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

Nudel and FAK as Antagonizing Strength Modulators of Nascent Adhesions through Paxillin

Competition for binding to the cellular protein paxillin by the proteins Nudel and focal adhesion kinase is important for the proper regulation of cell adhesion and migration

Vegetative Ecological Characteristics of Restored Reed (Phragmites australis) Wetlands in the Yellow River Delta, China

In this study, we compared ecological characteristics of wetland vegetation in a series of restoration projects that were carried out in the wetlands of Yellow River Delta. The investigated characteristics include plant composition structure, species diversity and community similarity in three kinds of Phragmites australis wetlands, i.e. restored P. australis wetlands (R1, R2, R3 and R4: restored in 2002, 2005, 2007 and 2009, respectively), natural P. australis wetland (N) and degraded P. australis wetland (D) to assess the process of wetlands restoration. The coverage of the R1 was 99%, which was similar to natural wetland. Among all studied wetlands, the highest and lowest stem density was observed in R1 and R2, respectively, Plant height and stem diameter show the same trend as N > R2 > R1 > R3 > D > R4. Species diversity of restored P. australis wetlands became closed to natural wetland. Both species richness and Shannon–Wiener index had similar tendency: increased first and then decreased with restored time. The highest species richness and species diversity were observed in R2, while the lowest values of those parameters were found in natural P. australis wetland. Similarity indexes between restored wetlands and natural wetland increased with the restoration time, but they were still less than 50%. The results indicate that the vegetation of P. australis wetlands has experienced a great improvement after several years’ restoration, and it is feasible to restored degraded P. australis wetlands by pouring fresh water into those wetlands in the Yellow River Delta. However, it is notable that costal degraded P. australis wetland in this region may take years to decades to reach the status of natural wetland

Microbial tolerance engineering for boosting lactic acid production from lignocellulose

Abstract Lignocellulosic biomass is an attractive non-food feedstock for lactic acid production via microbial conversion due to its abundance and low-price, which can alleviate the conflict with food supplies. However, a variety of inhibitors derived from the biomass pretreatment processes repress microbial growth, decrease feedstock conversion efficiency and increase lactic acid production costs. Microbial tolerance engineering strategies accelerate the conversion of carbohydrates by improving microbial tolerance to toxic inhibitors using pretreated lignocellulose hydrolysate as a feedstock. This review presents the recent significant progress in microbial tolerance engineering to develop robust microbial cell factories with inhibitor tolerance and their application for cellulosic lactic acid production. Moreover, microbial tolerance engineering crosslinking other efficient breeding tools and novel approaches are also deeply discussed, aiming to providing a practical guide for economically viable production of cellulosic lactic acid

An integrative genomic analysis of transcriptional profiles identifies characteristic genes and patterns in HIV-infected long-term non-progressors and elite controllers

Abstract Background Despite that most HIV-infected individuals experience progressive CD4+ T cell loss and develop AIDS, a minority of HIV-infected individuals remain asymptomatic and maintain high level CD4+ T cell counts several years after seroconversion. Efforts have been made to understand the determinants of the nonprogressive status, exemplified by the clinical course of elite controllers (ECs) who maintain an undetectable viremia and viremic nonprogressors (VNPs) who have a normal CD4+ count in spite of circulating viral load. However, the intrinsic mechanism underlying nonprogression remained elusive. In this study, we performed an integrative analysis of transcriptional profiles to pinpoint the underlying mechanism for a naturally occurring viral control. Methods Three microarray datasets, reporting mRNA expression of the LTNPs or ECs in HIV-infected patients, were retrieved from Gene Expression Ominbus (GEO) or Arrayexpress databases. These datasets, profiled on the same type of microarray chip, were selected and merged by a bioinformatic approach to build a meta-analysis derived transcriptome (MADNT). In addition, we investigated the different transcriptional pathways and potential biomarkers in CD4+ and CD8+ cells in ECs and whole blood in VNPs compared to HIV progressors. The combined transcriptome and each subgroup was subject to gene set enrichment analysis and weighted co-expression network analysis to search potential transcription patterns related to the non-progressive status. Results 30 up-regulated genes and 83 down-regulated genes were identified in lymphocytes from integrative meta-analysis of expression data. The interferon response and innate immune activation was reduced in both CD4+ and CD8+ T cells from ECs. Several characteristic genes including CMPK1, CBX7, EIF3L, EIF4A and ZNF395 were indicated to be highly correlated with viremic control. Besides that, we indicated that the reduction of ribosome components and blockade of translation facilitated AIDS disease progression. Most interestingly, among VNPs who have a relatively high viral load, we detected a two gene-interaction networks which showed a strong correlation to immune control even with a rigorous statistical threshold (p value = 2−e4 and p value = 0.004, respectively) by WGCNA. Conclusions We have identified differentially expressed genes and transcriptional patterns in ECs and VNPs compared to normal chronic HIV-infected individuals. Our study provides new insights into the pathogenesis of HIV and AIDS and clues for the therapeutic strategies for anti-retroviral administration

Predicting surface deformation during mechanical attrition of metallic alloys

Abstract Extensive efforts have been devoted in both the engineering and scientific domains to seek new designs and processing techniques capable of making stronger and tougher materials. One such method for enhancing such damage-tolerance in metallic alloys is a surface nano-crystallization technology that involves the use of hundreds of small hard balls which are vibrated using high-power ultrasound so that they impact onto the surface of a material at high speed (termed Surface Mechanical Attrition Treatment or SMAT). However, few studies have been devoted to the precise underlying mechanical mechanisms associated with this technology and the effect of processing parameters. As SMAT is dynamic plastic deformation process, here we use random impact deformation as a means to investigate the relationship between impact deformation and the parameters involved in the processing, specifically ball size, impact velocity, ball density and kinetic energy. Using analytical and numerical solutions, we examine the size of the indents and the depths of the associated plastic zones induced by random impacts, with results verified by experiment in austenitic stainless steels. In addition, global random impact and local impact frequency models are developed to analyze the statistical characteristics of random impact coverage, together with a description of the effect of random multiple impacts, which are more reflective of SMAT. We believe that these models will serve as a necessary foundation for further, and more energy-efficient, development of such surface nano-crystalline processing technologies for the strengthening of metallic materials

A Novel Virtual Network Embedding Algorithm with Load Balancing in Elastic Optical Networks

This paper proposes a novel load balancing algorithm for virtual network embedding problem in elastic optical networks. Simulation results show the algorithm achieves a better tradeoff between balancing spectrum resource load and reducing spectrum usage. ? 2014 OSA.EI