Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is an important endogenous regulator of the fibrinolytic system. Reduction of PAI-1 activity has been shown to enhance dissolution of blood clots. Like other serpins, PAI-1 binds covalently to a target serine protease, thereby irreversibly inactivating the enzyme. During this process the exposed reactive-centre loop of PAI-1 is believed to undergo a conformational change becoming inserted into beta sheet A of the serpin. Incubation with peptides from the reactive-centre loop transform serpins into a substrate for their target protease. It has been hypothesised that these peptides bind to beta sheet A, thereby hindering the conformational rearrangement leading to loop insertion and formation of the stable serpin-protease complex. RESULTS: We report here the 1.95 A X-ray crystal structure of a complex of a glycosylated mutant of PAI-1, PAI-1-ala335Glu, with two molecules of the inhibitory reactive-centre loop peptide N-Ac-TVASS-NH2. Both bound peptide molecules are located between beta strands 3A and 5A of the serpin. The binding kinetics of the peptide inhibitor to immobilised PAI-1-Ala335Glu, as monitored by surface plasmon resonance, is consistent with there being two different binding sites. CONCLUSIONS: This is the first reported crystal structure of a complex formed between a serpin and a serpin inhibitor. The localisation of the inhibitory peptide in the complex strongly supports the theory that molecules binding in the space between beta strands 3A and 5A of a serpin are able to prevent insertion of the reactive-centre loop into beta sheet A, thereby abolishing the ability of the serpin to irreversibly inactivate its target enzyme. The characterisation of the two binding sites for the peptide inhibitor provides a solid foundation for computer-aided design of novel, low molecular weight PAI-1 inhibitors.     

颗粒表面改性法制备PTC粉体的研究

本文介绍了一种通过液相颗粒表面改性技术添加二次掺杂物来制备ＰＴＣ粉体的新方法。即将烧结助熔剂Ａｌ２Ｏ３，ＳｉＯ２以及受主杂质ＭｎＯ采用溶液形式，包裹在ＢａＴｉＯ３基粉体颗粒表面进行改性，由此可以得到二次掺杂物Ａｌ２Ｏ３、ＳｉＯ２和ＭｎＯ分布均匀的ＰＴＣ粉体。     

Studies on purification and some properties of nisin from Lactococcus lactis subsp. lactis Al2

Protoporphyria is a genetic disorder in which patients may develop severe protoporphyrin-induced liver damage and require transplantation. Because unique problems occur in the perioperative period and because excess production of protoporphyrin by the bone marrow continues after liver transplantation, the efficacy of this procedure for protoporphyric liver disease is uncertain. We present follow-up of nine patients who underwent liver transplantation. Two patients died within 2 months of transplantation, one from complications of abdominal bleeding and the other from sepsis after bowel perforations. The remaining seven patients had follow-up at 14 months to 8 years after transplantation (mean, 3.8 years). Two of the seven had suffered skin burns from exposure to operating room lights, which healed without scarring. Three had axonal neuropathies in the postoperative period requiring prolonged mechanical ventilation, and motor defects persisted in two. Five patients had normal liver chemistries at follow-up (mean, 3.5 years), with liver biopsy results normal or showing mild portal triad abnormalities, but erythrocyte protoporphyrin levels remained significantly elevated (1,765 +/- 365 mcg/dL; normal, < 65). The other two patients, both of whom had rejection, cytomegalovirus infection, and biliary tract obstruction requiring endoscopic therapy, had a recurrence of protoporphyric liver disease as indicated by liver biopsy features. One died 5 years after transplantation from complications of the liver disease. The other was stable 3.3 years after transplantation and was being monitored for possible retransplantation. Thus, liver transplantation can be performed successfully in patients with protoporphyric liver disease, with intermediate survival rates comparable to the general transplant population. However, disease may recur in the graft, particularly if there are complications that cause cholestasis.     

漳泽水库最优兴利调度研究

漳泽水库供水能力下降。优化调度方式是提高水库效益的最有效途径。通过采用随机动态规划方法与模拟模型交互运算得到现行控制水位的水库优化调度图。采用同样方法对不同控制水位的水库运行方式进行优化调度，选出的规划水库最优控制水位为汛限水位９０４ ．５ ｍ ，正常高水位９０５ ．５ ｍ 。优化的控制水位方案在保障水库防洪安全的前提下可供给城市生活和工业用水６ ３００ 万ｍ３ ，较现行控制水位下的供水量提高１ ２５５ 万ｍ３ 。但农业用水仍然不足，应采取一定措施给予解决，如对灌区工程进行改造，因地制宜采取不同节水措施和污水回用等。     

高炉煤气干法除尘技术发展现状及宝钢应用前景

在对高炉煤气干法除尘技术应用现状进行综合分析的基础上结合宝钢实际，提出宝钢应用此技术的相关建议。     

利用Matlab来解决高等数学中的二维图形问题

本文探讨利用Matlab来解决高等数学中的二维图形问题,并对其中的初等函数、极坐标、统计图进行实例分析,对于这些很难用手工绘制的图形,利用Matlab则很轻易地解决。     

电解铝侧插自焙槽技术改造与环境保护

电解铝侧插自焙槽属于落后的生产工艺，由于其能耗高、物料消耗大、劳动强度大、环境污染严重，在国内电解铝中已开始进行大规模的淘汰改造。采用先进的预焙电解槽生产技术，降耗节能、改善生产劳动强度，环境污染得到有效治理，各项环境指标达标排放，经济技术指标提高，食业面貌发生了巨大大变化。     

电流变流体的研究进展

电流变流体是近年来逐渐受人们重视的一种功能材料，本文介绍其国内、外发展过程及研究现状。     

2006年中国钨工业发展报告

综述了2006年我国钨工业发展现状,分析了钨工业经济运行的政策环境、产业结构、市场供需、竞争态势,指出了当前钨工业发展中的几个突出问题,并提出了相应的对策建议。