黄土高原西缘在AD 1875~2003期间石笋氧同位素记录的季风降水变化与海气系统的联系

基于黄土高原西部甘肃武都万象洞中一根石笋0~16 mm之间的5个高精度²³⁰Th年代和103个δ¹⁸O数据, 重建了亚洲季风边缘区过去100多年来高分辨率的季风降水变化历史. 通过与武都器测降水数据对比发现, 最近50多年来石笋氧同位素组成受降雨量效应的影响, 指示了亚洲季风的强弱变化及其带来的降水量信息. 近100多年来亚洲季风的变化历史可分为季风降水增强期(AD 1875~1900)、季风降水减弱期(AD 1901~1946)和季风降水再次增强期(AD 1947~2003) 3个气候段, 而且这3个季风变化阶段与通过历史文献记载建立的旱涝指数变化相似. 近100多年来万象洞石笋氧同位素记录的季风强度变化与太平洋年代际振荡(PDO)密切相关, 年代际时间尺度上PDO暖(冷)相位与季风降水的减少(增加)对应; 但在1977年之后出现了季风降水变化和PDO的反相位关系, 很可能是北太平洋在1976/1977年前后发生的年代际气候跃变的反映. 说明现代亚洲季风强度及季风降水变化通过海气相互作用与太平洋密切相关. 这种关系将有助于亚洲季风区水循环的预测, 而且可以利用洞穴观测数据来提高气候模型的预测能力.     

Out of the fog: Catalyzing integrative capacity in interdisciplinary research

Social studies of interdisciplinary science investigate how scientific collaborations approach complex challenges that require multiple disciplinary perspectives. In order for collaborators to meet these complex challenges, interdisciplinary collaborations must develop and maintain integrative capacity, understood as the ability to anticipate and weigh tradeoffs in the employment of different disciplinary approaches. Here we provide an account of how one group of interdisciplinary fog scientists intentionally catalyzed integrative capacity. Through conversation, collaborators negotiated their commitments regarding the ontology of fog systems and the methodologies appropriate to studying fog systems, thereby enhancing capabilities which we take to constitute integrative capacity. On the ontological front, collaborators negotiated their commitments by setting boundaries to and within the system, layering different subsystems, focusing on key intersections of these subsystems, and agreeing on goals that would direct further investigation. On the methodological front, collaborators sequenced various methods, anchored methods at different scales, validated one method with another, standardized the outputs of related methods, and coordinated methods to fit a common model. By observing the process and form of collaborator conversations, this case study demonstrates that social studies of science can bring into critical focus how interdisciplinary collaborators work toward an integrated conceptualization of study systems.     

Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis

Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.     

Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.     

生锈的器官--血色素沉着症等疾病基因的发现

你可能从未听说过遗传性血色素沉着症，医生对其有所了解，但认为它罕见。然而，研究证实，这种钱起我性疾病折磨着约150万美国人。美国圣路易斯大学医学院的科学家布鲁斯·R·培根（BruCeR．Baco）说，"它是已知最常见的遗传性疾病之一。"亚特兰大市美国"疾病控制与预防中心"（CD）的统计资料表明，只有一小部分遗传性血色素沉着症患者获得了正确的诊断。尽管有一种诊断方法可用，但却很少有人应用。若不治疗，血色素沉着症能致患者于死地。患这种病时，患者的心脏、肝脏及人体的其他器官有大量铁沉积，50～ed年后，这些器官确确实实地…     

Three-dimensional structure of the myosin V inhibited state by cryoelectron tomography

Unconventional myosin V (myoV) is an actin-based molecular motor that has a key function in organelle and mRNA transport, as well as in membrane trafficking. MyoV was the first member of the myosin superfamily shown to be processive, meaning that a single motor protein can 'walk' hand-over-hand along an actin filament for many steps before detaching. Full-length myoV has a low actin-activated MgATPase activity at low [Ca2+], whereas expressed constructs lacking the cargo-binding domain have a high activity regardless of [Ca2+] (refs 5-7). Hydrodynamic data and electron micrographs indicate that the active state is extended, whereas the inactive state is compact. Here we show the first three-dimensional structure of the myoV inactive state. Each myoV molecule consists of two heads that contain an amino-terminal motor domain followed by a lever arm that binds six calmodulins. The heads are followed by a coiled-coil dimerization domain (S2) and a carboxy-terminal globular cargo-binding domain. In the inactive structure, bending of myoV at the head-S2 junction places the cargo-binding domain near the motor domain's ATP-binding pocket, indicating that ATPase inhibition might occur through decreased rates of nucleotide exchange. The actin-binding interfaces are unobstructed, and the lever arm is oriented in a position typical of strong actin-binding states. This structure indicates that motor recycling after cargo delivery might occur through transport on actively treadmilling actin filaments rather than by diffusion.     

Ferns diversified in the shadow of angiosperms

The rise of angiosperms during the Cretaceous period is often portrayed as coincident with a dramatic drop in the diversity and abundance of many seed-free vascular plant lineages, including ferns. This has led to the widespread belief that ferns, once a principal component of terrestrial ecosystems, succumbed to the ecological predominance of angiosperms and are mostly evolutionary holdovers from the late Palaeozoic/early Mesozoic era. The first appearance of many modern fern genera in the early Tertiary fossil record implies another evolutionary scenario; that is, that the majority of living ferns resulted from a more recent diversification. But a full understanding of trends in fern diversification and evolution using only palaeobotanical evidence is hindered by the poor taxonomic resolution of the fern fossil record in the Cretaceous. Here we report divergence time estimates for ferns and angiosperms based on molecular data, with constraints from a reassessment of the fossil record. We show that polypod ferns (> 80% of living fern species) diversified in the Cretaceous, after angiosperms, suggesting perhaps an ecological opportunistic response to the diversification of angiosperms, as angiosperms came to dominate terrestrial ecosystems.