Biology subjects

Thelma, B.

Publications and source records attributed to Thelma, B..

4 recordsLinked to original sources

bioRxiv2026

ARL15 promotes inflammatory fibroblast activation and disease severity in rheumatoid arthritis: integrated transcriptomic and collagen-induced arthritis model analyses

BackgroundADP-ribosylation factor-like protein 15 (ARL15) is a rheumatoid arthritis (RA) susceptibility gene identified through GWAS. Previous studies suggested a role for ARL15 in synovial fibroblast (SF) pathogenicity, but its contribution to inflammatory arthritis remains unclear. We investigated the inflammatory role of ARL15 and its therapeutic potential in RA. MethodsARL15 was overexpressed in MH7A cells followed by bulk RNA sequencing and pathway enrichment analyses. Therapeutic relevance was evaluated in collagen-induced arthritis (CIA) mouse model using anti-ARL15 monoclonal antibodies, ARL15-targeting siRNA, or isoquinoline. Arthritis scores, histopathology, micro-CT and serum cytokines were assessed. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were analyzed to determine ARL15 expression in RASF subsets. ResultsARL15 overexpression induced a pro-inflammatory transcriptional program characterized by upregulation of IL1A, IL1B, IL6, IL8, CXCL1, CXCL10, and CCL20. Gene set enrichment analysis revealed activation of IL6-JAK-STAT, TNF, interferon-response, and KRAS signaling pathways, with suppression of oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. In CIA mice, ARL15 inhibition significantly reduced arthritis severity, inflammatory infiltrates, and joint destruction while preserving cartilage and bone integrity. Serum TNF-, IL-6, and IL-1{beta} levels were markedly decreased following ARL15 blockade. Combination monoclonal antibody treatment demonstrated the greatest therapeutic benefit. scRNA-seq analysis showed broad ARL15 expression across RA fibroblast populations, with enrichment in inflammatory lining and SF subsets. ConclusionsARL15 is a pro-inflammatory regulator of SF activation and arthritis progression. Integrated transcriptomic, single-cell, and in vivo analyses identify ARL15 as a therapeutic target for RA and support further translational development of ARL15 based therapies.

immunology↗

bioRxiv2022

Genetic affinities and sub-structuring in Coorg population of Southern India

The Coorgs, also known as Kodavas, are one of the smallest religious and socio-culturally homogenous communities in the world, currently residing in the state of Karnataka, India. Due to a stark contrast with the surrounding subpopulations, their genetic architecture and population & demographic history have been a matter of debate for long. To better understand the population structure and demographic history of this caste group, we analysed the population, using high-resolution autosomal (n=70) as well uniparentally inherited markers (Y-chromosomal and mitochondrial DNA) (n=144). Our first ever findings elucidate that origin of Coorgs traces back to early or middle Bronze Age. We further found population substructure among Coorgs, which manifested as three distinct clusters in a Principal component analysis. One of these subgroups has undergone a rare and immense amount of population-specific drift but all three eventually admixed, both genetically and socio-culturally. The mtDNA analysis showed 40% South Asian-specific mitochondrial lineages among Coorgs; while the Y-chromosomal analysis revealed predominant presence of Eurasian, Middle-Eastern and Indian-specific haplogroups suggesting male-centric migration and eventual assimilation with local females. Our results for the first time identify these ancient and distinct genealogies that make up the contemporary Coorgs and may explain the socio-cultural differences with their immediate and distant neighbours in the country and the prevalent narrative history. In a wider context, the study also reveals an ancient, yet unknown, Middle Eastern source population that might have contributed to an early west to east migration into India.

genetics↗

bioRxiv2020

Cumulative effect of aging and SARS-CoV2 infection on poor prognosis in the elderly: Insights from transcriptomic analysis of lung and blood

IntroductionThe ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) has affected millions of people worldwide and with notable heterogeneity in its clinical presentation. Probability of contracting this highly contagious infection is similar across age groups but disease severity and fatality among aged patients with or without comorbidities are higher. We hypothesized that SARS-CoV-2 infection may augment aging-related gene expression alterations resulting in severe outcomes in elderly patients. MethodologyWe performed a comparative analysis of publicly available transcriptome data from Broncho Alveolar Lavage Fluid (BALF)/lung/blood of healthy aging group with i) COVID-19 patients; and ii) data of host genes interacting with SARS-CoV-2 proteins. ResultsWe observed i) a significant overlap of gene expression profiles of patients BALF and blood with lung and blood of the healthy group respectively; ii) a more pronounced overlap in blood compared to lung; and iii) a similar overlap between host genes interacting with SARS-CoV-2 and aging blood transcriptome. ConclusionsPathway enrichment analysis of overlapping gene sets suggests that infection alters expression of genes already dysregulated in the elderly, which together may lead to poor prognosis. eQTLs in these genes may also confer poor outcome in young patients worsening with age and co-morbidities. Furthermore, the pronounced overlap observed in blood may explain clinical symptoms including blood clots, strokes, heart attack, multi-organ failure etc. in severe cases. This model based on a limited patient dataset seems robust and holds promise for testing larger tissue specific datasets from patients with varied severity and across populations.

genetics↗

bioRxiv2019

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harboring de novo mutations in schizophrenia, autism, and intellectual disability: Evidence from multiplex families

Clinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease. More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.

genetics↗