Sharda University

About: Sharda University is a education organization based out in Greater Noida, Uttar Pradesh, India. It is known for research contribution in the topics: Computer science & Medicine. The organization has 1276 authors who have published 2012 publications receiving 16188 citations.

Dynamics of suspended sediment load with respect to summer discharge and temperatures in Shaune Garang glacierized catchment, Western Himalaya

Abstract: The observed and predicted rise in temperature will have deleterious impact on melting of snow and ice and form of precipitation which is already evident in Indian Himalayan Region The temperature-dependent entities like discharge and sediment load will also vary with the observed and predicted rise posing environmental, social and economic threat in the region There is little known about sediment load transport in relation to temperature and discharge in glacierized catchments in Himalaya mainly due to the scarcity of ground-based observation The present study is an attempt to understand the suspended sediment load and transportation in relation to variation in discharge and temperature in the Shaune Garang catchment The result shows strong dependence of sediment concentration primarily on discharge (R2 = 084) and then on temperature (R2 = 079) The catchments with similar geological and climate setting were observed to have comparatively close weathering rate The sediment load was found to be higher in the catchments in eastern and central part of Indian Himalayan Region in comparison with western part due to dominance of Indian Summer Monsoon leading to high discharge The annual physical weathering rate in Shaune Garang catchment was found to be 411 t km−2 year−1 which has increased from 327 t km−2 year−1 in around three decades due to rise in temperature causing increase in discharge and proportion of debris-covered glacierized area

Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival.

Abstract: Mycobacterium tuberculosis (M. tb) is an intracellular pathogen that exploits moonlighting functions of its proteins to interfere with host cell functions. PE/PPE proteins utilize host inflammatory signaling and cell death pathways to promote pathogenesis. We report that M. tb PE6 protein (Rv0335c) is a secretory protein effector that interacts with innate immune toll-like receptor TLR4 on the macrophage cell surface and promotes activation of the canonical NFĸB signaling pathway to stimulate secretion of proinflammatory cytokines TNF-α, IL-12, and IL-6. Using mouse macrophage TLRs knockout cell lines, we demonstrate that PE6 induced secretion of proinflammatory cytokines dependent on TLR4 and adaptor Myd88. PE6 possesses nuclear and mitochondrial targeting sequences and displayed time-dependent differential localization into nucleus/nucleolus and mitochondria, and exhibited strong Nucleolin activation. PE6 strongly induces apoptosis via increased production of pro-apoptotic molecules Bax, Cytochrome C, and pcMyc. Mechanistic details revealed that PE6 activates Caspases 3 and 9 and induces endoplasmic reticulum-associated unfolded protein response pathways to induce apoptosis through increased production of ATF6, Chop, BIP, eIF2α, IRE1α, and Calnexin. Despite being a potent inducer of apoptosis, PE6 suppresses innate immune defense strategy autophagy by inducing inhibitory phosphorylation of autophagy initiating kinase ULK1. Inversely, PE6 induces activatory phosphorylation of autophagy master regulator MtorC1, which is reflected by lower conversion of autophagy markers LC3BI to LC3BII and increased accumulation of autophagy substrate p62 which is also dependent on innate immune receptor TLR4. The use of pharmacological agents, rapamycin and bafilomycin A1, confirms the inhibitory effect of PE6 on autophagy, evidenced by the reduced conversion of LC3BI to LC3BII and increased accumulation of p62 in the presence of rapamycin and bafilomycin A1. We also observed that PE6 binds DNA, which could have significant implications in virulence. Furthermore, our analyses reveal that PE6 efficiently binds iron to likely aid in intracellular survival. Recombinant Mycobacterium smegmatis (M. smegmatis) containing pe6 displayed robust growth in iron chelated media compared to vector alone transformed cells, which suggests a role of PE6 in iron acquisition. These findings unravel novel mechanisms exploited by PE6 protein to subdue host immunity, thereby providing insights relevant to a better understanding of host-pathogen interaction during M. tb infection.

In silico docking and molecular dynamics simulation of 3-dehydroquinate synthase (DHQS) from Mycobacterium tuberculosis.

Abstract: The shikimate pathway is as an attractive target because it is present in bacteria, algae, fungi, and plants but does not occur in mammals. In Mycobacterium tuberculosis (MTB), the shikimate pathway is integral to the biosynthesis of naphthoquinones, menaquinones, and mycobactin. In these study, novel inhibitors of 3-dehydroquinate synthase (DHQS), an enzyme that catalyzes the second step of the shikimate pathway in MTB, were determined. 12,165 compounds were selected from two public databases through virtual screening and molecular docking analysis using PyRx 8.0 and Autodock 4.2, respectively. A total of 18 compounds with the best binding energies (−13.23 to −8.22 kcal/mol) were then selected and screened for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and nine of those compounds were found to satisfy all of the ADME and toxicity criteria. Among those nine, the three compounds—ZINC633887 (binding energy = −10.29 kcal/mol), ZINC08983432 (−9.34 kcal/mol), and PubChem73393 (−8.61 kcal/mol)—with the best binding energies were further selected for molecular dynamics (MD) simulation analysis. The results of the 50-ns MD simulations showed that the two compounds ZINC633887 and PubChem73393 formed stable complexes with DHQS and that the structures of those two ligands remained largely unchanged at the ligand-binding site during the simulations. These two compounds identified through docking and MD simulation are potential candidates for the treatment of TB, and should undergo validation in vivo and in vitro.