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

14 MeV calibration of JET neutron detectors-phase 1: Calibration and characterization of the neutron source

In view of the planned DT operations at JET, a calibration of the JET neutron monitors at 14 MeV neutron energy is needed using a 14 MeV neutron generator deployed inside the vacuum vessel by the JET remote handling system. The target accuracy of this calibration is 10% as also required by ITER, where a precise neutron yield measurement is important, e.g. for tritium accountancy. To achieve this accuracy, the 14 MeV neutron generator selected as the calibration source has been fully characterised and calibrated prior to the in-vessel calibration of the JET monitors. This paper describes the measurements performed using different types of neutron detectors, spectrometers, calibrated long counters and activation foils which allowed us to obtain the neutron emission rate and the anisotropy of the neutron generator, i.e.The neutron flux and energy spectrum dependence on emission angle, and to derive the absolute emission rate in 4π sr. The use of high resolution diamond spectrometers made it possible to resolve the complex features of the neutron energy spectra resulting from the mixed D/T beam ions reacting with the D/T nuclei present in the neutron generator target. As the neutron generator is not a stable neutron source, several monitoring detectors were attached to it by means of an ad hoc mechanical structure to continuously monitor the neutron emission rate during the in-vessel calibration. These monitoring detectors, two diamond diodes and activation foils, have been calibrated in terms of neutrons/counts within ± 5% total uncertainty. A neutron source routine has been developed, able to produce the neutron spectra resulting from all possible reactions occurring with the D/T ions in the beam impinging on the Ti D/T target. The neutron energy spectra calculated by combining the source routine with a MCNP model of the neutron generator have been validated by the measurements. These numerical tools will be key in analysing the results from the in-vessel calibration and to derive the response of the JET neutron detectors to DT plasma neutrons starting from the response to the generator neutrons, and taking into account all the calibration circumstances

Investigation of deuterium trapping and release in the JET divertor during the third ILW campaign using TDS

Selected set of samples from JET ITER-Like Wall (JET-ILW) divertor tiles exposed in 2015-2016 has been analysed using Thermal Desorption Spectrometry (TDS). The deuterium (D) amounts obtained with TDS were compared with Nuclear Reaction Analysis (NRA). The highest amount of D was found on the top part of inner divertor which has regions with the thickest deposited layers as for divertor tiles removed in 2014. This area resides deep in the scrape-off layer and plasma configurations for the second (ILW-2, 2013-2014) and the third (ILW-3, 2015-2016) JET-ILW campaigns were similar. Agreement between TDS and NRA is good on the apron of Tile 1 and on the upper vertical region whereas on the lower vertical region of Tile 1 the NRA results are clearly smaller than the TDS results. Inner divertor Tile 3 has somewhat less D than Tiles 0 and 1, and the D amount decreases towards the lower part of the tile. The D retention at the divertor inner and outer corner regions is not symmetric as there is more D retention poloidally at the inner than at the outer divertor corner. In most cases the TDS spectra for the ILW-3 samples are different from the corresponding ILW-2 spectra because HD and D-2 release occurs at higher temperatures than from the ILW-2 samples indicating that the low energy traps have been emptied during the plasma operations and that D is either in the energetically deep traps or located deeper in the sample