Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.     

Genome sequencing in microfabricated high-density picolitre reactors

The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine.     

GC/MS法追踪摇头丸杂质体系

本文运用GS/MS的总离子流法,选择离子法,对南京地区常见的几种摇头丸进行全面分析,找出与合成途径相关的痕量杂质,根据杂质情况初步确定其合成途径.     

鲁克沁构造带稠油成藏机制研究

吐哈盆地台南凹陷鲁克沁构造带中的北西走向断层受挤压强烈 ,封闭性好 ;而北东走向断层封闭性差 ,常成为油气运移的良好通道。由于本区断块圈闭的有效性差 ,故不具备大规模聚集稀油的条件 ,但对稠变到一定程度的稠油能起较好的封堵作用。鲁克沁构造带高粘重质油的形成是原油运移和成藏阶段双重稠变作用的结果 ,并且油气的聚集是一个动态的过程。随着原油的逐渐稠变 ,所需要的封堵条件逐渐降低 ,油气的聚集过程才趋于稳定。鲁克沁构造带构造后期变革主要表现在构造幅度的增大 ,而未发生强烈的断裂作用 ,因此 ,前侏罗系油藏得以完好地保存     

求取剩余油饱和度的一种实用方法

分析了水驱油田地质、测井及开发动态特征，提出了用生产井含水率资料结合测井资料求取产层平均剩余油饱和度的方法。阐述了该方法的基本模型和计算过程，并以实例计算说明了这种方法的实际应用效果。结果表明，该方法操作简便、实用性强、计算结果可靠，且能准确反映储层的剩余油分布特征。这种方法也避免了水淹层混合液电阻率、岩电系数和水淹层电阻率求取值失真的影响。     

TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.     

Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome.

X-linked dominant Conradi-Hünermann syndrome (CDPX2; MIM 302960) is one of a group of disorders with aberrant punctate calcification in cartilage, or chondrodysplasia punctata (CDP). This is most prominent around the vertebral column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis and atrophoderma. The phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. CDPX2 is presumed lethal in males, although a few affected males have been reported. We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples from seven female probands with CDPX2 (ref. 4). This pattern of accumulated cholesterol intermediates suggested a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-delta8-isomerase (EBP) has been identified and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands. We confirmed the functional significance of two missense alleles by expressing them in a sterol-delta8-isomerase-deficient yeast strain. Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and suggest a role for sterols in bone development.     

渤海湾盆地早第三纪构造样式与油气藏的关系

渤海湾盆地早第三纪构造样式可归结为５种基本类型和３个演化序列。研究结果表明,构造样式及其演化控制着烃源岩的发育,决定着油气藏的类型和展布,制约着含油气系统的范围。综合考虑含油气系统的各个要素,在渤海湾盆地可划分出６个大的含油气系统,分别位于各个坳陷中,并受坳陷的限制。进一步考虑坳陷内凸起构造单元的分割作用,可划分出１３个小的含油气系统。     

临清坳陷莘县凹陷油气勘探远景评价

对莘县凹陷的构造、沉积、盆地模拟及油气勘探远景等进行了深入研究。结果表明,该凹陷具有浅、中、深３个勘探层次,浅层馆陶组和沙一段以储集次生油及低成熟油气为主;中层沙二段、沙三段以自生自储型油藏为主;深层孔二段以储集高成熟油气、石炭－二迭系以煤成气为主。此地区有着极广阔的勘探远景。