REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.     

Inhibition of extracellular signal-regulated kinases ameliorates hypertension-induced renal vascular remodeling in rat models

The aim of this study is to investigate the effect of the extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, on high blood pressure and related vascular changes. Blood pressure was recorded, thicknesses of renal small artery walls were measured and ERK1/2 immunoreactivity and erk2 mRNA in renal vascular smooth muscle cells (VSMCs) and endothelial cells were detected by immunohistochemistry and in situ hybridization in normotensive wistar kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and PD98059-treated SHR. Compared with normo-tensive WKY rats, SHR developed hypertension at 8 weeks of age, thickened renal small artery wall and asymmetric arrangement of VSMCs at 16 and 24 weeks of age. Phospho-ERK1/2 immunoreactivity and erk2 mRNA expression levels were increased in VSMCs and endothelial cells of the renal small arteries in the SHR. Treating SHR with PD98059 reduced the spontaneous hypertension-induced vascular wall thickening. This effect was associated with suppressions of erk2 mRNA expression and ERK1/2 phosphorylation in VSMCs and endothelial cells of the renal small arteries. It is concluded that inhibition of ERK1/2 ameliorates hypertension induced vascular remodeling in renal small arteries.     

Fluorescence of leachates from three contrasting landfills

Landfill leachates are composed of a complex mixture of degradation products including dissolved organic matter, which includes a wide range of potentially fluorescent organic molecules and compounds. Here we investigate the excitation-emission matrix fluorescence of landfill leachates from three contrasting landfill sites. Landfill fluorescence properties are all characterized by intense fluorescence at lambda(ex) =220-230nm, and lambda(em) =340-370nm which we suggest derives from fluorescent components of the Xenobiotic Organic Matter fraction such as naphthalene, as well as at lambda(ex) =320-360nm, and lambda(em) =400-470nm from a higher molecular weight fulvic-like fraction. Landfill leachates are characterized by intense fluorescence, with approximately 10(2) intensity units of fluorescence at lambda(ex)=220-230nm, and lambda(em)=340-370nmmg(-1) of total organic carbon, demonstrating leachate detection limits of <0.1mgl(-1) total organic carbon. We demonstrate that for all landfill sites, leachate fluorescence intensity has a strong correlation with ground water quality determinants ammonia, total organic carbon and biochemical oxygen demand. We investigate both within-site and between-site leachate fluorescence properties, and demonstrate that although there is significant within-site variability, leachates from all 3 sites can be statistically discriminated using just fluorescence properties (65% success rate) or with a combination of fluorescence and basic geochemical parameters (85%). Our findings suggest that fluorescence can be used as a rapid and sensitive tracer of leachate contamination of ground water, as well as help discriminate, together with geochemical determinants, leachates from different landfill sources.     

变革中的墓地景观：英国墓地设计与管理的新发展

1993年英国自然安葬的兴起以及英国政府提议的坟墓再利用计划将对基地景观产生深远影响。长久以来,很多墓地因缺乏资金而疏于养护,致使其价值被低估。自然安葬的迅速发展一方面是对人们越来越关心的英国墓地疏于养护问题作出的直接回应,另一方面也与英国众多城市可用于传统殡葬的土地日益减少有关。在自然安葬不断发展改进的时候,＂坟墓再利用＂计划的再次引入将有利于防止墓地成为荒废空间。通过当前英国谢菲尔德大学景观系和社会学系正在进行的墓地研究,阐述自然安葬和坟墓再利用的发展以及它们对墓地景观产生的影响。     

系统级封装(SiP)组装技术与锡膏特性(续)

4 结果和讨论 4.1 焊盘间的桥接 结果比较表明,使用不同的治具配置有明显的区别.使用平台治具作为板支撑的激光切割钢网在80 μm间隙的情况下未发现桥接.使用真空支撑时,激光切割钢网在50 μm间隙的情况下也未发现桥接.这说明使用真空支撑在印刷时的钢网和电路板间间隙更小,支撑性能更好.图5显示了其在125 μm×15...     

Impact of Users’ Security Awareness on Desktop Security Behavior: A Protection Motivation Theory Perspective

This article uses the protection motivation theory to study the impact of information security awareness on desktop security behavior. It contributes to the literature by examining the roles played by awareness, an important antecedent to the cognitive processes in the protection motivation theory. The findings indicate that security awareness significantly affects perceived severity, response efficacy, self-efficacy, and response cost. Constructs in the coping appraisal process (except response cost), in turn, significantly impact recommended security behavior.     

Construction defect management using a telematic digital workbench

Real-time, rich-media data communication between the construction site and the off-site design office is becoming one of the important research areas in information technology for construction. This paper presents the concept of a telematic digital workbench, a horizontal tabletop user interface integrating mobile computing and wireless communication to facilitate synchronous construction site to office collaboration. We demonstrate the capabilities and potentials of this system concept for construction defect management. The on-site crew uses a handheld mobile device to collect defect information and transfers the information to the design office through wireless communication by sending the information to a database listener. The digital workbench application monitors the database and synchronizes the location of the visual information on the site with the 3D model on the server. Integrated with 3D viewing capability in a CAD system, designers can interact with the combined model/site data using a horizontal and vertical screen. A case study compared the telematic digital workbench against paper-based and Pocket PC-based methods for defect management in a controlled laboratory experiment. The case study results show that the telematic digital workbench has the potential to improve the accuracy of matching site data to digital data and reduce information loss between site and office collaboration.     

重塑印刷品牌 吸引青年从业

<正>中学和大学的学生们不会有很多人把印刷传播行业作为自己的职业生涯,这也是我们行业的一个大问题。因此,面临的挑战是如何激发学生,让其考虑将印刷传播行     

Isotopic identification of the sources of lead contamination for white storks (Ciconia ciconia) in a marshland ecosystem (Doñana,S.W. Spain)

White storks (Ciconia ciconia) fed in contaminated waters resulting from the Aznacollar acid mining-sludge spillage into the R. Guadiamar, which feeds the eastern flank of the Guadalquivir marshes (Do?ana), S.W. Spain. The sludge was rich in a range of toxic elements, and in organic pollutants such as the aromatic amines. Storks did not exhibit elevated metals in their blood immediately following the accident, but chick blood collected the year following the accident showed genotoxic damage compared to the controls. In this study lead isotope analysis was used to assess if the storks had ingested sludge-derived contaminants. The sludge lead isotope ratio was distinct from that of the Do?ana sediments. The stork blood lead isotope ratios exactly matched that of the sludge. It was concluded that the storks had ingested sludge-derived contaminants. A detailed study of the lead contamination along the R. Guadiamar and the R. Guadalquivir (of which the Guadiamar is a tributary) was also conducted to place the white stork colony lead exposure in the context of the spatial contamination of the storks' habitat.