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Summary Background We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. Methods We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Findings Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p=2·4×10 −8 ) in the interleukin-6 receptor ( IL6R ) gene and rs7130588 (OR 1·09, p=1·8×10 −8 ) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene ( LRRC32 , also known as GARP ). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10 −4 ), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1 , HLA-B , LPP , and BACH2 . Interpretation The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. Funding National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPredicting the stability of cyclic disulfides by molecular modeling: effective concentrations in thiol-disulfide interchange and the design of strongly reducing dithiolsJohn A. Burns and George M. WhitesidesCite this: J. Am. Chem. Soc. 1990, 112, 17, 6296–6303Publication Date (Print):August 1, 1990Publication History Published online1 May 2002Published inissue 1 August 1990https://pubs.acs.org/doi/10.1021/ja00173a017https://doi.org/10.1021/ja00173a017research-articleACS PublicationsRequest reuse permissionsArticle Views1195Altmetric-Citations102LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
<div>Abstract<p>We investigated the association between adulthood weight change and colorectal cancer risk in a prospective study with 24 to 34 years of follow-up among 90,988 women and 46,679 men. The primary exposures included weight change from early adulthood (age = 18 years for women, 21 years for men) to baseline enrollment (median age = 43 years for women, 52 years for men), and from baseline to present. In the secondary analyses, we also assessed 4-year weight change during follow-up, and during premenopausal (from age 18 years to menopause) and postmenopausal (from menopause to present) periods in women. Compared to men maintaining their weight from age 21 to baseline, those who gained 20 kg or more were at a higher risk of colorectal cancer (relative risk [RR], 1.64; 95% confidence interval [CI], 1.15–2.35, <i>P</i><sub>trend</sub> < 0.001), whereas those who lost 8 kg or more had a lower risk (RR, 0.61; 95% CI, 0.30–1.22, <i>P</i><sub>trend</sub> = 0.003). Similar but weaker associations were found in women and the corresponding RRs were 1.38 (95% CI, 1.13–1.69, <i>P</i><sub>trend</sub> < 0.001) and 0.80 (95% CI, 0.58–1.09, <i>P</i><sub>trend</sub> = 0.21). Weight change from baseline to present was not associated with colorectal cancer risk. Four-year weight change during follow-up was positively associated with colorectal cancer risk in men (<i>P</i><sub>trend</sub> = 0.03) but not in women (<i>P</i><sub>trend</sub> = 0.42). In addition, in women, weight change before, but not after, menopause was associated with colorectal cancer risk. Our findings provide further scientific rationale for recommendations to maintain a healthy body weight during adulthood. A potential differential association according to sex and timing of weight change warrants further investigation. <i>Cancer Prev Res; 8(7); 620–7. ©2015 AACR</i>.</p></div>
This chapter discusses charge density wave formation in nanocrystals. Physics in nanometer scale structures has attracted much interest during the last few decades because of enhanced quantum effects in these small systems. The study of nanostructures is, in part, motivated by the trend toward smaller devices in the semiconductor industry. As the elements in devices achieve nanometer dimensions, it is necessary to investigate the role of quantum confinement of electrons to understand new phenomena that manifest themselves in these nanoscale structures. The artificial nanometer structures used in this study range from semiconductor or metallic nanostructures fabricated by modern lithographic technologies to chemically synthesized nanocrystals. Various mesoscopic phenomena such as single electron tunneling, energy level quantization, phase coherence, and quantum transport have been intensively studied in these confined nanostructures. In addition to the investigation of enhanced quantum effects in confined structures, these systems enable one to understand the change of physical properties evolved from isolated atoms or small molecules to an infinite bulk phase. For example, well-defined discrete quantum levels of an atom/molecule are related to the electronic band structure of the bulk.
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We consider the nucleation of instability on a slip‐weakening fault subjected to a heterogeneous, locally peaked “loading” stress. That stress is assumed not only to gradually increase due to tectonic loading but also to retain its peaked character. The case of a linear stress versus slip law is considered in the framework of two‐dimensional quasi‐static elasticity for a planar fault. Slip initiates when the peak of the loading stress first reaches the strength level of the fault to start slip weakening. Then the size of the slipping region grows under increased loading stress until finally a critical nucleation length is reached, at which no further quasi‐static solution exists for additional increase of the loading. That marks the onset of a dynamically controlled instability. We prove that the nucleation length is independent of the shape of the loading stress distribution. Its universal value is proportional to an elastic modulus and inversely proportional to the slip‐weakening rate, and it is given by the solution to an eigenvalue problem. That is the same eigenvalue problem introduced by Campillo, Ionescu, and collaborators for dynamic slip nucleation under spatially uniform prestress on a fault segment of fixed length; the critical length that we derive is the same as in their case. To illustrate the nucleation process, and its universal feature, in specific examples, we consider cases for which the loading stress is peaked symmetrically or nonsymmetrically, and we employ a numerical approach based on a Chebyshev polynomial representation. Laboratory‐derived and earthquake‐inferred data are used to evaluate the nucleation size.
