Biology subjects

Gill, M. S.

Publications and source records attributed to Gill, M. S..

7 recordsLinked to original sources

bioRxiv2026

Geroprotective drug discovery with an AI-enabled assay for heat resistance

Drugs that slow the rate of organismal aging (geroprotectors) have the potential to improve human healthspan by preventing the development of multiple chronic diseases. The nematode C. elegans is a proven system for identifying anti-aging drugs, but methods for candidate nomination that scale to high throughput remain limited and have not been widely adopted. To accelerate the discovery process, we have developed an open-source AI-enabled screening platform that provides a rapid, automated, posture-based score of C. elegans survival. We used this workflow to screen a library of 2,782 FDA-approved drugs and identified 31 compounds that reproducibly increase heat stress resistance, a known predictor of longevity. Follow-up studies confirmed that many of these compounds confer lifespan extension in worms, and several compounds also have anti-senescent activity in human cells. This simplified and adaptable AI-enabled workflow therefore has the potential to accelerate the discovery of translatable drugs that slow aging.

pharmacology and toxicology↗

bioRxiv2026

Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

physiology↗

bioRxiv2025

Long-range mRNA folding shapes expression and sequence of bacterial genes

Accessibility of the ribosome binding site (RBS) plays an outsized role in bacterial mRNA decay and translation. Antagonistic mRNA sequences that reduce accessibility and regulate expression have been widely documented near the RBS. To determine whether such sequences are also the primary effectors of expression when placed far from the RBS, we measured impacts of all possible 8-nucleotide substitutions (65,536 variants) at different positions in mRNA in Bacillus subtilis. While the vast majority of substitutions negligibly affect RNA levels, pyrimidine-rich substitutions resembling the anti-Shine-Dalgarno (aSD) sequence exhibit strong inhibitory effects. Even several hundred nucleotides downstream of the RBS, these aSD-like sequences base-pair with the RBS, promote RNA decay, and inhibit translation initiation. We find aSD-like sequences to be depleted throughout endogenous genes, likely due to selective pressure for expression. Taken together, our findings reveal widespread long-range RNA intramolecular interactions in vivo and uncover a key constraint on gene sequence evolution. HIGHLIGHTSO_LILong-range mRNA folding tunes accessibility of the ribosome binding site (RBS) C_LIO_LIShort anti-RBS sequences are major mRNA repressors across the transcript body C_LIO_LIAnti-RBSs, even distally located, can promote RNA decay and inhibit translation C_LIO_LIAnti-RBS sequences are depleted throughout endogenous bacterial coding sequences C_LI

molecular biology↗

bioRxiv2024

Guava cv. Allahabad Safeda Chromosome scale assembly and comparative genomics decodes breeder choice marker trait association for pink pulp colour

Deciphering chromosomal length genome assemblies has the potential to unravel an organisms evolutionary relationships and genetic mapping of traits of commercial importance. We assembled guava genome using a hybrid sequencing approach with [~]450x depth Illumina short reads, [~]35x PacBio long reads and Bionano maps to [~]594 MB Scaffold length on 11 pseudo chromosomes ([~]479 MB contig length). Maker pipeline predicted 17,395 genes, 23% greater from earlier draft produced in same cultivar Allahabad Safeda. The genome assembly clarified guava evolutionary history, for example revealing predominance of gene expansion by dispersed duplications, in particular contributing to abundance of monoterpene synthases; and supporting evidence of a whole genome duplication event in guava as in other Myrtaceae. Guava breeders have been aiming to reduce screening time for selecting pink pulp colour progenies using marker-trait associations, but a previous comparative transcriptomics and comparative genomics approach with draft genome assembly to identify the effector gene associated with pink pulp was unsuccessful. Here, genome re-sequencing with Illumina short reads at [~]25x depth of 20 pink fleshed and/or non-coloured guava cultivars and comprehensive analysis for genes in the carotenoid biosynthesis pathway identified structural variations in Phytoene Synthase 2. Further, ddRAD based association mapping in core-collection of 82 coloured and non-coloured genotypes from Indian sub-continent found strong association with the same causal gene. Subsequently, we developed PCR based Indel/SSR breeder friendly marker that can readily be scored in routine agarose gels and empowers accurate selection for seedlings that will produce fruits with pink pulp.

plant biology↗

bioRxiv2020

A phylodynamic workflow to rapidly gain insights into the dispersal history and dynamics of SARS-CoV-2 lineages

Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of the causative virus (SARS-CoV-2) have been generated and shared with the scientific community. The unparalleled volume of available genetic data presents a unique opportunity to gain real-time insights into the virus transmission during the pandemic, but also a daunting computational hurdle if analysed with gold-standard phylogeographic approaches. We here describe and apply an analytical pipeline that is a compromise between fast and rigorous analytical steps. As a proof of concept, we focus on the Belgium epidemic, with one of the highest spatial density of available SARS-CoV-2 genomes. At the global scale, our analyses confirm the importance of external introduction events in establishing multiple transmission chains in the country. At the country scale, our spatially-explicit phylogeographic analyses highlight that the national lockdown had a relatively low impact on both the lineage dispersal velocity and the long-distance dispersal events within Belgium. Our pipeline has the potential to be quickly applied to other countries or regions, with key benefits in complementing epidemiological analyses in assessing the impact of intervention measures or their progressive easement.

evolutionary biology↗

bioRxiv2019

Phylogeographic and phylodynamic approaches to epidemiological hypothesis testing

Computational analyses of pathogen genomes are increasingly used to unravel the dispersal history and transmission dynamics of epidemics. Here, we show how to go beyond historical reconstructions and use spatially-explicit phylogeographic and phylodynamic approaches to formally test epidemiological hypotheses. We illustrate our approach by focusing on the West Nile virus (WNV) spread in North America that has been responsible for substantial impacts on public, veterinary, and wildlife health. WNV isolates have been sampled at various times and locations across North America since its introduction to New York twenty years ago. We exploit this genetic data repository to demonstrate that factors hypothesised to affect viral dispersal and demography can be formally tested. Specifically, we detail and apply an analytical workflow consisting of state-of-the art methods that we further improve to test the impact of environmental factors on the dispersal locations, velocity, and frequency of viral lineages, as well as on the genetic diversity of the viral population through time. We find that WNV lineages tend to disperse faster in areas with higher temperatures and we identify temporal variation in temperature as a main predictor of viral genetic diversity through time. Using a simulation procedure, we find no evidence that viral lineages preferentially circulate within the same migratory bird flyway, suggesting a substantial role for non-migratory birds or mosquito dispersal along the longitudinal gradient. Finally, we also separately apply our testing approaches on the three WNV genotypes that circulated in North America in order to understand and compare their dispersal ability. Our study demonstrates that the development and application of statistical approaches, coupled with comprehensive pathogen genomic data, can address epidemiological questions that might otherwise be difficult or impractically expensive to answer.

evolutionary biology↗

bioRxiv2018

Precision measurement of cis-regulatory energetics in living cells

Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of \"allelic manifolds\", a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and {sigma}70 RNA polymerase. Doing so, we consistently obtained energetic measurements precise to ~ 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.

biophysics↗