Hutchinsonhave8037

Specifically, the three C-terminal residues of peptide ligands with alanine or threonine at position 6 partially exit the binding groove; this does not occur in peptide ligands with isoleucine or valine at position 6. Structural changes associated with partial peptide exit from the binding groove, along with relevant peptide binding energetics and immunological results are discussed. Communicated by Ramaswamy H. Sarma.Cancer cells ferment glucose, even under aerobic conditions, following a phenomenon known as the 'Warburg effect.' Hexokinase 2 (HK2) catalyzes the crucial step of phosphorylation of glucose for subsequent utilization in glycolysis and other pathways. HK2 has been proposed as a potential therapeutic target for anti-cancer therapy because of its enhanced expression in glucose-dependent tumors. Here, we have employed structure-based virtual screening using in-house library to identify potential phytoconstituents which could inhibit the HK2 activity. The initial hits were selected based on their binding affinity towards HK2 using the molecular docking approach. Subsequently, the filters for physicochemical properties, PAINS patterns and PASS evaluation were applied to find potential hits against HK2. Finally, we have identified epigallocatechin gallate (EGCG) and quercitrin, two natural compounds with appreciable binding affinity, efficiency and specificity towards the HK2 binding pocket. Both compounds were found to be binding preferentially to the HK2 active site and showed a decent set of drug-like properties. All-atom molecular dynamics (MD) simulations for 100 ns were carried out to see the conformational dynamics, complexes stability and interaction mechanism of HK2 with EGCG and quercitrin. MD simulation results showed that HK2 forms stable protein-ligand complexes with EGCG and quercitrin with consistency throughout the trajectory. Overall, these findings suggest that EGCG and quercitrin might be further exploited as promising scaffolds in the drug development process against HK2..Communicated by Ramaswamy H. Sarma.SARS-CoV-2 mutations appeared recently and can lead to conformational changes in the spike protein and probably induce modifications in antigenicity. We assessed the neutralizing capacity of antibodies to prevent cell infection, using a live virus neutralization test with different strains [19A (initial one), 20B (B.1.1.241 lineage), 20I/501Y.V1 (B.1.1.7 lineage), and 20H/501Y.V2 (B.1.351 lineage)] in serum samples collected from different populations two-dose vaccinated COVID-19-naive healthcare workers (HCWs; Pfizer-BioNTech BNT161b2), 6-months post mild COVID-19 HCWs, and critical COVID-19 patients. No significant difference was observed between the 20B and 19A isolates for HCWs with mild COVID-19 and critical patients. However, a significant decrease in neutralization ability was found for 20I/501Y.V1 in comparison with 19A isolate for critical patients and HCWs 6-months post infection. Concerning 20H/501Y.V2, all populations had a significant reduction in neutralizing antibody titers in comparison with the 19A isolate. Interestingly, a significant difference in neutralization capacity was observed for vaccinated HCWs between the two variants but not in the convalescent groups.Macroautophagy/autophagy can selectively degrade misfolded proteins, damaged organelles and other cargoes. It is conceivable that alteration of the degradation processes could disrupt normal cellular signaling and contribute to human diseases such as cancer. To explore the link between aberrant autophagy selectivity and human cancer, we have developed a pipeline called "inference of cancer-associated LC3-interacting region-containing proteins" (iCAL), which integrates a sequence-based predictor, a model-based computational method, publicly available cancer mutations, and multiple experimental approaches. Using iCAL, we have identified 222 LIR motif-associated mutations (LAMs) in 148 LIR-containing proteins (LIRCPs), and validated that LAMs in ATG4B, STBD1, EHMT2 and BRAF impair their interactions with LC3 and/or autophagy activities. Moreover, we uncovered that STBD1, a previously poorly-characterized protein, inhibits tumor growth via metabolism reprogramming in cancer cells. A patient-derived mutation in STBD1 (W203C) disrupts the interaction with LC3 and promotes tumor growth. selleck inhibitor Taken together, iCAL provides an exciting new avenue to discover novel autophagy pathways that contribute to carcinogenesis.Chlamydia psittaci infection in humans, also known as psittacosis, is usually believed to be an uncommon disease which mainly presents as community-acquired pneumonia (CAP). It is usually sporadic, but outbreaks of infection may occasionally occur. In outbreaks, diagnosis and investigations were usually hampered by the non-specificity of laboratory testing methods to identify C. psittaci. In this study, we use metagenomic next-generation sequencing (mNGS) in the diagnosis of a family outbreak of psittacosis under COVID-19. Three members of an extended family of 6 persons developed psittacosis with pneumonia and hepatic involvement with common symptoms of fever and weakness. Two newly purchased pet parrots, which had died successively, were probably the primary source of infection. Imagings show lung consolidations and infiltrates, which are difficult to be differentiated from CAP caused by other common pathogens. mNGS rapidly identified the infecting agent as C. psittaci within 48 h. The results of this work suggest that there are not characteristic clinical manifestations and imagings of psittacosis pneumonia which can differentiate from CAP caused by other pathogens. The use of mNGS can improve accuracy and reduce the delay in the diagnosis of psittacosis especially during the outbreak, which can shorten the course of the disease control. Family outbreak under COVID-19 may be related to the familial aggregation due to the epidemic. To our knowledge, this is the first reported family outbreak of psittacosis in China, and the first reported psittacosis outbreak identified by the method of mNGS in the world.As a result of the low oral bioavailability of several drugs, there is a renewed interest for parenteral administration to target their absorption directly into the blood bypassing the long gastrointestinal route and hepatic metabolism. In order to address the potential side effects of frequent injections, sustained release systems are the most popular approaches for achieving controlled long-acting drug delivery. Injectable in-situ forming implants (ISFIs) have gained greater popularity in comparison to other sustained systems. Their significant positive aspects are attributed to easier production, acceptable administration route, reduced dosing frequency and patient compliance achievement. ISFI systems, comprising biodegradable polymers such as poly (lactide-co-glycolide) (PLGA) based on solvent exchange mechanisms, are emerged as liquid formulations that develop solid or semisolid depots after injection and deliver drugs over extended periods. The drug release from ISFI systems is generally characterized by an initial burst during the matrix solidification, followed by diffusion processes and finally polymeric degradation and erosion.