Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

Deep Underground Neutrino Experiment (DUNE), far detector technical design report, volume III: DUNE far detector technical coordination

The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. Volume III of this TDR describes how the activities required to design, construct, fabricate, install, and commission the DUNE far detector modules are organized and managed. This volume details the organizational structures that will carry out and/or oversee the planned far detector activities safely, successfully, on time, and on budget. It presents overviews of the facilities, supporting infrastructure, and detectors for context, and it outlines the project-related functions and methodologies used by the DUNE technical coordination organization, focusing on the areas of integration engineering, technical reviews, quality assurance and control, and safety oversight. Because of its more advanced stage of development, functional examples presented in this volume focus primarily on the single-phase (SP) detector module

Efeito da incorporação de casca de café nas propriedades físico-mecânicas de painéis aglomerados de Eucalyptus urophylla S.T. Blake Effect of the incorporation of coffee husks on the physico-mechanical properties of Eucalyptus urophylla S.T. Blake particleboards

Neste trabalho objetivou-se avaliar a influência da incorporação de casca de café nas propriedades físico-mecânicas de painéis aglomerados produzidos com Eucalyptus urophylla S.T. Blake. Os painéis foram produzidos com incorporação de 25, 50 e 75% de casca de café, em três teores da resina fenol-formaldeído (6, 9 e 12%) e 1% de parafina. A densidade nominal dos painéis foi de 0,7 g/cm³ e o ciclo de prensagem compreendeu uma pressão de 3,92 MPa e temperatura de 180ºC por 8 minutos. Pelos resultados obtidos foi possível observar que: as propriedades físicas dos painéis aglomerados apresentam relação linear decrescente com o aumento do teor de resina, e crescente com a porcentagem de casca de café, apresentando maiores valores de absorção de água e inchamento em espessura. As propriedades mecânicas apresentam relação linear crescente com o aumento do teor de resina, e decrescente com a porcentagem de associação de casca de café. Do modo que a pesquisa foi conduzida, a incorporação da casca de café prejudica a qualidade dos painéis produzidos.<br>The objective of this study was to evaluate the influence of the incorporation of Coffee husks in the production of particleboard with Eucalyptus urophylla S.T. Blake. The panels were produced incorporating 25%, 50%, and 75% of Coffee husks at three levels of resin phenol-formaldehyde (6, 9 and 12%) and 1% of paraffin. The nominal density of the panels was 0.7 g/cm³ and the cycle of pressing consisted in a pressure of 3.92 MPa under a temperature of 180°C for 8 minutes. By the results it was possible to observe that the physical properties of the particleboard have a linear relationship decreasing with the increase in the level of resin, and increasing with the increase in the percentage of coffee husks, showing higher values of water absorption and thickness swelling. The mechanical properties show a linear relationship growing with the increase of resin level, and decreasing with a reduction the percentage of coffee husk association. The way that the search was conducted, the incorporation of the Coffee husks harms the quality of the panels produced

Efficient visual information sampling develops late in childhood

It is often unclear which course of action gives the best outcome. We can reduce this uncertainty by gathering more information; but gathering information always comes at a cost. For example, a sports player waiting too long to judge a ball’s trajectory will run out of time to intercept it. Efficient samplers must therefore optimize a trade-off: when the costs of collecting further information exceed the expected benefits, they should stop sampling and start acting. In visually guided tasks, adults can make these trade-offs efficiently, correctly balancing any reductions in visuomotor uncertainty against cost factors associated with increased sampling. To investigate how this ability develops during childhood, we tested 6-11 year-olds, adolescents, and adults on a visual localization task in which the costs and benefits of sampling were formalized in a quantitative framework. This allowed us to compare participants to each other, and to an ideal observer who maximizes expected reward. Visual sampling became substantially more efficient between 6-11 years, converging onto adult performance in adolescence. Younger children systematically under-sampled information relative to the ideal observer and varied their sampling strategy more. Further analyses suggested that young children used a suboptimal decision rule that insufficiently accounted for the chance of task failure, in line with a late developing ability to compute with probabilities and costs. We therefore propose that late development of efficient information sampling, a crucial element of real-world decision-making under risk, may form an important component of sub-optimality in child perception, action, and decision-making