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.     

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.     

Observation of robust edge superconductivity in Fe(Se,Te) under strong magnetic perturbation

The iron-chalcogenide high temperature superconductor Fe(Se,Te) (FST) has been reported to exhibit complex magnetic ordering and nontrivial band topology which ...     

Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.     

φ混合序列的完全矩收敛性

主要利用φ混合序列的矩不等式和随机变量的截尾技术,在适当的矩条件下,研究了φ混合序列的完全矩收敛性。本文的结果推广了独立序列和已有文献关于φ混合序列的相应结果,同时也将φ混合序列的完全收敛性改进到完全矩收敛性。     

Experimental and numerical study on plasma nitriding of AISI P20 mold steel

In this study, plasma nitriding was used to fabricate a hard protective layer on AISI P20 steel, at three process temperatures (450°C, 500°C, and 550°C) and over a range of time periods (2.5, 5, 7.5, and 10 h), and at a fixed gas N₂:H₂ ratio of 75vol%:25vol%. The morphology of samples was studied using optical microscopy and scanning electron microscopy, and the formed phase of each sample was determined by X-ray diffraction. The elemental depth profile was measured by energy dispersive X-ray spectroscopy, wavelength dispersive spectroscopy, and glow dispersive spectroscopy. The hardness profile of the samples was identified, and the microhardness profile from the surface to the sample center was recorded. The results show that ε-nitride is the dominant species after carrying out plasma nitriding in all strategies and that the plasma nitriding process improves the hardness up to more than three times. It is found that as the time and temperature of the process increase, the hardness and hardness depth of the diffusion zone considerably increase. Furthermore, artificial neural networks were used to predict the effects of operational parameters on the mechanical properties of plastic mold steel. The plasma temperature, running time of imposition, and target distance to the sample surface were all used as network inputs; Vickers hardness measurements were given as the output of the model. The model accurately reproduced the experimental outcomes under different operational conditions; therefore, it can be used in the effective simulation of the plasma nitriding process in AISI P20 steel.