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

Physics research on the TCV tokamak facility: from conventional to alternative scenarios and beyond

The research program of the TCV tokamak ranges from conventional to advanced-tokamak scenarios and alternative divertor configurations, to exploratory plasmas driven by theoretical insight, exploiting the device’s unique shaping capabilities. Disruption avoidance by real-time locked mode prevention or unlocking with electron-cyclotron resonance heating (ECRH) was thoroughly documented, using magnetic and radiation triggers. Runaway generation with high-Z noble-gas injection and runaway dissipation by subsequent Ne or Ar injection were studied for model validation. The new 1 MW neutral beam injector has expanded the parameter range, now encompassing ELMy H-modes in an ITER-like shape and nearly non-inductive H-mode discharges sustained by electron cyclotron and neutral beam current drive. In the H-mode, the pedestal pressure increases modestly with nitrogen seeding while fueling moves the density pedestal outwards, but the plasma stored energy is largely uncorrelated to either seeding or fueling. High fueling at high triangularity is key to accessing the attractive small edge-localized mode (type-II) regime. Turbulence is reduced in the core at negative triangularity, consistent with increased confinement and in accord with global gyrokinetic simulations. The geodesic acoustic mode, possibly coupled with avalanche events, has been linked with particle flow to the wall in diverted plasmas. Detachment, scrape-off layer transport, and turbulence were studied in L- and H-modes in both standard and alternative configurations (snowflake, super-X, and beyond). The detachment process is caused by power ‘starvation’ reducing the ionization source, with volume recombination playing only a minor role. Partial detachment in the H-mode is obtained with impurity seeding and has shown little dependence on flux expansion in standard single-null geometry. In the attached L-mode phase, increasing the outer connection length reduces the in–out heat-flow asymmetry. A doublet plasma, featuring an internal X-point, was achieved successfully, and a transport barrier was observed in the mantle just outside the internal separatrix. In the near future variable-configuration baffles and possibly divertor pumping will be introduced to investigate the effect of divertor closure on exhaust and performance, and 3.5 MW ECRH and 1 MW neutral beam injection heating will be added

PROTOTYPE BOILING WATER REACTOR

Design of a nuclear power plant of 50-Mw(e) capacity which can be used to demonstrate advanced performance concepts for boiling water reactors is described. included are diagrams and data on core design, mechanical design, and heat transfer and fluid flow. Also included are sections containing information on physics, fuel cycle evaluation, and recominendations. 26 references. (J.R.D.

EBWR TURBINE BLADE FAILURE. Summary Report

This is a summary report on thc failure of the EBWR turbine blade. It includes a description of the turbine shutdown sequence, the investigation into the cause of vibration, the disassembly of turbine, and observations and conclusions concerning the cause of the blade failure. The cause of failure was traced to a fault in the holding fixture used during the machining operation. There was no indication that any adverse effect on the turbine, blades resulted from the fact that the steam came from a direct-cycle boiling water nuclear reactor power source. (auth

HAZARD SUMMARY REPORT ON THE EXPERIMENTAL BOILING WATER REACTOR (EBWR)

In addition to the nine cross-shaped control rods which pass through vertical guide channels in the core, a secondary noninherent safety mechanism in the form of a pressurized concentrated boric acid solution can reduce the reactivity by at least 12.5% k in about 20 seconds. With regard to inherent safety, the EBWR has a much stronger metal temperature coefficient, but a considerably weaker steam formation shutdown mechanlsm, than the Borax reactors. Estimates were made of the amount of reactivity which can be controlled by steam formation in the EBWR. The maximum heat flux in EBWR is believed to be below the burnout point by at least a factor of 4 to 5, based on laboratory tests with electrically heated plates. The EBWR is surrounded by a gas-tight steel building having a volume of abput 400,000 ft/sup 3/ and designed to withstand an internal pressure of 15 psig. A 15,000-gal reservoir of water is suspended from the dome of the building for emergency cooling. The gas-tight building could easily withstand the internal pressure resulting from blowdown of the pressurized water in the reactor. The major design and operating features of the EBWR facility are summarized. (M.H.R.

PRELIMINARY HAZARD SUMMARY REPORT ON THE BOILING EXPERIMENTAL REACTOR (BER)

A preliminary evaluation of the hazards associated with a 20-Mw boiling reactor for the purpose of determining site requirements is presented. The Boiling Experimental Reactor design, safety features, and performance are given and the surroundings of the site at Argonne National Laboratory are described. (T.R.H.