c-Met has been considered as an attractive target for developing antitumor agents. The highly selective c-Met inhibitors provide invaluable opportunities for the combination with other therapies safely to achieve the optimal efficacy. In this work, a series of triazolopyrazine c-Met inhibitors with exquisitely selectivity were investigated using a combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics simulation. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were developed to reveal the structural determinants for c-Met inhibition. Both models were validated to have high reliability and predictability, and contour map analysis suggested feature requirements for different substituents on the scaffold. It is worth noting that an important hydrogen bond rich region was identified in the unique narrow channel, which is distinct from other kinases. Molecular dynamics simulations and binding free energy calculations provided further support that suitable groups in this hydrogen bond rich region made great contributions to the binding of ligands. Moreover, hydrogen bonds with residues of the narrow channel were also indicated to be essential to improve the activity and selectivity. This study will facilitate the discovery and optimization of novel c-Met inhibitors with higher activity and selectivity.
Porcine epidemic diarrhea virus (PEDV) is a highly infectious and pathogenic virus causing high morbidity and mortality, especially in newborn piglets. There remain problems with contemporary PEDV vaccines, in part because of the rapid variation of PEDV, poor conferred immunity, and numerous side effects. The ability to produce PEDV-neutralizing antibodies suggests that we may be able to increase the success rate of PEDV prevention in piglets using these antibodies. In this study, we produced an anti-PEDV S protein monoclonal antibody (anti-PEDV mAb-2) that neutralized PEDV-CV777 (a G1 strain), PEDV-SDSX16 and PEDV-Aj1102 (two G2 strains). In vivo challenge experiments demonstrated that anti-PEDV mAb-2 inhibited the PEDV infection in piglets. We also produced three HEK293 cell lines that expressed anti-PEDV mAb-2. Overall, our study showed that anti-PEDV mAb-2 produced from hybridoma supernatants effectively inhibited PEDV infection in piglets, and the recombinant HEK293 cell lines expressed anti-PEDV mAb-2 genes.
Layer-by-layer heparinization of therapeutic cells prior to transplantation is an effective way to inhibit the instant blood-mediated inflammatory reactions (IBMIRs), which are the major cause of early cell graft loss during post-transplantation. Here, a conjugate of heparin-binding peptide (HBP) and human serum albumin (HSA), HBP-HSA, was synthesized by using heterobifunctional crosslinker. After the first heparin layer was coated on human umbilical vein endothelial cells (HUVECs) by means of the HBP-polyethylene glycol-phospholipid conjugate, HBP-HSA and heparin were then applied to the cell surface sequentially to form multiple layers. The immobilization and retention of heparin were analyzed by confocal microscopy and flow cytometry, respectively, and the cytotoxity of HBP-HSA was further evaluated by cell viability assay. Results indicated that heparin was successfully introduced to the cell surface in a layer-by-layer way and retained for at least 24 h, while the cytotoxity of HBP-HSA was negligible at the working concentration. Accordingly, this conjugate provides a promising method for co-immobilization of heparin and HSA to the cell surface under physiological conditions with improved biocompatibility.
Background: Tibial plateau fractures involving the posterior plateau (TPFIPs) are complex intra-articular fractures that are difficult to stabilize. Understanding the characteristics of these fractures together with the injury pattern is beneficial for surgeons to choose an optimal treatment strategy. However, the complicated morphology and injury patterns of TPFIPs are poorly characterized. The purpose of this retrospective study was to investigate the injury patterns and fracture characteristics of complex TPFs by applying threedimensional (3D) simulation and fracture mapping methods.Methods: In total, 171 TPFIPs were retrospectively reviewed, and the injury pattern was simulated and analyzed by applying a 3D method with Mimics software, which allowed matching of the fractured articular surfaces of the tibial plateau to the femoral condyle surface. The major articular fracture lines were mapped and then superimposed on a template. The tibial motion angle after fracture injury pattern simulation and the major fracture line angle were quantitatively analyzed, while the injury patterns and fracture characteristics were qualitatively analyzed.Results: Four main injury patterns with distinctive fracture characteristics were observed in this study.In total, 72 TPFs exhibited extension as the pattern of injury with a split posterolateral fragment, and 61 fractures exhibited the flexion-internal rotation injury pattern; compression was the main feature of posterolateral fractures. Furthermore, 21 fractures exhibited the flexion-external rotation injury pattern, with a small posteromedial fragment, and 17 fractures exhibited the flexion-neutral injury pattern, with both parts of the posterior plateau fracture and anterior dislocation being observable. The major articular fracture line angles were significantly different between the four main injury patterns (85.92°, 46.79°, 148.26°, and 16.21°, median values, P<0.05). Two injury patterns, namely, flexion-internal rotation and flexion-external rotation, exhibited rotation in the axial plane (24.13°±8.33°, −15.13°±5.14°, P<0.05).Conclusions: In this study, a method involving a simulated injury pattern was developed and combined with evaluations of fracture characteristics, including two-dimensional (2D) and 3D analyses, to comprehensively describe both the morphologies and injury patterns of TPFIPs.
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