Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10?1? and rs6687758, OR = 1.09, P = 2.27 × 10??, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10??), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10?1? and rs7136702, OR = 1.06, P = 4.02 × 10??) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10?1?). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.     

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.     

Scorpions are a food item of American black bears in Sonora, Mexico

The remains of the scorpion Diplocentrus peloncillensis Francke were found in 7 scats of black bears ( Ursus americanus ) collected in the Sierra de San Luis, Sonora, Mexico. The collection data and previously reported black bear population estimates for the study area suggested that, although scorpions are not a large part of black bear diets in Sonora, feeding on scorpions is not restricted to a single individual or family unit and is apparently a relatively common behavior in the population. Also, the discovery of D. peloncillensis in Sonora represents a new country record.     

6-相步光弹仪测试细纤维/树脂基体相界面剪应力

用新型的6-相步光弹仪,对直径25μm的单玻璃纤维增强环氧树脂复合材料的纤维-树脂相界面微观应力分布进行测试.相步弹性学分析表明纤维末端和纤维断裂处附近的等级条纹级数较高,存在较大的应力集中区域.试样两端加载18.38,25.61和32.53MPa时,纤维末端相界面剪应力最大值分别出现在距纤维末端7,18和33μm处,为26.87,30.22和33.20MPa.纤维断裂处,加载为24.69MPa时,相界面剪应力最大值出现在距纤维断裂25μm处,约30MPa;加载增加到33.09MPa时,高的等级条纹级数区域向远离纤维断裂处延伸,相界面剪应力最大值增加到约36MPa.     

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.     

General Relativity and the Standard Model: Why evidence for one does not disconfirm the other

General Relativity and the Standard Model often are touted as the most rigorously and extensively confirmed scientific hypotheses of all time. Nonetheless, these theories appear to have consequences that are inconsistent with evidence about phenomena for which, respectively, quantum effects and gravity matter. This paper suggests an explanation for why the theories are not disconfirmed by such evidence. The key to this explanation is an approach to scientific hypotheses that allows their actual content to differ from their apparent content. This approach does not appeal to ceteris-paribus qualifiers or counterfactuals or similarity relations. And it helps to explain why some highly idealized hypotheses are not treated in the way that a thoroughly refuted theory is treated but instead as hypotheses with limited domains of applicability.     

Dissecting the genomic complexity underlying medulloblastoma

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.     

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.     

A quantitative protein interaction network for the ErbB receptors using protein microarrays

Although epidermal growth factor receptor (EGFR; also called ErbB1) and its relatives initiate one of the most well-studied signalling networks, there is not yet a genome-wide view of even the earliest step in this pathway: recruitment of proteins to the activated receptors. Here we use protein microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain encoded in the human genome to measure the equilibrium dissociation constant of each domain for 61 peptides representing physiological sites of tyrosine phosphorylation on the four ErbB receptors. This involved 77,592 independent biochemical measurements and provided a quantitative protein interaction network that reveals many new interactions, including ones that fall outside of our current view of domain selectivity. By slicing through the network at different affinity thresholds, we found surprising differences between the receptors. Most notably, EGFR and ErbB2 become markedly more promiscuous as the threshold is lowered, whereas ErbB3 does not. Because EGFR and ErbB2 are overexpressed in many human cancers, our results suggest that the extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases, and perhaps other signalling proteins as well.