PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.     

Temperature and high salinity effects in germinating dimorphic seeds of Atriplex rosea

Atriplex rosea L. (Chenopodiaceae; tumbling orach), an annual herb, is a widely established weedy species of disturbed sites in all counties of Utah. Seeds of Atriplex rosea were collected from a salt marsh in Faust, Utah, and are dimorphic, light brown, and 2-2.5 mm wide, or black and 1-2 mm wide. Seed germination responses of the black and brown seeds were studied over a range of salinity and temperature. Both brown and black seeds germinated at 1000 mM NaCl, and the optimal temperature for germination of both types was 20°-30°C. Variation in temperature, however, affected germination of black seeds more than brown seeds. At lower thermoperiod only 40%-50% black seeds germinated in nonsaline control, and germination was almost completely inhibited with the inclusion of salinity. However, all brown seeds germinated in control at temperatures above 5°-15°C, and inhibition caused by salinity was comparatively lower. Brown seeds had a higher germination rate than black seeds at all temperature and salinity treatments. The highest rate of germination of both seeds occurred at the temperature regime of 5°-15°C. Recovery of germination for black seeds when transferred to distilled water after being in various salinity treatments for 20 days was quite variable. Recovery decreased with increase in salinity at lower temperature regimes, increased with salinity at optimal thermoperiod, and had no effect at 20°-30°C. Brown seeds recovered poorly from salinity at all thermoperiods except 5°-15°C, where recovery decreased with an increase in salinity. Brown seeds are adapted to germination in the early part of the growing season, whereas black seeds are capable of surviving harsher conditions and can germinate in later time periods. Characteristics of the dimorphic seeds increase chances for survival in the harsh saline desert environment.     

中小企业技术创新的现状与对策

分析了中国中小企业技术创新的特点和现状,指出中小企业技术创新能力不高、缺乏技术创新的人才队伍、产学研合作机制不健全、融资渠道少等问题,提出重视中小企业技术创新人才的培养、优化金融环境、建立健全产学研合作机制、通过培育中介组织推动企业自主创新、选择适合企业实际情况的技术创新战略等措施.     

s-单式环的交换性定理(英文)

本文将文献[3]的引理1推广到s-单式环上,并用迭代技术给出文献[4]的定理2一个简易的证明,将若干有1环的交换性定理推广到s-单式环上。     

人体经络复杂网络路由问题的求解

为了研究经络—免疫—神经—内分泌网络(jingluo-immune-nerve-endocrinenetwork)学说,采用复杂网络定义、模型、算法和理论,对穴位在经络中的信息传递方式、交互条件、路由途径、高导电性进行了测试和验证,建立了经络的复杂网络路由模型,证实了该网络的存在·信息物质沿经络路线传播,经络循行也有确定的方向和速度,确立了经络的基本功能是传递及调控生命信息物质为经络研究开辟了一条新的方法·     

互联网中的标准结构熵的时间演化分析

通过对Internet标准结构熵随时间变化规律的分析发现,Internet的标准结构熵具有随时间而逐渐降低的趋势,以riesling节点获得的Internet监测数据的计算结果为例,Internet标准结构熵从2000年4月的最大值0.379下降至2004年5月的0.318,月平均下降幅度为0.12%,即由高熵值拓扑结构向低熵值拓扑结构的状态变化.由此可知Internet的宏观拓扑结构在演化过程中存在着拓扑结构的信息代谢.     

基于VC和VIP的面向对象知识表示

知识表示是人工智能研究的基本问题之一。通过在 Visual C+ +的类中引入Visual Prolog的推理机制提出了一种基于 VC和 VIP的面向对象知识表示方法 ,完善了 Visual C+ +对象的推理功能 ,进一步增强了面向对象的知识表示能力以及 VisualProlog的接口和计算能力 ,并通过实验验证了方法的性能     

Caenorhabditis elegans expressed sequence tags identify gene families and potential disease gene homologues.

A database containing mapped partial cDNA sequences from Caenorhabditis elegans will provide a ready starting point for identifying nematode homologues of important human genes and determining their functions in C. elegans. A total of 720 expressed sequence tags (ESTs) have been generated from 585 clones randomly selected from a mixed-stage C. elegans cDNA library. Comparison of these ESTs with sequence databases identified 422 new C. elegans genes, of which 317 are not similar to any sequences in the database. Twenty-six new genes have been mapped by YAC clone hybridization. Members of several gene families, including cuticle collagens, GTP-binding proteins, and RNA helicases were discovered. Many of the new genes are similar to known or potential human disease genes, including CFTR and the LDL receptor.