Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band

We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer.     

Male-pattern baldness susceptibility locus at 20p11

We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)).     

MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis

Disruption of signaling pathways such as those mediated by sonic hedgehog (Shh) or platelet-derived growth factor (Pdgf) causes craniofacial abnormalities, including cleft palate. The role that microRNAs play in modulating palatogenesis, however, is completely unknown. We show that, in zebrafish, the microRNA Mirn140 negatively regulates Pdgf signaling during palatal development, and we provide a mechanism for how disruption of Pdgf signaling causes palatal clefting. The pdgf receptor alpha (pdgfra) 3' UTR contained a Mirn140 binding site functioning in the negative regulation of Pdgfra protein levels in vivo. pdgfra mutants and Mirn140-injected embryos shared a range of facial defects, including clefting of the crest-derived cartilages that develop in the roof of the larval mouth. Concomitantly, the oral ectoderm beneath where these cartilages develop lost pitx2 and shha expression. Mirn140 modulated Pdgf-mediated attraction of cranial neural crest cells to the oral ectoderm, where crest-derived signals were necessary for oral ectodermal gene expression. Mirn140 loss of function elevated Pdgfra protein levels, altered palatal shape and caused neural crest cells to accumulate around the optic stalk, a source of the ligand Pdgfaa. These results suggest that the conserved regulatory interactions of mirn140 and pdgfra define an ancient mechanism of palatogenesis, and they provide candidate genes for cleft palate.     

Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity

Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.     

基于专利引文数据的混合动力汽车创新扩散研究

以巴斯扩散模型为理论基础,利用1995～2011年的专利引文数据,对混合动力汽车的技术扩散模型进行了非线性最小二乘法估计。结果显示：①各参数均为统计上显著的,且可决系数与调整可决系数均较大;②该技术的扩散路径符合巴斯模型,且处于成熟阶段。同时,以普锐斯为例,对其1997～2010年的销售数据进行拟合与预测,结果显示,该产品的扩散过程符合巴斯模型。文章认为新技术的扩散与新产品之间存在时滞。     

Multispecies-compatible antitumor effects of a cross-species small-interfering RNA against mammalian target of rapamycin

Successful development of sequence-specific siRNA (small interfering RNA)-based drugs requires an siRNA design that functions consistently in different organisms. Utilizing the CAPSID program previously developed by our group, we here designed siRNAs against mammalian target of rapamycin (mTOR) that are entirely complementary among various species and investigated their multispecies-compatible gene-silencing properties. The mTOR siRNAs markedly reduced mTOR expression at both the mRNA and protein levels in human, mouse, and monkey cell lines. The reduction in mTOR expression resulted in inactivation of both mTOR complex I and II signaling pathways, as confirmed by reduced phosphorylation of p70S6K (70-kDa ribosomal protein S6 kinase), 4EBP1 (eIF4E-binding protein 1), and AKT, and nuclear accumulation of FOXO1 (forkhead box O1), with consequent cell-cycle arrest, proliferation inhibition, and autophagy activation. Moreover, interfering with mTOR activity in vivo using mTOR small-hairpin RNA-expressing recombinant adeno-associated virus led to significant antitumor effects in xenograft and allograft models. Thus, the present study demonstrates that cross-species siRNA successfully silences its target and readily produces multispecies-compatible phenotypic alterations-antitumor effects in the case of mTOR siRNA. Application of cross-species siRNA should greatly facilitate the development of siRNA-based therapeutic agents.     

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.     

华西雨屏区不同人工植被类型下土壤氮库及其有效性

为了解华西雨屏区人工植被类型对土壤氮库及其有效性的影响,选取华西雨屏区7种典型人工植被类型：橘树（Glycosmis cochinchinensi5）迹地、橘树林地、巨桉（Eucalyptus grandis）林地、玉米（Zeamays）地、香樟（Cinnamonum camphora）林地、柚子（Citrus mnxima）林地和桃树（Pmnnus persica）林地,于2010年7月分别采集土壤根层与根下层原状土样,分析其氮库及有效性。结果表明,华西雨屏区几种典型人工植被类型均表现出较大的氮库特征,但不同人工植被类型间具有较大的差异。相对于其他植被类型,玉米地根层和根下层土壤氮库均相对较小,而橘树、柚子和桃树林地根层土壤氮库相对较大,巨桉、香樟和桃树林地根下层土壤氮库相对较大。然而,玉米地具有较高的根层土壤铵态氮和硝态氮含量,但巨桉林地具有较低的根下层土壤铵态氮和硝态氮含量。这些结果为区域氮素合理利用、土地利用结构调整以及生态环境建设提供了一定理论依据。     

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.     

海上要地防空反导阵地优度排序研究

针对海上要地防空反导作战中发射阵地优度排序问题,结合要地面积较小、各备选阵地自然环境条件差别不大的实际情况,提出一种以各阵地与保卫目标间距离来衡量阵地优度的评价指标体系构建方法。首次将各己方目标的重要度作为对应评价指标的权值,并提出一种基于网页排名(PageRank, PR)算法的评价指标赋权方法。通过算例仿真可得,本文提出的方法能够给出科学、准确的备选阵地优度排序,为解决海上要地防空反导阵地选择问题提供了一种新思路、新方法。