Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels

Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting about 1 in 3,500 males. It is allelic with the milder Becker muscular dystrophy. The biochemical basis for both diseases is unknown and no effective treatment is available. Long-range physical mapping has shown that the DMD gene, localized in Xp21, is extremely large, exceeding 2 million base pairs. Until now, carrier detection and prenatal diagnosis has involved the use of linked restriction fragment length polymorphism markers which detect muscular dystrophy-associated deletions in about 10% of the cases. Field inversion gel electrophoresis (FIGE) allows the detection of structural rearrangements in 21 out of 39 of the DMD patients studied (54%), of which 14 (65%) were not detected by conventional methods. Large deletions seem to make up a much higher fraction of the DMD mutations than so far indicated by other methods. A region prone to deletion was located in the distal half of the gene. FIGE analysis could provide a valuable extension of information for carrier detection and prenatal diagnosis. The technique should be generally applicable to the study of diseases involving structural chromosomal rearrangements.     

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.     

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。     

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。     

Light in tiny holes

The presence of tiny holes in an opaque metal film, with sizes smaller than the wavelength of incident light, leads to a wide variety of unexpected optical properties such as strongly enhanced transmission of light through the holes and wavelength filtering. These intriguing effects are now known to be due to the interaction of the light with electronic resonances in the surface of the metal film, and they can be controlled by adjusting the size and geometry of the holes. This knowledge is opening up exciting new opportunities in applications ranging from subwavelength optics and optoelectronics to chemical sensing and biophysics.     

嵌套式建模支持

阐述了人的建模思维机制。引入等价关系和划分作为问题粒度研究的基础，定义了逆商集，使之与商集一起，构成了对问题不同粒度的完整描述，并讨论了粒度的性质，借助拓扑分析，给出了问题可分解、可细化和粗化、细化等一系列定义，在问题簇和模型簇概念的基础上，提出了嵌套式建模（支持）作为面向复杂系统的建模支持方法论，具体给出了其实施步骤，这是一个人机交互的启发式过程，将嵌套式建模与传统式建模作了比较，此外还作了若干说明。     

高容量温盘驱动器伺服码同步时钟录写技术

提出了可变频时钟写入方法和锁相环倍频时钟写入方法，给出了这两种写入法的读／写电路，并分析了其性能。结果证明，可变频时钟写入方法电路简单，刻写时钟周期短；锁相环倍频时钟写入过程较前者长，但其频率范围容易调整。两者均适合高密度小型温盘的时钟录写。     

Human gamma-chain genes are rearranged in leukaemic T cells and map to the short arm of chromosome 7

Three gene families that rearrange during the somatic development of T cells have been identified in the murine genome. Two of these gene families (alpha and beta) encode subunits of the antigen-specific T-cell receptor and are also present in the human genome. The third gene family, designated here as the gamma-chain gene family, is rearranged in murine cytolytic T cells but not in most helper T cells. Here we present evidence that the human genome also contains gamma-chain genes that undergo somatic rearrangement in leukaemia-derived T cells. Murine gamma-chain genes appear to be encoded in gene segments that are analogous to the immunoglobulin gene variable, constant and joining segments. There are two closely related constant-region gene segments in the human genome. One of the constant-region genes is deleted in all three T-cell leukaemias that we have studied. The two constant-region gamma-chain genes reside on the short arm of chromosome 7 (7p15); this region is involved in chromosomal rearrangements identified in T cells from individuals with the immunodeficiency syndrome ataxia telangiectasia and observed only rarely in routine cytogenetic analyses of normal individuals. This region is also a secondary site of beta-chain gene hybridization.