) - led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Bulk and single-nucleus RNA-sequencing revealed that ABP knockdowns elicited a strongly "aged" transcriptome. Actin dysfunction broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely-tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting evolutionary conservation of actins role in healthy aging. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how actin integrity intersects with diverse aging pathways across tissues and scales. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics contribute to aging.

cell biology↗

bioRxiv2025

Investigating The Potential of Division of Labour in Synthetic Bacterial Communities for the Production of Violacein

With advancements in synthetic biology and metabolic engineering, microorganisms can now be engineered to perform increasingly complex functions, which may be limited by the resources available in individual cells. Division of labour in synthetic microbial communities offers a promising approach to enhance metabolic efficiency and resilience in bioproduction. By distributing complex metabolic pathways across multiple subpopulations, the resource competition and metabolic burden imposed on an individual cell is reduced, potentially enabling more efficient production of target compounds. Violacein is a high-value pigment with anti-tumour properties that exemplifies such a challenge due to its complex bioproduction pathway, imposing a significant metabolic burden on host cells. In this study we investigated the benefits of division of labour for violacein production by splitting the violacein bioproduction pathway between two subpopulations of Escherichia coli based synthetic communities. We tested several pathway splitting strategies and reported that splitting the pathway into two subpopulations expressing VioABE and VioDC at a final composition of 60:40 yields a 2.5 fold increase in violacein production as compared to a monoculture. We demonstrated that the coculture outperforms the monoculture when both subpopulations exhibit similar metabolic burden levels, resulting in comparable growth rates, and when both subpopulations are present in sufficiently high proportions.

bioengineering↗

bioRxiv2024

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair for somatic benchmarks

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, and Hi-C, and karyotyping. In future publications, these data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

genomics↗

bioRxiv2023

Experimental evolution of Pseudomonas aeruginosa to colistin in spatially confined microdroplets identifies evolutionary trajectories consistent with adaptation in microaerobic lung environments

Antibiotic resistance is a continuing global health crisis. Identifying the evolutionary trajectories leading to increased antimicrobial resistance can be critical to the discovery of biomarkers for clinical diagnostics and new targets for drug discovery. While the combination of patient data and in vitro experimental evolution has been remarkably successful in extending our understanding of antimicrobial resistance, it can be difficult for in vitro methods to recapitulate the spatial structure and consequent microenvironments that characterize in vivo infection. Notably, in cystic fibrosis (CF) patients, changes to either the PmrA/PmrB or PhoP/PhoQ two-component systems have been identified as critical drivers for high levels of colistin and polymyxin resistance. When using microfluidic emulsions to provide spatially structured, low-competition environments, we found that adaptive mutations to phoQ were more successful than pmrB in increasing colistin resistance. Conversely, mutations to pmrB were readily identified using well-mixed unstructured cultures. We found that oxygen concentration gradients within the microdroplet emulsions favored adaptive changes to the PhoP/PhoQ pathway consistent with microaerobic conditions that can be found in the lungs of CF patients. We also observed mutations linked to hallmark adaptations to the CF lung environment, such as loss of motility (fleQ, fliC, fleS, flg, flh, and fleQ) and loss of O antigen biosynthesis (wbpL). Mutation to wbpL, in addition to causing loss of O antigen, was additionally shown to confer moderately increased colistin resistance. Taken together, our data suggest that distinct evolutionary trajectories to colistin resistance may be shaped by the microaerobic partitioning and spatial separation imposed within the CF lung. ImportanceAntibiotic resistance remains one of the great challenges confronting public health in the world today. Individuals with compromised immune systems or underlying health conditions are often at an increased for bacterial infections. Patients with Cystic Fibrosis (CF) produce thick mucus that clogs airways and provides a very favorable environment for infection by bacteria that further decrease lung function and, ultimately, mortality. CF patients are often infected by bacteria such as Pseudomonas aeruginosa early in life and experience a series of chronic infections that, over time, become increasingly difficult to treat due to increased antibiotic resistance. Colistin is a major antibiotic used to treat CF patients. Clinical and laboratory studies have identified PmrA/PmrB and PhoP/PhoQ as responsible for increased resistance to colistin. Both have been identified in CF patient lungs, but why, in some cases, is it one and not the other? In this study, we show that distinct evolutionary trajectories to colistin resistance may be favored by the microaerobic partitioning found within the damaged CF lung.

microbiology↗

bioRxiv2023

Host-aware RNA-based control of synthetic microbial consortia

Microbial consortia have been utilised for centuries to produce fermented foods and have great potential in applications such as therapeutics, biomaterials, fertilisers, and biobased production. Working together, microbes become specialized and perform complex tasks more efficiently, strengthening both cooperation and stability of the microbial community. However, imbalanced proportions of microbial community members can lead to unoptimized and diminished yields in biotechnology. To address this, we developed a burden-aware RNA-based multicellular feedback control system that stabilises and tunes coculture compositions. The system consists of three modules: a quorum sensing-based communication module to provide information about the densities of cocultured strains, an RNA-based comparator module to compare the ratio of densities of both strains to a pre-set desired ratio, and a customisable growth module that relies either on heterologous gene expression or on CRISPRi knockdowns to tune growth rates. We demonstrated that heterologous expression burden could be used to stabilise composition in a two-member E. coli coculture. This is the first coculture composition controller that does not rely on toxins or syntrophy for growth regulation and uses RNA sequestration to stabilise and control coculture composition. This work provides a fundamental basis to explore burden-aware multicellular feedback control strategies for robust stabilisation of synthetic community compositions.

synthetic biology↗

bioRxiv2022

Mitochondrial TFAM in the Regulation of FOXP3+ T cell Mediated Maintenance of CD4+ T Cell Landscapes

Foxp3 regulatory T cells (Tregs) maintain immune homeostasis, yet the process that preserves their stability during aging remain unclear. Mechanistic progress has been hindered by models that ablate Tregs or delete Foxp3, which induce acute autoimmunity and prevent longitudinal study of physiological regulatory drift. Here, we establish a dose-dependent mitochondrial framework that preserves Treg lineage survival while permitting gradual metabolic attenuation. Using Treg-restricted TFAM modulation, a complementary haploinsufficient model, and whole-spleen single-cell profiling. We identify lineage-selective immune remodeling characterized by contraction of naive CD8 and follicular B-cell pools, alteration of CD4 states, expansion of activated Tregs, and emergence of neuroimmune stress linked transcriptional modules that parallel physiological aging. Mechanistically, mitochondrial insufficiency is associated with functional loss of FOXP3-centered chromatin coordination and enrichment of NF-{kappa}B/NFAT/AP-1 inflammatory and senescence programs while lineage identity remains detectable. Partial mitochondrial attenuation within Tregs alone is sufficient to drive chronic low-grade systemic inflammation, neuromuscular decline, gut microbial restructuring, and elevated microglial responsiveness without Treg depletion. Pharmacologic and microbiota-directed interventions partially reduce inflammatory tone and improve functional metrics. Together, our findings identify TFAM as a key regulator of immune aging and reveal that healthy mitochondrial function in Tregs is essential for protecting against inflammaging and age-associated functional decline.

immunology↗