Biology subjects

Varughese, S.

Publications and source records attributed to Varughese, S..

5 recordsLinked to original sources

bioRxiv2026

Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression

Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.

immunology↗

bioRxiv2024

How mucilage helps seeds from being washed away? A mechanical interpretation of myxodiaspory using rheology

Cellulosic, hemicellulosic and pectinaceous mucilages produced by certain angiosperms as adaptation in myxodiaspory are investigated in the past for seed dispersal. The present understanding of zoochory and telechory are based on mucilage amount, state of hydration and to a limited extent, role of mucilage microstructure studied using adhesion and friction. Pectinaceous mucilages have less adhesion and supports dispersal by zoochory. However, in the case of cellulosic mucilages, the role played by the cellulosic fibrils in seed dispersal is not clear, especially, since they have a negative correlation with endozoochory. Using fresh cellulosic seed mucilages from, sweet basil (Ocimum basilicum) and chia (Salvia hispanica) we investigate the role of microstructure of the mucilage in two key behaviours: anchoring and adhesion properties of the seeds through rheology. We report a special large deformation mechanism triggered through strain stiffening operational in these cellulosic mucilages. In many biopolymers semi-flexible polymer chains and other aligning elements contribute to the strain stiffening. However, the strain stiffening and strong wet adhesion observed in these mucilages have a significant role from the cellulosic components. This behaviour is more pronounced in basil seeds and presents a plausible structure-property mechanism for anti-telechory favoured by plant species found in arid habitats.

physiology↗

bioRxiv2022

A novel fluorobenzothiazole RBx 10080758 as a dual inhibitor against bacterial GyraseB (GyrB) and Topoisomerase IV (parE) of Gram-positive pathogens causing skin and respiratory infections

Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 M against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 g/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.

microbiology↗

bioRxiv2021

Pectin self-assembly and its disruption by water: Insights into plant cell wall mechanics

Plant cell walls undergo multiple cycles of dehydration and rehydration during their life. Calcium crosslinked low methoxy pectin is a major constituent of plant cell walls. Understanding the dehydration-rehydration behavior of pectin gels may shed light on the water transport and mechanics of plant cells. In this work, we report the contributions of microstructure to the mechanics of pectin-Ca gels subjected to different extents of dehydration and subsequent rehydration. This is investigated using a pectin gel composition that forms egg-box bundles, a characteristic feature of the microstructure of low methoxy pectin-Ca gels. Large Amplitude Oscillatory Shear (LAOS) rheology along with Small Angle Neutron Scattering and Near Infrared (NIR) spectroscopy on pectin gels are used to elucidate the mechanical and microstructural changes during dehydration-rehydration cycles. As the extent of dehydration increase, the reswelling ability, strain-stiffening behavior and the yield strain decreases. These effects are more prominent at faster rates of dehydration and are not completely reversible upon rehydration to the initial undried state. Microstructural changes due to the aggregation of egg-box bundles and single chains and the associated changes in the water configurations lead to these irreversible changes.

plant biology↗

bioRxiv2020

Origin and evolutionary dynamics of multi-drug resistant and highly virulent community-associated methicillin-resistant Staphylococcus aureus ST772-SCCmec V lineage

BackgroundCommunity-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are increasing in prevalence across the world. However, studies on the molecular epidemiology and the genomic investigation of MRSA are limited in India. ObjectivesTo understand the molecular epidemiology of MRSA and to reconstruct the origin and evolution of S. aureus belonged to the sequence type (ST772). MethodsA total of 233 non-repetitive MRSA isolates were screened for the presence staphylococcal cassette chromosome (SCCmec) types, multi-locus sequence types (MLST) and staphylococcal protein A (spa) types. Whole genome sequence data of ST772-SCCmec V (n=32) isolates were generated and analysed along with the publically available ST772-SCCmec V (n=273) genome. ResultsST772 (27%), ST22 (19%) and ST239 (16%) were found as the predominant STs. Analysis of the core SNPs using Bayesian time scaled phylogenetic analysis showed ST772-SCCmec V was emerged on the Indian subcontinent in 1960s. The acquisition of integrated resistance plasmid (IRP) in the ST772-SCCmec V lineage during 1990s, fixation of SCCmec V (5C2) and the double serine mutations (S84L, S80Y) appears to have played a key role in the successful expansion. The IRP carries the loci for multiple antibiotic resistant genes: beta-lactam (blaZ), aminoglycosides (aphA3-sat-aadE), macrolide (mphC), macrolide-lincosamide-streptogramin B (msrA) and bacitracin (bacA, bacB). ConclusionThe Panton Valentine Leukocidin (PVL) positive ST772 and ST22 MRSA lineages are observed in the hospital settings. ST772-SCCmec V has the multi-drug resistance trait of hospital-associated (HA) MRSA and the epidemiological characteristics of CA-MRSA. The antimicrobial use pattern may have driven the spread and survival of ST772 MRSA in hospitals.

microbiology↗