Essential role for oncogenic Ras in tumour maintenance.

Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.     

Structural and mechanistic insights into the interaction between Rho and mammalian Dia

Formins are involved in a variety of cellular processes that require the remodelling of the cytoskeleton. They contain formin homology domains FH1 and FH2, which initiate actin assembly. The Diaphanous-related formins form a subgroup that is characterized by an amino-terminal Rho GTPase-binding domain (GBD) and an FH3 domain, which bind somehow to the carboxy-terminal Diaphanous autoregulatory domain (DAD) to keep the protein in an inactive conformation. Upon binding of activated Rho proteins, the DAD is released and the ability of the formin to nucleate and elongate unbranched actin filaments is induced. Here we present the crystal structure of RhoC in complex with the regulatory N terminus of mammalian Diaphanous 1 (mDia1) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with two subdomains of GBD/FH3. We show that the FH3 domain of mDia1 forms a stable dimer and we also identify the DAD-binding site. Although binding of Rho and DAD on the N-terminal fragment of mDia1 are mutually exclusive, their binding sites are only partially overlapping. On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD.     

文廷式与徐建寅的交谊

以百余年前的文字碎片连缀起文廷式与徐建寅的交谊始末;分析两人建立在志同道合基础上的深切情谊对于各自的人生历程的深远影响;由此也可见晚清士林君子志趣之一斑。     

Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21.

The stimulation of a variety of cell surface receptors promotes the accumulation of the active, GTP-bound form of Ras proteins in cells. This is a critical step in signal transduction because inhibition of Ras activation by anti-Ras antibodies or dominant inhibitory Ras mutants blocks many of the effects of these receptors on cellular function. To reach the active GTP-bound state, Ras proteins must first release bound GDP. This rate-limiting step in GTP binding is thought to be catalysed by a guanine-nucleotide-releasing factor (GRF). Here we report the cloning of complementary DNAs from a rat brain library that encode a approximately 140K GRF for Ras p21 (p140Ras-GRF). Its carboxy-terminal region is similar to that of CDC25, a GRF for Saccharomyces cerevisiae RAS. This portion of Ras-GRF accelerated the release of GDP from RasH and RasN p21 in vitro, but not from the related RalA, or CDC42Hs GTP-binding proteins. A region in the amino-terminal end of Ras-GRF is similar to both the human breakpoint cluster protein, Bcr, and the dbl oncogene product, a guanine-nucleotide-releasing factor for CDC42Hs. An understanding of Ras-GRF function will enhance our knowledge of the many signal transduction pathways mediated by Ras proteins.     

Spatio-temporal images of growth-factor-induced activation of Ras and Rap1.

G proteins of the Ras family function as molecular switches in many signalling cascades; however, little is known about where they become activated in living cells. Here we use FRET (fluorescent resonance energy transfer)-based sensors to report on the spatio-temporal images of growth-factor-induced activation of Ras and Rap1. Epidermal growth factor activated Ras at the peripheral plasma membrane and Rap1 at the intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve growth factor-induced activation of Ras was initiated at the plasma membrane and transmitted to the whole cell body. After three hours, high Ras activity was observed at the extending neurites. By using the FRAP (fluorescence recovery after photobleaching) technique, we found that Ras at the neurites turned over rapidly; therefore, the sustained Ras activity at neurites was due to high GTP/GDP exchange rate and/or low GTPase activity, but not to the retention of the active Ras. These observations may resolve long-standing questions as to how Ras and Rap1 induce different cellular responses and how the signals for differentiation and survival are distinguished by neuronal cells.     

情感隐喻与颜色词的语义关联阐释

隐喻核心不在于语言本身,而在于从始发域到目标域的跨域映现。分析颜色词语义理据可以得知:情感隐喻发挥了巨大的作用,使思维的扩展成为可能,隐喻的使用者通过知识可以理解颜色词的隐喻义。同时,文化内涵也对颜色词隐喻义的理解产生了较大的影响。     

Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.

The mammalian shc gene encodes two overlapping, widely expressed proteins of 46 and 52K, with a carboxy-terminal SH2 domain that binds activated growth factor receptors, and a more amino-terminal glycine/proline-rich region. These shc gene products (Shc) are transforming when overexpressed in fibroblasts. Shc proteins become phosphorylated on tyrosine in cells stimulated with a variety of growth factors, and in cells transformed by v-src (ref. 2), suggesting that they are tyrosine kinase targets that control a mitogenic signalling pathway. Here we report that tyrosine-phosphorylated Shc proteins form a specific complex with a non-phosphorylated 23K polypeptide encoded by the grb2/sem-5 gene. The grb2/sem-5 gene product itself contains an SH2 domain, which mediates binding to Shc, and is implicated in activation of the Ras guanine nucleotide-binding protein by tyrosine kinases in both Caenorhabditis elegans and mammalian cells. Consistent with a role in signalling through Ras, shc overexpression induced Ras-dependent neurite outgrowth in PC12 cells. These results suggest that Shc tyrosine phosphorylation can couple tyrosine kinases to Grb2/Sem-5, through formation of a Shc-Grb2/Sem-5 complex, and thereby regulate the mammalian Ras signalling pathway.     

外周血白细胞计数与冠心病

目的:研究外周血白细胞计数及其亚群与冠脉病变之间的关系。方法:收集本院2009年3月至2010年5月所有进行冠脉造影患者的相关数据,并进行统计分析。结果:和冠脉造影正常者(n=20)相比,冠心病患者(n=52)外周血白细胞计数、中性粒细胞计数、中性粒细胞比例、中性/淋巴细胞比例显著升高,淋巴细胞比例显著降低(P≤0.03)。对冠脉病变范围与白细胞计数及其亚群的分析发现,与冠脉无病变者相比,冠脉病变者外周血白细胞计数、中性粒细胞计数、中性粒细胞比例、中性/淋巴细胞比例显著升高,淋巴细胞比例显著降低(P≤0.02)。结论:外周血白细胞计数及分类可能有助于预测冠状动脉病变及其严重程度。     

探寻自治立法与哈耶克的自由主义理论之关联——《自由秩序原理》读后

哈耶克是20世纪自由主义的重要代表人物之一,主张法治下的自由.<自由秩序原理>是其自由主义理论的代表作,该书关于自由的论述极为精辟,为进一步深入理解和把握哈耶克的自由主义理论提供了一种适当的研究路径.自治立法思想与哈耶克的自由秩序原理相契合,属于自生自发秩序的范畴.     

清代满汉民族的交往与融合

清初,满族贵族凭藉权势,通过多种手段,获得大量汉人,采取强制措施,迫使旗内汉人迅速满化,但是,为了维护清朝统治,经济,化落后,人口很少的满族人,吸收了大量的汉族化,又使八旗人员在清代中晚期大量汉化,所以,满汉交往与融合,成为清代满汉关系发展的必然趋势。     

GTPase activity of dynamin and resulting conformation change are essential for endocytosis

Dynamin is a large GTPase with a relative molecular mass of 96,000 (Mr 96K) that is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Although its function is apparently essential for scission of newly formed vesicles from the plasma membrane, the nature of dynamin's role in the scission process is still unclear. It has been proposed that dynamin is a regulator (similar to classical G proteins) of downstream effectors. Here we report the analysis of several point mutants of dynamin's GTPase effector (GED) and GTPase domains. We show that oligomerization and GTP binding alone, by dynamin, are not sufficient for endocytosis in vivo. Rather, efficient GTP hydrolysis and an associated conformational change are also required. These data argue that dynamin has a mechanochemical function in vesicle scission.     

萃取过程的量热研究：Ⅲ.萃取剂之间的缔合作用

本文利用量热滴定的方法,研究了萃取有机相中酸性萃取剂P204、P507、P272和PMBP与中性磷酸酯之间的缔合作用,求出相应的缔合常数β以及热力学函数△H、△S、△G。