Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P(meta) = 4.41 × 10(-11), per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P(meta) = 3.08 × 10(-10), per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.     

Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer

Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.     

Deep Geothermal:The‘Moon Landing’ Mission in the Unconventional Energy and Minerals Space

Deep geothermal from the hot crystalline basement has remained an unsolved frontier for the geothermal industry for the past 30 years. This poses the challenge for developing a new un-conventional geom...     

ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks

Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.     

复合污染背景下陆地棉对土壤镉的耐受和富集特征

采用田间调查采样与可控盆栽试验的方法,研究了我国大面积种植的非食源性经济作物——陆地棉在土壤复合污染条件下对重金属镉(Cd)的耐受与富集特征.结果表明:陆地棉对石灰性壤质土壤中Cd具有显著的忍耐性,即当土壤中Cd质量分数w达到20.258 mg.kg-1时,陆地棉生长发育才趋向缓慢或病态;陆地棉对土壤中Cd具有显著的富集性,其各组织对Cd富集系数(biological concentration factor,BCF)由大到小的序列为:叶片、茎秆、根系、果壳、籽粒、纤维,其中茎秆、根系、果壳大小相当;在污灌区土壤中w(Cd)未超标的情况下,通过陆地棉萃取可使棉田表土层(0~20cm)中w(Cd)每年降低0.001 3~0.002 0 mg.kg-1;陆地棉各组织对土壤中Cd的BCF(Y)值随土壤中w(Cd)(X)的增加呈现指数递减,其拟合关系式为:Y=Y0+a.e-b.X,即当w(Cd)由0.258 mg.kg-1增加到约1.00 mg.kg-1时,BCF值急剧递减;当w(Cd)由1.00 mg.kg-1继续增加时,BCF值则趋于平缓的低值区间,表明这时陆地棉对土壤Cd污染只具有忍耐性,其吸附机能可能已经退化.     

Optimal proportional reinsurance under dependent risks

This paper considers a correlated risk model with thinning-dependence structure.The authors investigate the optimal proportional reinsurance that maximizes the adjustment coefficient and the optimal proportional reinsurance under mean variance principle for the proposed model.The authors derive the optimal solutions and the numerical illustrations to show the impact of the dependence among the classes of business on the optimal reinsurance arrangements.     

Unusual stable isotope ratios in amino acid and carboxylic acid extracts from the Murchison meteorite

Much effort has been directed to analyses of organic compounds in carbonaceous chondrites because of their implications for organic chemical evolution and the origin of life. We have determined the isotopic composition of hydrogen, nitrogen and carbon in amino acid and monocarboxylic acid extracts from the Murchison meteorite. The unusually high D/H and 15N/14N ratios in the amino acid fraction (delta D = 1,370% after correction for isotope exchange; delta 15N = 90) are uniquely characteristic of known interstellar organic materials. The delta D value of the monocarboxylic acid fraction is lower (377%), but still consistent with an interstellar origin. These results confirm the extraterrestrial origin of both classes of compound, and provide the first evidence suggesting a direct relationship between the massive organo-synthesis occurring in interstellar clouds and the presence of pre-biotic compounds in primitive planetary bodies. The isotope data also bear on the historical problem of distinguishing indigenous material from terrestrial contaminants.