Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide–valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC₅₀ of 7 nM and EC_2×PT of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide–valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.     

Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors

Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d-amino acids in the P3 position. Cbz-d-Phe-Phe-Arg-bk (33) was found to be the best candidate with a potency of K_i = 8 μM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l-Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.     

西藏台错古湖晚第四纪轮藻类及其生态环境、气候变化探讨

西藏台错TT-1剖面厚369 cm,为一套碳酸盐粘土和粘土碳酸盐沉积,地层测年为41.4-4.5 ka,含丰富的轮藻化石,分属于11个轮藻植物群,群落所在地层的碳酸盐和钙质含量分别为80％和33％.从老到新(剖面自下而上):①41.4-26.64 ka(369-319 cm),处于末次冰期间冰阶MIS3a暖期,湖区气候...     

Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole

A new bioactive photoaffinity probe KPU-252-B1 (4) possessing a biotin tag on the oxazole ring of a potent plinabulin derivative KPU-244 (2) was synthesized via the Cu^I-catalyzed Huisgen’s cycloaddition reaction to understand the precise binding mode of the diketopiperazine-based anti-microtubule agent plinabulin on tubulin. Probe 4 showed significant binding affinity toward tubulin and cytotoxicity against an HT-29 cells. A photoaffinity labeling study suggested that probe 4 specifically recognizes tubulin at a binding site that binds plinabulin or colchicine, most likely near or at the colchicine binding site, which is located at the interfacial region formed by ??-and ??-tubulin association. The results also demonstrated that probe 4 may serve as a useful plinabulin chemical probe to investigate the molecular mechanism by which anti-microtubule diketopiperazine derivatives operate.     

污染土壤生态修复的理论内涵、方法及应用

讨论了污染土壤生态修复的理论内涵、修复方法的优化组合及其应用案例.将污染土壤生态修复的目标拓展为:目标污染物降低到可接受程度、土壤生态毒理性降低到可接受程度、部分恢复或全部恢复土壤的生态服务功能.归纳出污染土壤生态修复的5个特点、5个原则.初步提出污染土壤生态修复方法优化组合的原则.污染土壤生态修复方法优化组合表现出以...     

基于物元模型的鄱阳湖生态经济区土地生态安全评价

基于2001-2007年的相关数据,借助物元模型对鄱阳湖生态经济区的土地生态安全状况进行研究.结果表明:2001年鄱阳湖生态经济区土地生态安全状况为较安全状态,2002—2004年处于临界安全状态,2005年下降为不安全状态,2006年后土地生态安全状况有所好转,处于临界安全状态.表明利用物元模型进行区域土地生态安全评价是可行的,具有计算简便、意义明确、评价精度高等优点,为土地生态安全评价提供了另一种途径.     

疏勒河中游生态服务价值对土地利用变化的响应

利用ArcGIS 9.2和ERDAS 9.1软件平台和生态经济学方法,采用Costanza等生态系统服务价值计算公式,结合中国陆地生态系统服务单位面积价值,探讨了疏勒河中游1990-2010年土地利用和生态系统服务价值变化特征.结果表明:1990-2010年,疏勒河中游土地利用以未利用地、牧草地、耕地为主,三者面积占研究区总面积的98.2％,20年间土地利用整体特征并未发生重大变化;疏勒河中游主要土地利用变化发生在耕地、建设用地和牧草地,土地利用动态度分别为13.6％、8.0％和7.7％;生态系统服务价值总体呈上升趋势,从344.85亿元增加到485.11亿元,牧草地和水域对研究区总体生态系统服务价值的贡献率最大.研究区生态经济的发展已经处于低度协调水平的边缘,需要加强生态环境保护力度.     

Factors influencing progress toward sympatric speciation

Many factors could influence progress towards sympatric speciation. Some of the potentially important ones include competition, mate choice and the degree to which alternative sympatric environments (resources) are discrete. What is not well understood is the relative importance of these different factors, as well as interactions among them. We use an individual-based numerical model to investigate the possibilities. Mate choice was modelled as the degree to which male foraging traits influence female mate choice. Competition was modelled as the degree to which individuals with different phenotypes compete for portions of the resource distribution. Discreteness of the environment was modelled as the degree of bimodality of the underlying resource distribution. We find that strong mate choice was necessary, but not sufficient, to cause sympatric speciation. In addition, sympatric speciation was most likely when the resource distribution was strongly bimodal and when competition among different phenotypes was intermediate. Even under these ideal conditions, however, sympatric speciation occurred only a fraction of the time. Sympatric speciation owing to competition on unimodal resource distributions was also possible, but much less common. In all cases, stochasticity played an important role in determining progress towards sympatric speciation, as evidenced by variation in outcomes among replicate simulations for a given set of parameter values. Overall, we conclude that the nature of competition is much less important for sympatric speciation than is the nature of mate choice and the underlying resource distribution. We argue that an increased understanding of the promoters and inhibitors of sympatric speciation is best achieved through models that simultaneously evaluate multiple potential factors.     

Frequency and inheritance of non‐male producing clones in Daphnia magna: evolution towards sex specialization in a cyclical parthenogen?

In Daphnia (Cladocera, Crustacea), parthenogenetic reproduction alternates with sexual reproduction. Individuals of both sexes that belong to the same parthenogenetic line are genetically identical, and their sex is determined by the environment. Previously, non-male producing (NMP) genotypes have been described in species of the Daphnia pulex group. Such genotypes can only persist through phases of sexual reproduction if they co-occur with normal (MP) genotypes that produce both males and females, and thus the breeding system polymorphism is similar to gynodioecy (coexistence of females with hermaphrodites), which is well known in plants. Here we show that the same breeding system polymorphism also occurs in Daphnia magna, a species that has diverged from D. pulex more than 100 MY ago. Depending on the population, between 0% and 40% of D. magna females do not produce males when experimentally exposed to a concentration of the putative sex hormone methyl farnesoate that normally leads to male-only clutches. Natural broods of these NMP females never contained males, contrasting with high proportions of male offspring in MP females from the same populations. The results from a series of crossing experiments suggest that NMP is determined by a dominant allele at a single nuclear locus (or a several closely linked loci): NMP × MP crosses always yielded 50% NMP and 50% MP offspring, whereas MP × MP crosses always yielded 100% MP offspring. Based on cytochrome c oxidase subunit I-sequences, we found that NMP genotypes from different populations belong to three highly divergent mitochondrial lineages, potentially representing three independent evolutionary origins of NMP in D. magna. Thus, the evolution of NMP genotypes in cyclical parthenogens may be more common than previously thought. Moreover, MP genotypes that coexist with NMP genotypes may have responded to the presence of the latter by partially specializing on male production. Hence, these populations of D. magna may be a model for an evolutionary transition from a purely environmental to a partially genetic sex determination system.     

Differences in bacterial diversity of host-associated populations of Phylloxera notabilis Pergande (Hemiptera: Phylloxeridae) in pecan and water hickory

Host‐associated differentiation (HAD) is the presence of genetically divergent, host‐associated populations. It has been suggested that microbial symbionts of insect herbivores may play a role in HAD by allowing their insect hosts to use different plant species. The objective of this study was to document if host‐associated populations of Phylloxera notabilis Pergande (Hemiptera: Phylloxeridae) in pecan and water hickory corresponded with differences in the composition of their associated bacteria. To test this hypothesis, we characterized the symbionts present in P. notabilis associated with these two tree species through metagenomic analyses using 454 sequencing. Differences in bacterial diversity were found between P. notabilis populations associated with pecan and water hickory. The bacteria, Pantoea agglomerans and Serratia marcescens, were absent in the P. notabilis water hickory population, whereas both species accounted for more than 69.72% of bacterial abundance in the pecan population.