Structural Based Screening of Antiandrogen Targeting Activation Function-2 Binding Site

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current antiandrogen therapies induce resistant mutations at the hormone binding pocket (HBP) that convert the activity of these agents from antagonist to agonist. Thus, there is a high unmet medical need for the development of novel antiandrogens which circumvent mutation-based resistance. Herein, through the analysis of AR structures with ligands binding to the activation function-2 (AF2) site, we built a combined pharmacophore model. In silico screening and the subsequent biological evaluation lead to the discovery of the novel lead compound IMB-A6 that binds to the AF2 site, which inhibits the activity of either wild-type (WT) or resistance mutated ARs. Our work demonstrates structure-based drug design is an efficient strategy to discover new antiandrogens, and provides a new class of small molecular antiandrogens for the development of novel treatment agents against PCa

H5N1 avian influenza re-emergence of Lake Qinghai: phylogenetic and antigenic analyses of the newly isolated viruses and roles of migratory birds in virus circulation

Highly pathogenic avian influenza H5N1 virus has swept west across the globe and caused serious debates on the roles of migratory birds in virus circulation since the first large-scale outbreak in migratory birds of Lake Qinghai, 2005. In May 2006, another outbreak struck Lake Qinghai and six novel strains were isolated. To elucidate these QH06 viruses, the six isolates were subjected to whole-genome sequencing. Phylogenetic analyses show that QH06 viruses are derived from the lineages of Lake Qinghai, 2005. Five of the six novel isolates are adjacent to the strain A/Cygnus olor/Croatia/1/05, and the last one is related to the strain A/duck/Novosibirsk/02/05, an isolate of the flyway. Antigenic analyses suggest that QH06 and QH05 viruses are similar to each other. These findings implicate that QH06 viruses of Lake Qinghai may travel back via migratory birds, though not ruling out the possibility of local circulation of viruses of Lake Qinghai

The Different Metabolic Responses of Resistant and Susceptible Wheats to Fusarium graminearum Inoculation

Fusarium head blight (FHB) is a serious wheat disease caused by Fusarium graminearum (Fg) Schwabe. FHB can cause huge loss in wheat yield. In addition, trichothecene mycotoxins produced by Fg are harmful to the environment and humans. In our previous study, we obtained two mutants TPS1− and TPS2−. Neither of these mutants could synthesize trehalose, and they produced fewer mycotoxins. To understand the complex interaction between Fg and wheat, we systematically analyzed the metabolic responses of FHB-susceptible and -resistant wheat to ddH2O, the TPS− mutants and wild type (WT) using NMR combined with multivariate analysis. More than 40 metabolites were identified in wheat extracts including sugars, amino acids, organic acids, choline metabolites and other metabolites. When infected by Fg, FHB-resistant and -susceptible wheat plants showed different metabolic responses. For FHB-resistant wheat, there were clear metabolic differences between inoculation with mutants (TPS1−/TPS2−) and with ddH2O/WT. For the susceptible wheat, there were obvious metabolic differences between inoculation with mutant (TPS1−/TPS2−) and inoculation with ddH2O; however, there were no significant metabolic differences between inoculation with TPS− mutants and with WT. Specifically, compared with ddH2O, resistant wheat increased the levels of Phe, p-hydroxy cinnamic acid (p-HCA), and chlorogenic acid in response to TPS− mutants; however, susceptible wheat did not. Shikimate-mediated secondary metabolism was activated in the FHB-resistant wheat to inhibit the growth of Fg and reduce the production of mycotoxins. These results can be helpful for the development of FHB-resistant wheat varieties, although the molecular relationship between the trehalose biosynthetic pathway in Fg and shikimate-mediated secondary metabolism in wheat remains to be further studied

N-(2,6-Dimethoxypyridin-3-yl)-9-methyl-9H-carbazole-3-sulfonamide

In the title compound, C20H19N3O4S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87 (10)°. In the crystal, the molecules are held together by N—H...O and C—H...O hydrogen bonds into layers, which are assembled into a three-dimensional network via π–π stacking interactions between inversion-related pyridine rings, with centroid–centroid distances of 3.5101 (12) Å

Comparative metagenomics of the gut microbiota in wild greylag geese (Anser anser) and ruddy shelducks (Tadorna ferruginea)

Abstract Gut microbiome contributes to host health by maintaining homeostasis, increasing digestive efficiency, and facilitating the development of immune system. Wild greylag geese (Anser anser) and ruddy shelducks (Tadorna ferruginea), migrating along the central Asian flyway, appear to be one of the most popular species in the rare birds rearing industries of China. However, the structure and function of the gut microbial communities associated with these two bird species remain poorly understood. Here, for the first time, we compared gut metagenomes from greylag geese to ruddy shelducks and investigated the similarities and differences between these two bird species in detail. Taxonomic classifications revealed the top three bacterial phyla, Firmicutes, Proteobacteria, and Fusobacteria, in both greylag geese and ruddy shelducks. Furthermore, between the two species, 12 bacterial genera were found to be more abundant in ruddy shelducks and 41 genera were significantly higher in greylag geese. A total of 613 genera (approximately 70%) were found to be present in both groups. Metabolic categories related to carbohydrate metabolism, metabolism of cofactors and vitamins, lipid metabolism, amino acid metabolism, and glycan biosynthesis and metabolism were significantly more abundant in ruddy shelducks, while greylag geese were enriched in nucleotide metabolism and energy metabolism. The herbivorous greylag geese gut microbiota harbored more carbohydrate‐active enzymes than omnivorous ruddy shelducks. In our study, a range of antibiotic resistance categories were also identified in the gut microbiota of greylag geese and ruddy shelducks. In addition to providing a better understanding of the composition and function of wild birds gut microbiome, this comparative study provides reference values of the artificial domestication of these birds

Highly Pathogenic Avian Influenza A(H5N8) Virus in Wild Migratory Birds, Qinghai Lake, China

In May 2016, a highly pathogenic avian influenza A(H5N8) virus strain caused deaths among 3 species of wild migratory birds in Qinghai Lake, China. Genetic analysis showed that the novel reassortant virus belongs to group B H5N8 viruses and that the reassortment events likely occurred in early 2016