Detection of structural mosaicism from targeted and whole-genome sequencing data.

Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Overview of the JET results

Since the installation of an ITER-like wall, the JET programme has focused on the consolidation of ITER design choices and the preparation for ITER operation, with a specific emphasis given to the bulk tungsten melt experiment, which has been crucial for the final decision on the material choice for the day-one tungsten divertor in ITER. Integrated scenarios have been progressed with the re-establishment of long-pulse, high-confinement H-modes by optimizing the magnetic configuration and the use of ICRH to avoid tungsten impurity accumulation. Stationary discharges with detached divertor conditions and small edge localized modes have been demonstrated by nitrogen seeding. The differences in confinement and pedestal behaviour before and after the ITER-like wall installation have been better characterized towards the development of high fusion yield scenarios in DT. Post-mortem analyses of the plasma-facing components have confirmed the previously reported low fuel retention obtained by gas balance and shown that the pattern of deposition within the divertor has changed significantly with respect to the JET carbon wall campaigns due to the absence of thermally activated chemical erosion of beryllium in contrast to carbon. Transport to remote areas is almost absent and two orders of magnitude less material is found in the divertor

Micro ion beam analysis for the erosion of beryllium marker tiles in a tokamak limiter

Beryllium limiter marker tiles were exposed to plasma in the Joint European Torus to diagnose the erosion of main chamber wall materials. A limiter marker tile consists of a beryllium coating layer (7-9 mu m) on the top of bulk beryllium, with a nickel interlayer (2-3 mu m) between them. The thickness variation of the beryllium coating layer, after exposure to plasma, could indicate the erosion measured by ion beam analysis with backscattering spectrometry. However, interpretations from broad beam backscattering spectra were limited by the non-uniform surface structures. Therefore, micro-ion beam analysis (mu-IBA) with 3 MeV proton beam for Elastic back scattering spectrometry (EBS) and PIXE was used to scan samples. The spot size was in the range of 3-10 mu m. Scanned areas were analysed with scanning electron microscopy (SEM) as well. Combining results from mu-IBA and SEM, we obtained local spectra from carefully chosen areas on which the surface structures were relatively uniform. Local spectra suggested that the scanned area (approximate to 600 mu m x 1200 mu m) contained regions with serious erosion with only 2-3 mu m coating beryllium left, regions with intact marker tile, and droplets with 90% beryllium. The nonuniform erosion, droplets mainly formed by beryllium, and the possible mixture of beryllium and nickel were the major reasons that confused interpretation from broad beam EBS

Hybrid cancellation of ripple disturbances arising in AC/DC converters

In AC/DC converters, a peculiar periodic nonsmooth waveform arises, the so-called ripple. In this paper we propose a novel model that captures this nonsmoothness by means of a hybrid dynamical system performing state jumps at certain switching instants, and we illustrate its properties with reference to a three phase diode bridge rectifier. As the ripple corrupts an underlying desirable signal, we propound two observer schemes ensuring asymptotic estimation of the ripple, the first with and the second without knowledge of the switching instants. Our theoretical developments are well placed in the context of recent techniques for hybrid regulation and constitute a contribution especially for our second observer, where the switching instants are estimated. Once asymptotic estimation of the ripple is achieved, the ripple can be conveniently canceled from the desirable signal, and thanks to the inherent robustness properties of the proposed hybrid formulation, the two observer schemes require only that the desirable signal is slowly time varying compared to the ripple. Exploiting this fact, we illustrate the effectiveness of our second hybrid observation law on experimental data collected from the Joint European Torus tokamak

Overview of the JET results

Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. \ua9 2011 IAEA, Vienna

EDGE2D-EIRENE simulations of the influence of isotope effects and anomalous transport coefficients on near scrape-off layer radial electric field

EDGE2D-EIRENE (the 'code') simulations show that radial electric field, Er, in the near scrape-off layer (SOL) of tokamaks can have large variations leading to a strong local E x B shear greatly exceeding that in the core region. This was pointed out in simulations of JET plasmas with varying divertor geometry, where the magnetic configuration with larger predicted near SOL E-r was found to have lower H-mode power threshold, suggesting that turbulence suppression in the SOL by local E. x. B shear can be a player in the L-H transition physics (Delabie et al 2015 42nd EPS Conf. on Plasma Physics (Lisbon, Portugal, 22-26 June 2015) paper O3.113 (http://ocs.ciemat.es/EPS2015PAP/pdf/O3.113.pdf), Chankin et al 2017 Nucl. Mater. Energy 12 273). Further code modeling of JET plasmas by changing hydrogen isotopes (H-D-T) showed that the magnitude of the near SOL E-r is lower in H cases in which the H-mode threshold power is higher (Chankin et al 2017 Plasma Phys. Control. Fusion 59 045012). From the experiment it is also known that hydrogen plasmas have poorer particle and energy confinement than deuterium plasmas, consistent with the code simulation results showing larger particle diffusion coefficients at the plasma edge, including SOL, in hydrogen plasmas (Maggi et al 2018 Plasma Phys. Control. Fusion 60 014045). All these experimental observations and code results support the hypothesis that the near SOL E x B shear can have an impact on the plasma confinement. The present work analyzes neutral ionization patterns of JET plasmas with different hydrogen isotopes in L-mode cases with fixed input power and gas puffing rate, and its impact on target electron temperature, T-e, and SOL E-r. The possibility of a self-feeding mechanism for the increase in the SOL E-r via the interplay between poloidal E x B drift and target T-e is discussed. It is also shown that reducing anomalous turbulent transport coefficients, particle diffusion and electron and ion heat conductivities, leads to higher peak target T-e and larger E-r, suggesting the possibility of a positive feedback loop, under an implicitly made assumption that the E x B shear in the SOL is capable of suppressing turbulence