Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

"Hidden" Social Networks in Behavior Change Interventions

We investigated whether “hidden” (or unobserved) social networks were evident in a 2011 physical activity behavior change intervention in Belfast, Northern Ireland. Results showed evidence of unobserved social networks in the intervention and illustrated how the network evolved over short periods and affected behavior. Behavior change interventions should account for the interaction among participants (i.e., social networks) and how such interactions affect intervention outcome.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

A Tree Augmented Classifier Based on Extreme Imprecise Dirichlet Model

In this paper we present TANC, i.e., a tree-augmented naive credal classifier based on imprecise probabilities; it models prior near-ignorance via the Extreme Imprecise Dirichlet Model (EDM) (Cano et al., 2007) and deals conservatively with missing data in the training set, without assuming them to be missing-at-random. The EDM is an approximation of the global Imprecise Dirichlet Model (IDM), which considerably simplifies the computation of upper and lower probabilities; yet, having been only recently introduced, the quality of the provided approximation needs still to be verified. As first contribution, we extensively compare the output of the naive credal classifier (one of the few cases in which the global IDM can be exactly implemented) when learned with the EDM and the global IDM; the output of the classifier appears to be identical in the vast majority of cases, thus supporting the adoption of the EDM in real classification problems. Then, by experiments we show that TANC is more reliable than the precise TAN (learned with uniform prior), and also that it provides better performance compared to a previous (Zaffalon, 2003) TAN model based on imprecise probabilities. TANC treats missing data by considering all possible completions of the training set, but avoiding an exponential increase of the computational times; eventually, we present some preliminary results with missing data.

"'Nothing but a printer's devil ever drives me into finishing': the Genesis of Thomas Moore's Irish Melodies'

This chapter outlines the working methods of the prolific writer and lyricist Thomas Moore—which were characterized by the unfortunate combination of a perfectionist streak, a tendency to release material to the publishers while still in the creative mode, and a tendency to re-visit previously-published material. The Gibson-Massie Moore collection at Queen's University Belfast teaches us a great deal about Moore’s creative processes, and also records the nineteenth-century publishing industry’s response to one of its most prolific and popular creative artists. This chapter is illustrated by an online Exhibition, the 'Thomas Moore Project', Digital Collections, Special Collections, McClay library (see URL below).

Thomas Moore Music Project:The Genesis of Thomas Moore's Irish Melodies

This is a selection of images from the Gibson-Massie Moore Collection, supplement by a table created by curator Sarah McCleave. The purpose is to identify the numerous creators involved in the Irish Melodies series (music editor, illustrators, engravers, etc.), and to illustrate some characteristics kinds of variants

Clinical and Cost-Effectiveness of Procalcitonin Test for Prodromal Meningococcal Disease-A Meta-Analysis

BACKGROUND: Despite vaccines and improved medical intensive care, clinicians must continue to be vigilant of possible Meningococcal Disease in children. The objective was to establish if the procalcitonin test was a cost-effective adjunct for prodromal Meningococcal Disease in children presenting at emergency department with fever without source.

METHODS AND FINDINGS: Data to evaluate procalcitonin, C-reactive protein and white cell count tests as indicators of Meningococcal Disease were collected from six independent studies identified through a systematic literature search, applying PRISMA guidelines. The data included 881 children with fever without source in developed countries.The optimal cut-off value for the procalcitonin, C-reactive protein and white cell count tests, each as an indicator of Meningococcal Disease, was determined. Summary Receiver Operator Curve analysis determined the overall diagnostic performance of each test with 95% confidence intervals. A decision analytic model was designed to reflect realistic clinical pathways for a child presenting with fever without source by comparing two diagnostic strategies: standard testing using combined C-reactive protein and white cell count tests compared to standard testing plus procalcitonin test. The costs of each of the four diagnosis groups (true positive, false negative, true negative and false positive) were assessed from a National Health Service payer perspective. The procalcitonin test was more accurate (sensitivity=0.89, 95%CI=0.76-0.96; specificity=0.74, 95%CI=0.4-0.92) for early Meningococcal Disease compared to standard testing alone (sensitivity=0.47, 95%CI=0.32-0.62; specificity=0.8, 95% CI=0.64-0.9). Decision analytic model outcomes indicated that the incremental cost effectiveness ratio for the base case was £-8,137.25 (US $ -13,371.94) per correctly treated patient.

CONCLUSIONS: Procalcitonin plus standard recommended tests, improved the discriminatory ability for fatal Meningococcal Disease and was more cost-effective; it was also a superior biomarker in infants. Further research is recommended for point-of-care procalcitonin testing and Markov modelling to incorporate cost per QALY with a life-time model.

Accumulation of the PX domain mutant Frank-ter Haar syndrome protein Tks4 in aggresomes

BACKGROUND: Cells deploy quality control mechanisms to remove damaged or misfolded proteins. Recently, we have reported that a mutation (R43W) in the Frank-ter Haar syndrome protein Tks4 resulted in aberrant intracellular localization.

RESULTS: Here we demonstrate that the accumulation of Tks4(R43W) depends on the intact microtubule network. Detergent-insoluble Tks4 mutant colocalizes with the centrosome and its aggregate is encaged by the intermediate filament protein vimentin. Both the microtubule inhibitor nocodazole and the histone deacetylase inhibitor Trichostatin A inhibit markedly the aggresome formation in cells expressing Tks4(R43W). Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4(R43W). Furthermore, two additional mutant Tks4 proteins (Tks4(1-48) or Tks4(1-341)) have been investigated. Whereas the shorter Tks4 mutant, Tks4(1-48), shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells.

CONCLUSIONS: Our results suggest that misfolded Frank-ter Haar syndrome protein Tks4(R43W) is transported via the microtubule system to the aggresomes. Lack of expression of Tks4(1-48) or aberrant intracellular expressions of Tks4(R43W) and Tks4(1-341) strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.

‘Twenty-six things at once’: Pragmatic perspectives on Frank O’Hara and Norman Bluhm’s Poem-Paintings

Created over a couple of Sunday mornings in the Fall of 1960, the twenty-six collaborative Poem-Paintings of the artist Norman Bluhm and the poet Frank O'Hara represent what Bluhm later called a spontaneous 'conversation' between the painter and the poet. In this essay, Catherine Gander adopts a number of pragmatist positions to reconsider these overlooked works as essential examples of verbal-visual interaction that extend their 'conversation' to greet and involve us in a relationship that is at once interpersonal, integrated, and embodied. The works, Gander argues, constitute what John Dewey terms 'art as experience'; in their back and forth exchange of verbal and visual gesture, abstraction and denotation, the Poem-Paintings are the 'cumulative continuity' of 'the process of living', dramatising the shifting, spontaneous and multiple dimensions of interpersonal conversation, and in so doing, indicating a new path toward interconnective and equal exchange between word and image.

Old World megadroughts and pluvials during the Common Era

Climate model projections suggestwidespread drying in the Mediterranean Basin and wetting in Fennoscandia in the coming decades largely as a consequence of greenhouse gas forcing of climate. To place these and other “Old World” climate projections into historical perspective based on more complete estimates of natural hydroclimatic variability, we have developed the “Old World Drought Atlas” (OWDA), a set of year-to-year maps of tree-ring reconstructed summer wetness and dryness over Europe and the Mediterranean Basin during the Common Era.
The OWDA matches historical accounts of severe drought and wetness with a spatial completeness not previously available. In addition, megadroughts reconstructed over north-central Europe in the 11th and mid-15th centuries
reinforce other evidence from North America and Asia that droughts were more severe, extensive, and prolonged over Northern Hemisphere land areas before the 20th century, with an inadequate understanding of their causes. The OWDA provides new data to determine the causes of Old World drought and wetness and attribute past climate variability to forced and/or internal variability.

Max Weber and the First World War: Protestant and Catholic living standards in Germany, 1915-1919

We assess informal institutions of Protestants and Catholics by investigating their economic
resilience in a natural experiment. The First World War constitutes an exogenous shock to living standards since the duration and intensity of the war exceeded all expectations. We assess the ability of Protestant and Catholic communities to cope with increasing food prices and wartime black markets. Literature based on Weber (1904, 1905) suggests that Protestants must be more resilient than their Catholic peers. Using individual height data on some 2,800 Germans to assess levels of malnutrition during the war, we find that living standards for both Protestants and Catholics declined; however, the decrease of Catholics’ height was disproportionately large. Our empirical analysis finds a large statistically significant difference between Protestants and Catholics for the 1914-19 birth cohort, and we argue that this height gap cannot be attributed to socioeconomic background and fertility alone.

Complementarity’s monopoly on justice in Uganda: the International Criminal Court, victims and Thomas Kwoyelo

Complementarity has been extolled as the pioneering way for the International Criminal Court (ICC) to navigate the difficulties of state sovereignty when investigating and prosecuting international crimes. Victims have often been held up to justify and legitimise the work of the ICC and states complementing the Court through domestic processes. This article examines how Uganda has developed its laws, legal procedure, and accountability for international crimes over the past decade. This has culminated in the trial of Thomas Kwoyelo, which after five years of proceedings, has yet to move to the trial phase, due to the issue of an amnesty. While there has been a profusion of provisions to allow victims to participate, avail of protection measures and reparations, in practice very little has changed for them. This article highlights the dangers of complementarity being the sole solution to protracted conflicts, in particular the realisation of victims’ rights.