Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies : an exome-based case-control study

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compared with controls (OR 1.46 [95% CI 1.02-2.08]; p(Nonsyn)=0.013, adjusted p(Nonsyn)=0.027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABA(A) receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Carbonised red mud – A new water treatment product made from a waste material

Proposals to use red mud, the waste produced by the extraction of alumina from bauxite ore in the Bayer process, as a material for treatment of heavy metal-contaminated water are limited by its inherent alkalinity and variability. Attempts to lower its pH have been largely unreliable. However, an alternative strategy is carbonisation of red mud by catalytic hydrocarbon cracking, which results in a magnetic material of greater surface area. The efficacy of this material has been compared with that of the untreated parent red mud and acidified red mud for the sorption of , Cu<sup>2+</sup> and Pb<sup>2+</sup>. Carbonised red mud does not remove from solution, but shows enhancement of Cu<sup>2+</sup> and Pb<sup>2+</sup> removal. There is an approximate ten-fold increase in removal of Cu<sup>2+</sup> and Pb<sup>2+</sup> by carbonised red mud compared with acidified red mud

Long-sought isomer turns out to be the ground state of 76^{76}Cu

International audienceIsomers close to the doubly magic nucleus $^{78}$Ni ($Z=28$, $N=50$) provide essential information on the shell evolution and shape coexistence far from stability. The existence of a long-lived isomeric state in $^{76}$Cu has been debated for a long time. We have performed high-precision mass measurements of $^{76}$Cu with the JYFLTRAP double Penning trap mass spectrometer at the Ion Guide Isotope Separator On-Line facility and confirm the existence of such a isomeric state with an excitation energy $E_x=64.8(25)$ keV. Based on the ratio of detected ground- and isomeric-state ions as a function of time, we show that the isomer is the shorter-living state previously considered as the ground state of $^{76}$Cu. The result can potentially change the conclusions made in previous works related to the spin-parity and charge radius of the $^{76}$Cu ground state. Additionally, the new $^{76}$Cu$(n,\gamma)$ reaction $Q$-value has an impact on the astrophysical rapid neutron-capture process