Identification of cells initiating human melanomas

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.     

Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIgamma (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIgamma markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIgamma, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.     

The genome of the model beetle and pest Tribolium castaneum

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.     

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.     

Molecular cloning and polymorphism of major histocompatibility complex class Ⅰ genes from grass carp (Ctenophayngodon idellus)

In order to clarify the molecular sequences, allelic polymorphism and the tertiary structure of grass carp(Ctenophayngodon idellus) MHC class Ⅰ, and to further study their relationship with disease resistances, grass carp MHC class Ⅰ gene (Ctid-MHC I) was cloned from a cDNA library and the allelic polymorphism in the population was investigated. The results showed that most of the variations exist in the peptide-binding domain (PBD) and high polymorphism was identified in the Ctid-MHC I allelic genes from 12 individuals. Based on the genetic distance, Ctid-MHC class Ⅰ can be classified into 6 types (from Ctid-MHC I-UA to Ctid-MHC I-UF) which were subdivided into 9 lineages (from A to I). Comparison of the Ctid-MHC I among animals and humans showed that the key amino acids of the peptide binding sites are conserved. Analysis of the tertiary structure of the PBD between Grass carp and human crystallographic data of HLA-A2, the variation with insertion or deletion was found in eight regions (A-H). The p     

An ancient nova shell around the dwarf nova Z Camelopardalis

Cataclysmic variables (classical novae and dwarf novae) are binary star systems in which a red dwarf transfers hydrogen-rich matter, by way of an accretion disk, to its white dwarf companion. In dwarf novae, an instability is believed to episodically dump much of the accretion disk onto the white dwarf. The liberation of gravitational potential energy then brightens these systems by up to 100-fold every few weeks or months. Thermonuclear-powered eruptions thousands of times more luminous occur in classical novae, accompanied by significant mass ejection and formation of clearly visible shells from the ejected material. Theory predicts that the white dwarfs in all dwarf novae must eventually accrete enough mass to undergo classical nova eruptions. Here we report a shell, an order of magnitude more extended than those detected around many classical novae, surrounding the prototypical dwarf nova Z Camelopardalis. The derived shell mass matches that of classical novae, and is inconsistent with the mass expected from a dwarf nova wind or a planetary nebula. The shell observationally links the prototypical dwarf nova Z Camelopardalis with an ancient nova eruption and the classical nova process.     

IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro

Distinctive properties of stem cells are not autonomously achieved, and recent evidence points to a level of external control from the microenvironment. Here, we demonstrate that self-renewal and pluripotent properties of human embryonic stem (ES) cells depend on a dynamic interplay between human ES cells and autologously derived human ES cell fibroblast-like cells (hdFs). Human ES cells and hdFs are uniquely defined by insulin-like growth factor (IGF)- and fibroblast growth factor (FGF)-dependence. IGF 1 receptor (IGF1R) expression was exclusive to the human ES cells, whereas FGF receptor 1 (FGFR1) expression was restricted to surrounding hdFs. Blocking the IGF-II/IGF1R pathway reduced survival and clonogenicity of human ES cells, whereas inhibition of the FGF pathway indirectly caused differentiation. IGF-II is expressed by hdFs in response to FGF, and alone was sufficient in maintaining human ES cell cultures. Our study demonstrates a direct role of the IGF-II/IGF1R axis on human ES cell physiology and establishes that hdFs produced by human ES cells themselves define the stem cell niche of pluripotent human stem cells.     

THEMIS observation of a magnetotail current sheet flapping wave

A flapping wave was observed by THEMIS-B （P1） and THEMIS-C （P2） probes on the dawn side of the magnetotail, while the solar wind was generally stable. The magnetic activity was quite weak, suggesting that this flapping wave was generated by an internal instability, which normally occurs during magnetic quiet times. Our analysis shows that the flapping wave was propagating downward with a tail-aligned scale of at least 3.7 RE and did not show much change in shape during its propagation from P1 to P2. Correlation analysis employed to estimate the time lag between the corresponding half waveforms of P1 and P2 shows that the propagating velocities along the current sheet normal directions were close to each other in the beginning, but increased linearly later on. The average wavelength of the flapping wave is approximately 4 RE. Theoretical analysis suggests that the ballooning type wave model may not be the mechanism for the observed flapping wave, but that the magnetic double-gradient instability model is a more plausible candidate.     

违约回收率密度函数模拟的非参数估计方法研究

本文研究违约回收率密度函数的模拟估计问题. 本文的工作由两个方面组成. 首先,我们解决了在应用非参数方法估计违约回收率密度函数时如何选取窗宽,以及在使用对称核时如何处理在有界区间上产 生的边界问题. 针对如何选取合理窗宽提高估计效果的问题,我们通过将最优窗宽选取通过渐近积分误差最小作为 标准,然后将满足渐近积分误差最小的问题转换为一个非线性方程,进而应用插入法与迭代算法,求出最优窗 宽的收敛解. 第二,针对应用普通对称核拟合分布于[0,1] 区间内的回收率会产生的估计量偏差在边界有增大趋势问题,我们通过引入边界核来改善这一现象：首先对两种核的统计性质进行理论推导,随后使用蒙特卡罗模拟（Monte Carlo Simulation）方法对其拟合绩效进行数值分析. 本文的数值结果表明我们引入边界核方法,这较之普通对称核可以有效改善边界问题,同时边界核方法在各个指标上效果更优. 最后,基于穆迪公司官方网站公布的2006年到2011年全球每年违约公司债券和贷款的违约回收率统计数据共653个数据,我们的实证案例分析表明,本文引入的边界核方法与现有普遍使用的以Beta分布刻画回收率的方法相比较,通过拟合优度检验和Bootstrap检验,我们的违约回收率密度函数模拟的非参数边界核方法比对应的Beta分布刻画方法更可靠,同时我们的结果也明显优于Beta分布刻画的回收率模型.