A loss-of-function RNA interference screen for molecular targets in cancer

The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-kappaB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IkappaB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes.     

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.     

ELNF归约演算

ＥＬＮＦ演算是在ＬＮＦ演算的基础上扩充而成的函数／逻辑归约演算系统，扩充的主要工作包括逻辑变量、谓词名的引进。提出并描述了逻辑函子ＳＯＬＵＴＩＯＮ和ＰＲＯＶＥ及其归约规则．讨论了ＥＬＮＦ演算的基本概念。为表征ＨＯＲＮ子句提供了一种有效方式。     

弘扬国学精粹 提高人文素质--高校非中文专业开设"中国古典文学鉴赏"课的必要性与可行性

从高校非中文专业学生知识结构的现状出发，阐述加强人文素质教育的重要性；“中国古典文学鉴赏”课的课程特点及其在人文素质教育中所起的作用决定了在高校非中文专业学生中开设这门课程的必要性和可行性。     

正二十面体正五角十二面体的几何参数及其在准晶格中的应用

本文推导出正二十面体和正五角十二面体的几何参数,探讨了平面理想准晶格模型[1][2]的两种空间结构,得到了一种以五角十二面体为特征的平面格子,利用所得到的几何参数,也可对以上两种多面体为基本单位的其它空间结构进行研究。     

Synapsin I bundles F-actin in a phosphorylation-dependent manner

Synapsin I is a neuron-specific phosphoprotein localized to the cytoplasmic surface of synaptic vesicles. This phosphoprotein is a major substrate for cyclic AMP-dependent and calcium/calmodulin-dependent protein kinases. Its state of phosphorylation can be altered both in vivo and in vitro by a variety of physiological and pharmacological manipulations known to affect synaptic function. Recent direct evidence suggests that it may be involved in the regulation of neurotransmitter release from the nerve terminal. In the nerve terminal, synaptic vesicles are embedded in a cytoskeletal network, consisting in part of actin. We report here the ability of the dephospho-form of synapsin I to bundle F-actin. This bundling activity is reduced when synapsin I is phosphorylated by cAMP-dependent protein kinase and virtually abolished when it is phosphorylated by calcium/calmodulin-dependent protein kinase II or by both kinases. These results, demonstrating an interaction of synapsin I with actin in vitro, support the possibility that synapsin I is involved in clustering of synaptic vesicles at the presynaptic terminal and that the phosphorylation of synapsin I may be involved in regulating the translocation of synaptic vesicles to their sites of release.     

基于分级遗传算法的结构损伤识别方法

提出了一种基于遗传算法的利用不完整振动数据识别结构损伤的新方法，该方法首先扩展不完整的振型并利用单元能量熵差比确定结构损伤的大致位置，然后采用二级搜索策略，借助遗传算法确定结构损伤的程度，数值计算结果表明，当可能的损伤区域较大时，本方法较直接搜索策略更能有效地确定结构损伤的程度。     

尺度变化对形状的比例不变特征的影响

分析了在实际应用中，摄像机拍摄距离或焦距发生变化时，同一对象形状在不同图像中出现细节差别的原因；结合常用的如圆形度、矩不变量和傅里叶描述子等形状特征，通过试验分析，说明了在不同尺度下。这些细节上的变化在一定程度上会影响同一对象的同类形状特征之间的比较，也说明了对形状特征的比例不变性的应用应当是有一定范围限制的．     

表面激子极化激元的定域化

在存在着随机粗糙和空间色散时，利用了一个数字模型研究表面激子极化激元的定域化．发现定域化出现在表面激子极化激元的最大频率附近，在广延态上的衰减长度大于定域态上的衰减长度，表面激子极化激元的定域化是受到粗糙表面散射波的毁灭性干涉所引起的．     

钢筋表面微区电位分布的原位测量

应用自行研制的扫描微参比电极联机测量系统,原位测量了钢筋在模拟混凝土孔隙液中表面微区电位分布.结果表明,钢筋在纯饱和Ca(OH)2溶液中处于钝态.当溶液的pH降低和外加Cl-时,钢筋表面微区电位分布即发生变化,电位差变大,钢筋表面随之发生点腐蚀.