Identification of ALK as a major familial neuroblastoma predisposition gene

Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.     

Identification of talin as a major cytoplasmic protein implicated in platelet activation

During platelet activation there is a major reorganization in the platelet cytoskeleton that accompanies a rapid change in platelet shape. Many of the events associated with activation are attributed to a rise in calcium concentration within the platelet cytoplasm. One direct consequence of the elevated calcium is the activation of a calcium-dependent protease that cleaves a major platelet protein of relative molecular mass (Mr) approximately 235,000 (235K) to 200K. This protein, P235, has been purified and reported to interact with actin, but the significance of the proteolytic cleavage is unknown. Talin, a cytoskeletal protein in smooth muscle and fibroblasts, binds vinculin and, together with vinculin, is localized in fibroblasts at sites of actin-membrane attachment. Talin and P235 have similar purification procedures, sedimentation coefficients and Stokes' radii (ref. 6 and Molony et al., unpublished observations). Of particular significance, talin is readily cleaved by proteases from approximately 215K to a fragment of approximately 190K. Given these similarities we have investigated the possible relationship between these proteins. Here we demonstrate that platelet P235 is recognized by anti-talin antibody and that it binds vinculin. Both proteins are cleaved in vitro by the calcium-activated protease to yield similar fragments. We conclude that P235 corresponds to the platelet form of talin.     

多目标规划问题的aκ—弱较多最优解的有关性质

在文 [1]、[2 ]、[3]的基础上 ,提出了aκ -弱较多最优解的概念 ,并讨论了其相应的性质。     

多目标规划问题的ak-弱较多最优解的有关性质

在文[1]、[2]、[3]的基础上，提出了ak－弱较多最优解的概念，并讨论了其相应的性质。     

稀土及其配合物药理学性质研究概况

综述了稀土化合物在生物学及药理学研究中的发展状况， 对其抗炎、抗凝血、抗肿瘤、抗动脉硬化等方面作用的研究作了阐述     

北里湖总氮、总磷主要输入外源辨识

为了确定影响杭州西湖的主要污染源,以相对封闭的西湖北里湖为研究对象,通过在沿湖路面设置采样点以及在湖中设置大气沉降采样点,对路面及大气入湖的N和P进行监测、估算,结果表明:(a)各月大气总沉降中TN及TP的输入变化趋势不明显,但干沉降中TN及TP的输入却有着明显的春、夏差异;3—8月北里湖TN输入量为1202.20kg,TP输入量为15.02kg.(b)沿岸人行道路面由草地及不透水路面构成,路面灰尘以细颗粒(d<150μm)物质为主,可占总量的79.12%~90.04%;不同粒级组的灰尘中TN含量呈现以下规律:细颗粒组(28μm≤d<150μm)>极细颗粒组(d<28μm)>粗颗粒组(d≥150μm),但TN含量分布特征不明显.(c)草地的N和P输出通过输出系数法估算,不透水路面的N和P输出通过模拟路面灰尘的累积、冲刷进行估算,得到2010年3—8月北里湖来自沿岸人行道的TN输入量为60.13kg,TP输入量为12.52kg.分析结果表明,大气沉降是北里湖N输入的主要外源,同时也是湖水中P的相对重要的来源.     

建筑工程重大危险源的辨识、评价与控制

系统安全理论认为,导致建筑安全事故发生的根源是工程中存在着大量的危险源.对建筑工程中的危险源进行辨识、评价、控制是解决工程安全问题的一个重要思路.该文运用作业条件危险性评价方法(LEC方法)对施工中的脚手架作业进行风险评价,可准确辨识出施工中的重大危险源,从而低成本、高效率的控制施工中的危险源.     

A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors.

Neuropsychiatric disorders such as anxiety, depression, migraine, vasospasm and epilepsy may involve different subtypes of the 5-hydroxytryptamine (5-HT) receptor. The 1B subtype, which has a unique pharmacology, was first identified in rodent brain. But a similar receptor could not be detected in human brain, suggesting the absence in man of a receptor with equivalent function. Recently a human receptor gene was isolated (designated 5-HT1B receptor, 5-HT1D beta receptor, or S12 receptor) which shares 93% identity of the deduced protein sequence with rodent 5-HT1B receptors. Although this receptor is identical to rodent 5-HT1B receptors in binding to 5-HT, it differs profoundly in binding to many drugs. Here we show that replacement of a single amino acid in the human receptor (threonine at residue 355) with a corresponding asparagine found in rodent 5-HT1B receptors renders the pharmacology of the receptors essentially identical. This demonstrates that the human gene does indeed encode a 1B receptor, which is likely to have the same biological functions as the rodent 5-HT1B receptor. In addition, these findings show that minute sequence differences between homologues of the same receptor from different species can cause large pharmacological variation. Thus, drug-receptor interactions should not be extrapolated from animal to human species without verification.