The African Genome Variation Project shapes medical genetics in Africa.

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa

Portrait of a reference material: zircon production in the Middledale Gabbroic Diorite, Australia, and its implications for the TEMORA standard

The Middledale Gabbroic Diorite (MGD) in New South Wales, Australia, is host to the internationally distributed TEMORA 2 zircon reference material and its prototype, TEMORA 1. The original characterisation of the source of the reference zircons revealed that the more altered TEMORA 2 host rock contains an order of magnitude more zircon than the TEMORA 1 host, despite similar bulk-rock Zr concentrations. Although TEMORA 1 and 2 preserve the same U-Pb age, they are variable in oxygen isotope composition.In this study, petrographic observations in concert with bulk-rock and mineral geochemistry and zircon U-Pb geochronology have been applied to new samples of the MGD to investigate the link between alteration and zircon abundance. Trace element maps reveal that the products of late-stage, deuteric alteration (particularly actinolite after hornblende) are depleted in Zr, and many other trace elements, relative to the unaltered mafic, magmatic phases. It is posited that the conversion of hornblende to secondary amphiboles in the latter stages of magma solidification liberated Zr, permitting the crystallisation of additional zircon.New high resolution SIMS U-Pb determinations on four samples confirm the age homogeneity of the zircon across the pluton and reaffirm the value of TEMORA 2 as a valuable geochronological reference material. Zircon oxygen isotope data have been acquired for these same samples and the mean δ18O values encompass the accepted values for TEMORA 1 and 2. Likewise, the Hf-isotope determinations are similar to the accepted TEMORA 2 composition. Together with petrographic observations, these data reveal the TEMORA 2 zircon and its host to be broadly reflective of the relatively coarse-grained portions of the MGD, and that the isotopically less evolved compositions (i.e. the lower δ18O of TEMORA 1 and low δ18O, high 176Hf/177Hf of one sample from this study) are associated with a relatively fine-grained, marginal lithology. Given δ18O values greater than typical mantle-derived zircon and the broad correlation between O- and Hf-isotopic compositions, the data imply the pluton evolved by crustal contamination of a primitive magma

A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis

Background: This randomized phase 3 study evaluated the efficacy and safety of cinacalcet in children with secondary hyperparathyroidism (SHPT) receiving dialysis. Methods: This study had double-blind and open-label phases. Eligible patients aged 6-<18years were randomized to cinacalcet (starting dose 0.20mg/kg) or placebo. The primary endpoint was 30% reduction from baseline in mean intact parathyroid hormone (iPTH). Secondary endpoints included mean iPTH 300pg/mL; percentage change from baseline in corrected total serum calcium, phosphorus, and calcium phosphorus product (CaxP); and safety. Results: The double-blind phase comprised 43 patients (cinacalcet, n=22; placebo, n=21). Nineteen months into the study, regulatory authorities were notified of a fatality; the study was subsequently terminated after a 14-month clinical hold. Before the hold, 12 patients (55%) on cinacalcet and four (19%) on placebo achieved the primary endpoint (p=0.017), and 27% and 24%, respectively, achieved iPTH 300pg/mL. The between-group differences (95% CI) in percentage changes for total serum calcium, phosphorus, and CaxP were -4% (-9 to 1%), -6% (-21 to 8%), and -10% (-23 to 3%). The mean maximum actual weight-adjusted daily cinacalcet dosage administered was 0.99mg/kg/day. Overall, 82% of patients on cinacalcet and 86% on placebo had 1 treatment-emergent adverse event; the most common were vomiting (32%, 24%, respectively), hypocalcemia (23%, 19%), nausea (18%, 14%), and hypertension (14%, 24%). Conclusions: Despite early termination, efficacy and safety outcomes observed with cinacalcet in children with SHPT on dialysis were consistent with adult observations, suggesting cinacalcet may meet an unmet medical need for this population

The African Genome Variation Project shapes medical genetics in Africa.

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa

Deep Underground Neutrino Experiment (DUNE) Near Detector Conceptual Design Report

International audienceThe Deep Underground Neutrino Experiment (DUNE) is an international, world-class experiment aimed at exploring fundamental questions about the universe that are at the forefront of astrophysics and particle physics research. DUNE will study questions pertaining to the preponderance of matter over antimatter in the early universe, the dynamics of supernovae, the subtleties of neutrino interaction physics, and a number of beyond the Standard Model topics accessible in a powerful neutrino beam. A critical component of the DUNE physics program involves the study of changes in a powerful beam of neutrinos, i.e., neutrino oscillations, as the neutrinos propagate a long distance. The experiment consists of a near detector, sited close to the source of the beam, and a far detector, sited along the beam at a large distance. This document, the DUNE Near Detector Conceptual Design Report (CDR), describes the design of the DUNE near detector and the science program that drives the design and technology choices. The goals and requirements underlying the design, along with projected performance are given. It serves as a starting point for a more detailed design that will be described in future documents