Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

从陈述语气看主谓短语与句子的联系和区别

不少学者认为短语与句子之间是“实现关系”,结构规则具有很强的一致性。但是各类短语成句能力存在一定的差异,有的短语可以自主成句,还有的短语根本不能单独成句,短语能否成句与不同的语气有关。     

仿形磨削凸轮机构运动学的CAD/CAG

对用仿形磨削方法磨削硬质合金可转位刀片周边的仿形凸轮机构进行了运动学分析,根据凸轮机构的运动学特性开发出一套设计和绘制仿形凸轮的CAD和CAG软件,采用该软件可以省去大量的繁复计算与绘图工作量,缩短设计制造周期,实现设计、绘图自动化。     

面向对象环境参数设置与模拟研究

模拟一般是为了应用于特定领域的问题而设计的,而模拟语言可以设计通用领域的问题,相对难度较大.开发模拟软件,有必要提供使用者容易掌握的参数和模拟技术环境,从而降低开发难度.介绍一种灵活的利用总体构造信息和各种规模参数自动建立模型的设计方法.构建以程序文档作为模拟技术中各种模型的基础,储存于模型数据库,选定相应模型的模板,输入相应参数,就可自动生成所需的特定模型.利用这一系统,建模者可以用最小的工作量形成复杂的大模型.选用两个案例实验验证其实用性和有效性.     

A single origin of phenylketonuria in Yemenite Jews

Phenylketonuria (PKU) is a metabolic disease caused by recessive mutations of the gene encoding the hepatic enzyme phenylalanine hydroxylase (PAH). The incidence of PKU varies widely across different geographic areas, and is highest (about 1 in 5,000 live births) in Ireland and western Scotland, and among Yemenite Jews. A limited number of point mutations account for most of the PKU cases in the European population. Here we report that a single molecular defect--a deletion spanning the third exon of the PAH gene--is responsible for all the PKU cases among the Yemenite Jews. Examination of a random sample of Yemenite Jews using a molecular probe that detects the carriers of this deletion indicated a high frequency of the defective gene in this community. Although the deleted PAH gene was traced to 25 different locations throughout Yemen, family histories and official documents of the Yemenite Jewish community showed that the common ancestor of all the carriers of this genetic defect lived in San'a, the capital of Yemen, before the eighteenth century.     

DNA-programmable nanoparticle crystallization

It was first shown more than ten years ago that DNA oligonucleotides can be attached to gold nanoparticles rationally to direct the formation of larger assemblies. Since then, oligonucleotide-functionalized nanoparticles have been developed into powerful diagnostic tools for nucleic acids and proteins, and into intracellular probes and gene regulators. In contrast, the conceptually simple yet powerful idea that functionalized nanoparticles might serve as basic building blocks that can be rationally assembled through programmable base-pairing interactions into highly ordered macroscopic materials remains poorly developed. So far, the approach has mainly resulted in polymerization, with modest control over the placement of, the periodicity in, and the distance between particles within the assembled material. That is, most of the materials obtained thus far are best classified as amorphous polymers, although a few examples of colloidal crystal formation exist. Here, we demonstrate that DNA can be used to control the crystallization of nanoparticle-oligonucleotide conjugates to the extent that different DNA sequences guide the assembly of the same type of inorganic nanoparticle into different crystalline states. We show that the choice of DNA sequences attached to the nanoparticle building blocks, the DNA linking molecules and the absence or presence of a non-bonding single-base flexor can be adjusted so that gold nanoparticles assemble into micrometre-sized face-centred-cubic or body-centred-cubic crystal structures. Our findings thus clearly demonstrate that synthetically programmable colloidal crystallization is possible, and that a single-component system can be directed to form different structures.     

Compressive deformation behavior of an indirect-extruded Mg-8Sn-1Al-1Zn alloy

The medium and warm deformation behaviors of an indirect-extruded Mg-8Sn-1Al-1Zn alloy were investigated by compression tests at temperatures between 298 and 523 K and strain rates of 0.001–10 s?1. It was found that the twinning-slip transition temperature was strain rate dependent, and all the true stress-true strain curves could be divided into two groups: concave and convex curves. Associated microstructural investigations indicated that the dynamic recrystallization (DRX) behavior of the alloy varied with deformation conditions. At high strain rate and low temperature, dynamically recrystallized grains preferentially nucleated and developed in the twinned regions, indicating that twinning-induced DRX was dominant. While, at low strain rate, DRX developed extensively at grain boundaries and twins, and the process of twinning contributed to both oriented nucleation and selective growth. For the studied alloy, cracks mainly initiated from the shear band and twinning lamellar over the ranges of temperature and strain rate currently applied.     

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.     

高水基液压液的蒸发特性研究

通过对高水基液压液在不同工作条件下因蒸发而产生的失水量的测定及对试验数据进行回归分析,揭示了液压液蒸发率与工作温度和工作时间的函数关系,并指明了高水基液玉液的蒸发特性,从而对合理使用高水基液压液提供了一定的理论根据。     

DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z

The alpha 1-protease inhibitor, or alpha-antitrypsin (AAT), a major plasma inhibitor of leukocyte elastase and bacterial proteases, is encoded at the PI locus on chromosome 14 (14q24.3-q32.1). A deficiency of AAT in individuals homozygous for the PI Z allele occurs in about 1 in 2,000-8,000 caucasians and is associated with an increased risk of early adult onset emphysema and liver disease in childhood. We have now used DNA polymorphisms associated with the AAT gene to investigate the origin of the PI Z allele. Using two genomic probes extending into the 5' and 3' flanking regions, respectively, we have identified eight polymorphic restriction sites. Extensive linkage disequilibrium occurs throughout the probed region with the PI Z allele, but not with normal PI M alleles. The Z allele occurs mainly with one haplotype, indicating a single, relatively recent, origin in caucasians.