Biology subjects

Aryal, P.

Publications and source records attributed to Aryal, P..

6 recordsLinked to original sources

bioRxiv2025

Analyzing the role of a dual-function diguanylate cyclase/phosphodiesterase for attachment and motility in Agrobacterium tumefaciens

Cyclic diguanylate monophosphate (c-di-GMP) is a second messenger that controls the signaling pathway for the motile to sessile transition in many bacteria. Diguanylate cyclases (DGCs), characterized by a GGDEF domain, are responsible for the synthesis of c-di-GMP. c-di-GMP is degraded by EAL and HD-GYP domains that exhibit phosphodiesterase activity (PDE). In Agrobacterium tumefaciens, out of 31 predicted proteins regulating the c-di-GMP levels, this work focuses on the predicted dual-function DGC/PDE, DcpB. We show that DcpB is a cycle-dependent PDE under our experimental conditions, resulting in cell cycle-dependent control of motility and biofilm formation in A. tumefaciens. DcpB also exhibits polar and mid-cell localization. Finally, we identify genetic interactions between dcpB and a LacI-family transcriptional regulators, thuR, suggesting additional regulatory inputs for DcpB-dependent phenotypes. Importancec-di-GMP is a universal secondary messenger known to control various biological processes in bacteria including attachment, motility, virulence, and cell cycle progression. In A. tumefaciens, there are 31 predicted c-di-GMP-metabolizing proteins predicted to affect the c-di-GMP pool, raising the question of why so many proteins are involved and how the activities of these proteins are coordinated. This work describes a cell cycle-dependent PDE activity that helps coordinate cell cycle progression and developmental phenotypes including biofilm formation and motility.

microbiology↗

bioRxiv2023

Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders

Women of reproductive age widely experience the physical, mental, and emotional effects of hormonal imbalances. The levels of two hormones, estrogen, and progesterone, were particularly high. When these two hormones are unbalanced, symptoms such as irregular menstrual cycles, pelvic pain, and uterine fibroids can appear. Statistics show that 80 percent of women have hormonal imbalances. The creation of novel disease-containing drug candidates may be facilitated by computer-aided drug design (CADD), as many drugs and surgical treatments have unique adverse effects. Achieving good data coverage requires an optimized process for protein identification and enhanced selection techniques for medicinal compounds, including their metabolic characterization. In this study, aromatase is the prioritized protein that acted as a rate-limiting enzyme in steroidogenesis. To maintain its expression and regulation to control estrogen production, natural compounds were retrieved from the ZINC15 database through ADME/TOX property filtration. Compound B, specifically designated as (1R,3S,6S,7S,10S,11R)-7-[(dimethylamino)methyl]-3,12-dimethyl-2,9-dioxatetracyclo [9.3.0.01,3.06,10] tetradec-12-en-8-one, exhibits remarkable therapeutic potential, as evidenced by its inability to inhibit S-adenosyl methionine (SAM) biosynthesis, the observed stability of molecular interactions based on Density Functional Theory (DFT), and a favorable energy gap between molecular orbital stages. This research can be employed as a utility module for fast screening of drug-like molecules and taking these leads forward to clinical trials, assessing their value as potential suitors for drug repurposing against female hormonal disorders.

bioinformatics↗

bioRxiv2022

Repurposing of Drugs against mutated strain of Eurasian Avian like H1N1 (EA H1N1) Swine flu, Genotype-4 (G4) virus

Mutation, reassortment and recombination have led to the evolution and the emergence of more pathogenic and new subtypes of influenza virus. The surge of highly mutated viruses has prompted the need of coherent solution for the so called "medical holocaust" viral outbreaks. The genotype 4 of EAH1N1 strain has been circulating in the swine population as a dominant genotype, exhibiting even human to human transmission. This has risen the possibility of causing another global health threat as a lethal viral outbreak in the future. The Computer Aided Drug Discovery (CADD) could be a prudent mechanism to develop new drug candidates against such disease for its mitigation. In this regard, the computational in silico methods had been envisaged in this research for the prediction of lead compounds against the selected proteins of EA H1N1 G4 strain, namely Haemagglutinin (HA) and Polymerase acidic protein(PA). The research focused on the selection of the target viral protein and molecular docking for the identification of putative ligands. It was followed by the identification of the probable mutations and assessment of effectiveness of identified drugs against their respective targets. Total of 3 compounds Enalapril, Enalaprilat and Ivabradine have been identified as a potential inhibitor of HA and PA protein that were prioritized on the basis of preference index parameter and binding energy of compound with the respective target. Besides, the probable mutations in each target protein in future were predicted and all these 3 top hits were found to be effective against mutated variant of these proteins. Thus, Enalapril, Enalaprilat and Ivabradine could be the lead compounds to explore further as multi target inhibiting drugs against wild and mutant variant of target proteins.

bioinformatics↗

bioRxiv2020

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

Overnutrition and obesity promote adipose tissue dysfunction, often leading to systemic insulin resistance. The thiazolidinediones (TZDs) are a potent class of insulin-sensitizing drugs and ligands of PPAR{gamma} that improve insulin sensitivity, but their use is limited due to significant side effects. Recently, we demonstrated a mechanism by which TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPAR{gamma} at Serine 273. However, the role of this modification has not been tested genetically. Here we demonstrate that mice encoding an allele of PPAR{gamma} which cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm improved insulin sensitivity, as evidenced by increased whole-body glucose uptake. RNA-seq experiments reveal PPAR{gamma} S273 phosphorylation specifically enhances transcription of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find that Gdf3 can impact metabolism by inhibition of BMP signaling. Together, these results highlight the diabetogenic role of PPAR{gamma} S273 phosphorylation and focuses attention on a putative target, Gdf3.

cell biology↗

bioRxiv2019

Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.

systems biology↗

bioRxiv2019

Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2)

Polycystin-2 (PC2) is a member of the TRPP subfamily of TRP channels and is present in ciliary membranes of the kidney. PC2 can be either homo-tetrameric, or heterotetrameric with PC1. PC2 shares a common transmembrane fold with other TRP channels, in addition to having a novel extracellular domain. Several TRP channels have been suggested to be regulated by lipids, including phosphatidylinositol phosphates (PIPs). We have combined molecular dynamics simulations with cryoelectron microscopy to explore possible lipid interactions sites on PC2. We propose that PC2 has a PIP-binding site close to the equivalent vanilloid/lipid-binding site in the TRPV1 channel. A 3.0 [A] cryoelectron microscopy map reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are further characterized by MD simulations. These results help to position PC2 within an emerging model of the complex roles of lipids in the regulation and organization of ciliary membranes.

biophysics↗