Characterization of the ligand binding of PGRP-L in half-smooth tongue sole ( Cynoglossus semilaevis ) by molecular dynamics and free energy calculation

Background: Peptidoglycan (PGN) recognition proteins (PGRPs) are important pattern recognition receptors of the host innate immune system that are involved in the immune defense against bacterial pathogens. PGRPs have been characterized in several fish species. The PGN-binding ability is important for the function of PGRPs. However, the PGRP-PGN interaction mechanism in fish remains unclear. In the present study, the 3-D model of a long PGRP of half-smooth tongue sole (Cynoglossus semilaevis) (csPGRP-L), a marine teleost with great economic value, was constructed through the comparative modeling method, and the key amino acids involved in the interaction with Lys-type PGNs and Dap-type PGNs were analyzed by molecular dynamics and molecular docking methods. Results: csPGRP-L possessed a typical PGRP structure, consisting of five \u3b2-sheets and four \u3b1-helices. Molecular docking showed that the van der Waals forces had a slightly larger contribution than Coulombic interaction in the csPGRP-L-PGN complex. Moreover, the binding energies of csPGRP-L-PGNs computed by MM-PBSA method revealed that csPGRP-L might selectively bind both types of MTP-PGNs and MPP-PGNs. In addition, the binding energy of each residue of csPGRP-L was also calculated, revealing that the residues involved in the interaction with Lys-type PGNs were different from that with Dap-type PGNs. Conclusions: The 3-D structure of csPGRP-L possessed typical PGRP structure and might selectively bind both types of MTP- and MPP-PGNs, which provided useful insights to understanding the functions of fish PGRPs

Research on the Interrelation between Temperature Distribution and Dry Band on Wet Contaminated Insulators

In this paper, the interrelation between temperature distribution and dry band on wet contaminated insulators is studied by theoretical analysis, numerical simulation, and a high-voltage artificial contamination experiment. The influences of the composition of the contaminant and the relative humidity of the environment on the moisture absorption of the contamination layer are studied. It is indicated that the critical relative humidity (CRH) of the soluble mixture in the contamination layer decreases with the increase of the variety of soluble substances. This can be considered as a previously neglected reason for the inconsistency between the result of an artificial contamination test and that of a natural contamination test. Furthermore, the influences of the maximum temperature, wind speed, altitude, relative humidity, and the composition of the contamination on the water evaporation rate of the contaminated layer are also studied. The formation of dry band is predicted by studying the law of water transport in the contamination layer. The influence of the location, width, drying degree, and quantity of dry bands on the insulator surface temperature are studied by numerical simulation. An infrared thermal imager and ultraviolet camera are adopted to measure the temperature distribution and the discharge phenomenon on the insulator surface separately, which verifies the above numerical simulation. The study results deepen the research on the moisture absorption characteristics, the law of temperature distribution, the formation of dry bands, and the influence of dry bands on the temperature distribution of wet contaminated insulators

Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein–inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors

Molecular dynamics simulation of six β-blocker drugs passing across POPC bilayer

<div><p>Six selected β-blocker drugs (alprenolol, atenolol, metoprolol, nadolol, pindolol and propranolol) passing across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer were studied using all-atom molecular dynamics simulation. The free energy profiles can be divided into two groups, according to their shapes: the free energy curve of group one (atenolol, nadolol and pindolol) has an obvious minimum while that of the other group (propranolol, metoprolol and alprenolol) is flat inside membrane. Energy analysis shows that electrostatic interaction plays an important role for the first group drugs. The hydrogen bond analysis results also certify that the first group drugs form more hydrogen bonds than the other β-blockers. The calculated permeability sequence agrees with the experimental ones. Our calculation suggests that the permeability model using potential of mean force (PMF) method can be also applied to chemically similar compounds besides chemically diverse compounds.</p></div

Micelles Prepared with Cinnamaldehyde and Vancomycin by Schiff Base Reaction

To design a micelle which has a hydrophilic inner shell formed with vancomycin and a hydrophobic outer shell formed with cinnamaldehyde, vancomycin and cinnamaldehyde will be linked with the schiff base reaction, and then a further research on its properties will be conducted. Vancomycin, a good hydrophilic antibiotic drug, is highly effective in the treatment of methicillin resistant Staphylococcus aureus. Cinnamaldehyde, owning the effects of sterilization and antisepsis, has obvious curative effect on fungi and is a hydrophobic drug. When vancomycin was reacted with cinnamaldehyde via schiff base reaction, self-assembled micelles, formed by their hydrophobic differences, were given with not only synergistic bactericidal action but also increasing the cycle time of drugs in vivo. At the same time, its pH response performance enhanced antibacterial properties and drug efficacy of micelles. This study focused on the preparation of micelles modified by cinnamaldehyde

Cloning and Expression of β-Defensin from Soiny Mullet (Liza haematocheila), with Insights of its Antibacterial Mechanism.

Beta-defensins are important part of innate immunity of fish, which are the first defense line against invading pathogens. In this study, the β-defensin (Lhβ-defensin) gene was cloned from spleen tissue of soiny mullet (Liza haematocheila). Lhβ-defensin cDNA was 747 bp in length, encoding 63 amino acids. Sequence alignment revealed that Lhβ-defensin contained six conserved cysteine residues and shared 97.5% sequence identities with grouper (Epinephelus coioides) β-defensin. Realtime PCR revealed that Lhβ-defensin was highest expressed in the immune related organs, such as spleen, kidney and gut of healthy fish. Following Streptococcus dysgalactiae infection, Lhβ-defensin was up-regulated in immune related organs, e.g. 17.6-fold in spleen and 10.87-fold in gut at 24 h post infection (hpi). Lhβ-defensin possessed a monomeric structure of a three-stranded anti-parallel β-sheet and an α-helix stabilized by three disulfide bonds formed by Cys30-Cys58, Cys36-Cys52, and Cys40-Cys59. In addition to the experimental work, computer simulation was also carried out to determine the possible conformation of β-defensin and its interaction with palmitoyloleoylphosphatidylglycerol (POPG), a model of bacteria membrane. The Lhβ-defensin was found to form dimeric structure stabilized by the van der Waals contacts of Leu35 and Cys37 in two anti-parallel β1-strands and the cation-π interaction between Tyr32 and Arg54 respectively in the two β1-strands. The most important interactions between β-defensin and membrane are the electrostatic interactions between Arg residues in β-defensin and head group of POPG bilayer as well as hydrogen bond interactions between them. Our results were useful for further understanding the potential mechanism of antimicrobial property of fish β-defensins