Biology subjects

Kshitiz, K.

Publications and source records attributed to Kshitiz, K..

2 recordsLinked to original sources

bioRxiv2025

Phylogenetic Analysis of Beta-Lactamases Reveals Distinct Evolutionary Patterns of Chromosomal and Plasmid-Encoded BLs and the Mosaic Role of VIM Linking NDM and IMP

Beta-lactamases (BLs) are a major driver of antibiotic resistance in pathogens like Acinetobacter baumannii, Enterobacteriaceae and Pseudomonas aeruginosa. This study explores the structural stability and functional divergence of metallo-beta-lactamases (MBLs) and AmpC through study of protein-protein interaction (PPI) network analysis, phylogenetics and identification of conserved domains and motifs. The study also involves analysis of co-evolutionary dynamics of BLs with related genes. PPI analysis identified NagZ as central interacting partner for BLs in P. aeruginosa and Enterobacteriaceae, suggesting its pivotal role in BL expression, and highlighting its probable role as a potential drug target. In contrast, A. baumannii exhibited such a high diversity in protein interactions, that considering a single protein as topmost interacting partner was difficult. Phylogenetic analysis revealed strong co-evolutionary trends between functionally-related proteins. A. baumannii and Enterobacteriaceae were found to be closely related in case of not just the chromosomally-encoded MBL-fold containing proteins, but also the true MBLs which are plasmid-encoded. On the other hand, similar evolutionary patterns for chromosomally-encoded BLs like AmpC and related genes was found in A. baumannii and P. aeruginosa. Analysis of PFAM domains showed that catalytic and substrate binding domains are more conserved than accessory ones. Several motifs, such as, ASNGLI were found to be conserved across all MBLs and thus carry the potential to be significant drug targets. Finally, inter-BL analysis revealed that VIM acts as an evolutionary link by acting like a mosaic between IMP and NDM as supported by intermediate GC content, positioning in phylogenetic trees and shared sequence features.

evolutionary biology↗

bioRxiv2020

Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

evolutionary biology↗