How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?

Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes. Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1, Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the possibility that LS mutations may not simply exhibit dominant negative activity. Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007     

国家自然科学基金面上项目资助额的地区分布规律

本文讨论了国家自然科学基金面上项目资助额的地区分布特点,发现基金面上项目资助额的地区分布与博士生人数的地区分布有很大的相关性,从而可以看出国家自然科学基金的资助在很大程度上取决于申请者所在地区具有的科研和教育水平。     

Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.     

某库岸滑坡稳定分析及治理措施研究

从地质条件出发,详细分析了滑坡的成因,以大型的岩土工程数值分析软件(ADINA)为研究手段,建立有限元计算模型,用强度折减的方法分析了滑坡体在初始工况、蓄水工况、暴雨工况、水位骤降工况和地震工况下的稳定情况,根据滑坡的失稳情况,在综合考虑的基础上,提出了削坡减载和地表排水相结合的治理措施,计算结果表明,治理措施是可行的,研究结果对设计和施工具有较大的参考价值.     

育种目标性状间的同一关系分析方法研究

借助集对分析理论,提出了一种新的育种目标性状间的关系分析方法,阐明了其基本原理与分析步骤,并结合小麦育种实例,介绍了这种分析方法的具体应用。在此基础上,讨论了这种分析方法的优越性及尚待改进之处。表3,参9。     

选择性催化氧化H2S的催化剂研究

在考察了几种单组分氧化物把硫化氢催化氧化为单质硫的基础上，采用共沉淀法合成了3种复合氧化物催化剂A，B，C，并考察了它们的催化活性和选择性．结果表明，在一定条件下，催化剂B的转化率和选择性分别在90％和97％以上，在40h的催化性能稳定性测试中，其转化率和选择性均能保持稳定，具有良好的催化性能．     

吴消元法在精确求解电力系统潮流方程中的应用

应用吴消元法求得算例系统潮流方程的全部精确解，得到了其他方法难以得到的完整的Py、Qy曲线，包括低压运行曲线，并通过平衡点稳定性分析，得到节点电压状态参数空间中平衡点稳定与不稳定的区域分界．阐述了系统受大扰动后过渡到低电压运行状态的可行性，为电压失稳机理的探明提供了依据．