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8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage
Ten years on from the finishing of the human reference genome sequence, it remains unclear what fraction of the human genome confers function, where this sequence resides, and how much is shared with other mammalian species. When addressing these questions, functional sequence has often been equated with pan-mammalian conserved sequence. However, functional elements that are short-lived, including those contributing to species-specific biology, will not leave a footprint of long-lasting negative selection. Here, we address these issues by identifying and characterising sequence that has been constrained with respect to insertions and deletions for pairs of eutherian genomes over a range of divergences. Within noncoding sequence, we find increasing amounts of mutually constrained sequence as species pairs become more closely related, indicating that noncoding constrained sequence turns over rapidly. We estimate that half of present-day noncoding constrained sequence has been gained or lost in approximately the last 130 million years (half-life in units of divergence time, d1/2 = 0.25-0.31). While enriched with ENCODE biochemical annotations, much of the short-lived constrained sequences we identify are not detected by models optimized for wider pan-mammalian conservation. Constrained DNase 1 hypersensitivity sites, promoters and untranslated regions have been more evolutionarily stable than long noncoding RNA loci which have turned over especially rapidly. By contrast, protein coding sequence has been highly stable, with an estimated half-life of over a billion years (d1/2 = 2.1-5.0). From extrapolations we estimate that 8.2% (7.1-9.2%) of the human genome is presently subject to negative selection and thus is likely to be functional, while only 2.2% has maintained constraint in both human and mouse since these species diverged. These results reveal that the evolutionary history of the human genome has been highly dynamic, particularly for its noncoding yet biologically functional fraction.
Journal Article
Of bone and thunder : a novel
\"In this strange, new world deep among the shadows under a triple-canopy jungle and plagued by dangers real and imagined, soldiers strive to fulfill a mission they don't understand and are ill-equipped to carry out. And high above them, the heavy rush of wings slashing through the humid air herald a coming wave of death and destruction, and just possibly, salvation\"-- Provided by publisher.
Book
A more accurate method for colocalisation analysis allowing for multiple causal variants
In genome-wide association studies (GWAS) it is now common to search for, and find, multiple causal variants located in close proximity. It has also become standard to ask whether different traits share the same causal variants, but one of the popular methods to answer this question, coloc, makes the simplifying assumption that only a single causal variant exists for any given trait in any genomic region. Here, we examine the potential of the recently proposed Sum of Single Effects (SuSiE) regression framework, which can be used for fine-mapping genetic signals, for use with coloc. SuSiE is a novel approach that allows evidence for association at multiple causal variants to be evaluated simultaneously, whilst separating the statistical support for each variant conditional on the causal signal being considered. We show this results in more accurate coloc inference than other proposals to adapt coloc for multiple causal variants based on conditioning. We therefore recommend that coloc be used in combination with SuSiE to optimise accuracy of colocalisation analyses when multiple causal variants exist.
Journal Article
Doing what works : 10 common-sense leadership practices to improve student learning
\"In (Un)Common Sense: Making Common Sense More Common in Education, author Chris Weber addresses how to effectively meet the learning needs of students to prepare them for their futures in a rapidly changing world. Educators have their pick of new, innovative ideas and practices to use in their classrooms. However, while effective, these strategies and programs can overcomplicate and hinder the learning process. This book aims to strengthen and reflect upon current practices that are proven to support student achievement. By reading (Un)Common Sense, K-12 educators will examine specific common-sense practices that, when thoughtfully planned and implemented, guarantee to transform student learning and propel school success\"-- Provided by publisher.
Book
Vascular endothelial growth factor-A promoter polymorphisms, circulating VEGF-A and survival in acute coronary syndromes
Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort.
The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype.
This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.
Journal Article
Architecture after Deleuze and Guattari
This study illuminates the complex interplay between Deleuze and Guattari's philosophy and architecture. Presenting their wide-ranging impact on late 20th- and 21st-century architecture, each chapter focuses on a core Deleuzian/Guattarian philosophical concept and one key work of architecture which evokes, contorts, or extends it. Challenging the idea that a concept or theory defines and then produces the physical work and not vice versa, Chris L. Smith positions the relationship between Deleuze and Guattari's philosophy and the field of architecture as one that is mutually substantiating and constitutive. In this framework, modes of architectural production and experimentation become inextricable from the conceptual territories defined by these two key thinkers, producing a rigorous discussion of theoretical, practical, and experimental engagements with their ideas.
BOOK
Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses
Horizontal integration of summary statistics from different GWAS traits can be used to evaluate evidence for their shared genetic causality. One popular method to do this is a Bayesian method, coloc, which is attractive in requiring only GWAS summary statistics and no linkage disequilibrium estimates and is now being used routinely to perform thousands of comparisons between traits. Here we show that while most users do not adjust default software values, misspecification of prior parameters can substantially alter posterior inference. We suggest data driven methods to derive sensible prior values, and demonstrate how sensitivity analysis can be used to assess robustness of posterior inference. The flexibility of coloc comes at the expense of an unrealistic assumption of a single causal variant per trait. This assumption can be relaxed by stepwise conditioning, but this requires external software and an LD matrix aligned to study alleles. We have now implemented conditioning within coloc, and propose a new alternative method, masking, that does not require LD and approximates conditioning when causal variants are independent. Importantly, masking can be used in combination with conditioning where allelically aligned LD estimates are available for only a single trait. We have implemented these developments in a new version of coloc which we hope will enable more informed choice of priors and overcome the restriction of the single causal variant assumptions in coloc analysis.
Journal Article
The Ordinal Effects of Ostracism: A Meta-Analysis of 120 Cyberball Studies
We examined 120 Cyberball studies (N = 11,869) to determine the effect size of ostracism and conditions under which the effect may be reversed, eliminated, or small. Our analyses showed that (1) the average ostracism effect is large (d > |1.4|) and (2) generalizes across structural aspects (number of players, ostracism duration, number of tosses, type of needs scale), sampling aspects (gender, age, country), and types of dependent measure (interpersonal, intrapersonal, fundamental needs). Further, we test Williams's (2009) proposition that the immediate impact of ostracism is resistant to moderation, but that moderation is more likely to be observed in delayed measures. Our findings suggest that (3) both first and last measures are susceptible to moderation and (4) time passed since being ostracized does not predict effect sizes of the last measure. Thus, support for this proposition is tenuous and we suggest modifications to the temporal need-threat model of ostracism.
Journal Article