VAP-1 as drug target in inflammation : structural features determining ligand interactions

Vascular adhesion protein-1 (VAP-1), which belongs to the copper amine oxidases (CAOs), is a validated drug target in inflammatory diseases. Inhibition of VAP-1 blocks the leukocyte trafficking to sites of inflammation and alleviates inflammatory reactions. In this study, a novel set of potent pyridazinone inhibitors is presented together with their X-ray structure complexes with VAP-1. The crystal structure of serum VAP-1 (sVAP-1) revealed an imidazole binding site in the active site channel and, analogously, the pyridazinone inhibitors were designed to bind into the channel. This is the first time human VAP-1 has been crystallized with a reversible inhibitor and the structures reveal detailed information of the binding mode on the atomic level. Similarly to some earlier studied inhibitors of human VAP-1, the designed pyridazinone inhibitors bind rodent VAP-1 with a lower affinity than human VAP-1. Therefore, we made homology models of rodent VAP-1 and compared human and rodent enzymes to determine differences that might affect the inhibitor binding. The comparison of the crystal structures of the human VAP-1 and the mouse VAP-1 homology model revealed key differences important for the species specific binding properties. In general, the channel in mouse VAP-1 is more narrow and polar than the channel in human VAP-1, which is wider and more hydrophobic. The differences are located in the channel leading to the active site, as well as, in the entrance to the active site channel. The information obtained from these studies is of great importance for the development and design of drugs blocking the activity of human VAP-1, as rodents are often used for in vivo testing of candidate drugs. In order to gain more insight into the selective binding properties of the different CAOs in one species a comprehensive evolutionary study of mammalian CAOs was performed. We found that CAOs can be classified into sub-families according to the residues X1 and X2 of the Thr/Ser-X1-X2-Asn-Tyr-Asp active site motif. In the phylogenetic tree, CAOs group into diamine oxidase, retina specific amine oxidase and VAP-1/serum amine oxidase clades based on the residue in the position X2. We also found that VAP-1 and SAO can be further differentiated based on the residue in the position X1. This is the first large-scale comparison of CAO sequences, which explains some of the reasons for the unique substrate specificities within the CAO family.

Design of Streaming Media Panoramic Video System Based on WebGL

2016 is the outbreak year of the virtual reality industry. In the field of virtual reality, 3D surveying plays an important role. Nowadays, 3D surveying technology has received increasing attention. This project aims to establish and optimize a WebGL three-dimensional broadcast platform combined with streaming media technology. It takes streaming media server and panoramic video broadcast in browser as the application background. Simultaneously, it discusses about the architecture from streaming media server to panoramic media player and analyzing relevant theory problem. This paper focuses on the debugging of streaming media platform, the structure of WebGL player environment, different types of ball model analysis, and the 3D mapping technology. The main work contains the following points: Initially, relay on Easy Darwin open source streaming media server, built a streaming service platform. It can realize the transmission from RTSP stream to streaming media server, and forwards HLS slice video to clients; Then, wrote a WebGL panoramic video player based on Three.js lib with JQuery browser playback controls. Set up a HTML5 panoramic video player; Next, analyzed the latitude and longitude sphere model which from Three.js library according to WebGL rendering method. Pointed out the drawbacks of this model and the breakthrough point of improvement; After that, on the basis of Schneider transform principle, established the Schneider sphere projection model, and converted the output OBJ file to JS file for media player reading. Finally implemented real time panoramic video high precision playing without plugin; At last, I summarized the whole project. Put forward the direction of future optimization and extensible market.