Biology subjects

Chitrala, K. N.

Publications and source records attributed to Chitrala, K. N..

4 recordsLinked to original sources

bioRxiv2024

Bioinformatics analysis of the potential biomarkers of Multiple Sclerosis and Guillain-Barre syndrome

Recent research emphasizes the intricate interplay of genetics and epigenetics in neurological disorders, notably Multiple Sclerosis (MS) and Guillain-Barre Syndrome (GBS), both of which exhibit cardiovascular dysregulation, with GBS often featuring serious bradyarrhythmias requiring prompt recognition and treatment. While cardiovascular autonomic dysfunction in MS is typically less severe, orthostatic intolerance affects around half of MS patients. Their distinction lies in their autoimmune responses, MS is an autoimmune disease affecting the central nervous system, causes demyelination and axon damage, leading to cognitive, ocular, and musculoskeletal dysfunction. In contrast, GBS primarily affects the peripheral nervous system, resulting in paralysis and respiratory complications. Despite their differences, both diseases share environmental risk factors such as viral infections and Vitamin D deficiency. This study aims to explore shared gene expression pathways, functional annotations, and molecular pathways between MS and GBS to enhance diagnostics, pathogenesis understanding, and treatment strategies through molecular analysis techniques. Through the gene expression analysis, five significant genes were found UTS2, TNFSF10, GBP1, VCAN, FOS. Results shows that Common DEGs are linked to apoptosis, bacterial infections, and atherosclerosis. Molecular docking analysis suggests Aflatoxin B1 as a potential therapeutic compound due to its high binding affinity with common differentially expressed proteins.

bioinformatics↗

bioRxiv2024

Analysis of gene expression profiles to elucidate racial differences in African American and White patients with Triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the second most diagnosed subtype of breast cancer. It is known to be the most aggressive one that lacks known targetable receptors. One of the concerns in TNBC is the disparities in its prevalence and tumor pathogenesis among women with non-Hispanic African American backgrounds. Despite extensive research, the genetic underpinnings that lead to these disparities remain elusive. The current study aims to provide initiative for further clinical research in the development of targeted therapy for TNBC. Gene expression profiles from African American (AA) and European American (EA) patients with TNBC were collected from Gene Expression Omnibus and performed differential gene expression (DEG)analysis. Candidate genes for a significant correlation between expression and survival rates for breast invasive carcinoma were analyzed using UALCAN. The DAVID annotation tool, Enrichr web server, KEGG database, and Gene Ontology (GO) database were used for functional enrichment analysis of target genes. The Network Analyst server was used to identify ligands with strong affinities, SeamDock server for molecular docking between the biomarkers/associated ligands and examined protein-protein interactions (PPI) from the STRING server. Data from public breast cancer cohorts was utilized to identify expression patterns associated with poor survival outcomes of AA patients with TNBC. Our results showed three genes of interest (CCT3, LSM2, and MRPS16) and potential ligands for molecular docking. Molecular docking was performed for the ICG001 ligand to CCT3 (binding affinities of -9.3 kcal/mol and -8.9 kcal/mol) and other interacting proteins (CDC20 and PPP2CA) with high degrees of connectivity. The results determined molecular docking of ICG001 to the CDC20 protein resulted in the highest binding affinity. Our results demonstrated that CCT3 and its interacting partners could serve as potential biomarkers due to their association with the survival outcome of AA patients with TNBC and ICG 001 could be the therapeutic lead for these biomarkers.

bioinformatics↗

bioRxiv2022

Loss of ZNF251 stimulates NHEJ resulting in PARP inhibitor resistance in BRCA1-mutated cancer cells

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a promising new class of agents that have demonstrated efficacy in treating various cancers, particularly those with BRCA1/2 mutations. Cancer-associated BRCA1/2 mutations disrupt DNA double-strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPis) have been used to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, resistance to PARPis is common and can occur through multiple mechanisms, including the restoration of HR and/or stabilization of replication forks. To gain a better understanding of the mechanisms underlying PARPis resistance, we conducted an unbiased CRISPR-pooled genome-wide library screen to identify new genes whose deficiency confers resistance to the PARPi olaparib. Our research revealed that haploinsufficiency of the ZNF251 gene, which encodes zinc finger protein 251, is associated with resistance to PARPis in various breast and ovarian cancer cell lines carrying BRCA1 mutations. Mechanistically, we discovered that ZNF251 haploinsufficiency leads to stimulation of RAD51-mediated HR repair of DSBs in olaparib-treated BRCA1-mutated cancer cells. Moreover, we demonstrated that a RAD51 inhibitor reversed PARPi resistance in ZNF251 haploinsufficient cancer cells harboring BRCA1 mutations. Our findings provide important insights into the mechanisms underlying PARPis resistance by highlighting the role of RAD51 in this phenomenon.

cancer biology↗

bioRxiv2019

Genome-wide association study of Parkinson's disease progression biomarkers in 12 longitudinal patients' cohorts

BackgroundSeveral reports have identified different patterns of Parkinsons disease progression in individuals carrying missense variants in the GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinsons disease, however, has not been well studied. ObjectivesTo test the association between genetic variants and the clinical features and progression of Parkinsons disease on a genome-wide scale. MethodsWe accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes. ResultsTwo variants were genome-wide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL for ADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinsons risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. ConclusionsWe identified novel genetic factors associated with heterogeneity of progression in Parkinsons disease. The results provide new insights into the pathogenesis of Parkinsons disease as well as patient stratification for clinical trials.

genetics↗