Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the alpha II-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative alpha II-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes

EM Calorimeters for SoLID at Jefferson Lab

Several approved experiments at Jefferson Lab for the 12 GeV era will use the proposed Solenoid Large Intensity Device (SoLID) spectrometer. Two EM calorimeters with a total area of 15 square meters are required for electron identification and electron-pion separation. The challenge is to build calorimeters that can withstand high radiation doses in high magnetic field region and bring photon signals to low field region for readout. Several types of calorimeters were considered and we are favoring Shashlyk type as a result of balancing performance and cost. Our preliminary design and simulation of SoLID EM calorimeters are presented

Cerenkov-like radiation in a binary Schr{\"o}dinger flow past an obstacle

We consider the dynamics of two coupled miscible Bose-Einstein condensates, when an obstacle is dragged through them. The existence of two different speeds of sound provides the possibility for three dynamical regimes: when both components are subcritical, we do not observe nucleation of coherent structures; when both components are supercritical they both form dark solitons in one dimension (1D) and vortices or rotating vortex dipoles in two dimensions (2D); in the intermediate regime, we observe the nucleation of a structure in the form of a dark-antidark soliton in 1D; subcritical component; the 2D analog of such a structure, a vortex-lump, is also observed.Comment: 4 pages, 4 figures, submitted to Phys Rev

Beam-Target Double-Spin Asymmetry A(LT) in Charged Pion Production from Deep Inelastic Scattering on a Transversely Polarized He-3 Target at 1.4 \u3c Q(2) \u3c 2.7 GeV2

We report the first measurement of the double-spin asymmetry A(LT) for charged pion electroproduction in semi-inclusive deep-inelastic electron scattering on a transversely polarized He-3 target. The kinematics focused on the valence quark region, 0.16 \u3c x \u3c 0.35 with 1.4 \u3c Q(2) \u3c 2.7 GeV2. The corresponding neutron A(LT) asymmetries were extracted from the measured He-3 asymmetries and proton over He-3 cross section ratios using the effective polarization approximation. These new data probe the transverse momentum dependent parton distribution function g(1T)(q) and therefore provide access to quark spin-orbit correlations. Our results indicate a positive azimuthal asymmetry for pi(-) production on He-3 and the neutron, while our pi(+) asymmetries are consistent with zero

Climatic and palaeoceanographic changes during the Pliensbachian (Early Jurassic) 2 inferred from clay mineralogy and stable isotope (C-O) geochemistry (NW Europe)

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Available online 17 January 2017The Early Jurassic was broadly a greenhouse climate period that was punctuated by short warm and cold climatic events, positive and negative excursions of carbon isotopes, and episodes of enhanced organic matter burial. Clay minerals from Pliensbachian sediments recovered from two boreholes in the Paris Basin, are used here as proxies of detrital supplies, runoff conditions, and palaeoceanographic changes. The combined use of these minerals with ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT stable isotope data (C-O) from bulk carbonates and organic matter allows palaeoclimatic reconstructions to be refined for the Pliensbachian. Kaolinite/illite ratio is discussed as a reliable proxy of the hydrological cycle and runoff from landmasses. Three periods of enhanced runoff are recognised within the Pliensbachian. The first one at the SinemurianPliensbachian transition shows a significant increase of kaolinite concomitant with the negative carbon isotope excursion at the so-called Sinemurian Pliensbachian Boundary Event (SPBE). The Early/Late Pliensbachian transition was also characterised by more humid conditions. This warm interval is associated with a major change in oceanic circulation during the Davoei Zone, likely triggered by sea-level rise; the newly created palaeogeography, notably the flooding of the London-Brabant Massif, allowed boreal detrital supplies, including kaolinite and chlorite, to be exported to the Paris Basin. The last event of enhanced runoff occurred during the late Pliensbachian (Subdonosus Subzone of the Margaritatus Zone), which occurred also during a warm period, favouring organic matter production and preservation. Our study highlights the major role of the London Brabant Massif in influencing oceanic circulation of the NW European area, as a topographic barrier (emerged lands) during periods of lowstand sea-level and its flooding during period of high sea-level. This massif was the unique source of smectite in the Paris Basin. Two episodes of smectite-rich sedimentation (‘smectite events’), coincide with regressive intervals, indicating emersion of the London Brabant Massif and thus suggesting that an amplitude of sea-level change high enough to be linked to glacio-eustasy. This mechanism is consistent with sedimentological and geochemical evidences of continental ice growth notably during the Latest Pliensbachian (Spinatum Zone), and possibly during the Early Pliensbachian (late Jamesoni/early Ibex Zones).The study was supported by the “Agence Nationale pour la Gestion des Déchets Radioactifs” (Andra––French National Radioactive Waste Management Agency)

Measurement of the Neutron Radius of Pb-208 through Parity Violation in Electron Scattering

We report the first measurement of the parity-violating asymmetry A(PV) in the elastic scattering of polarized electrons from Pb-208. APV is sensitive to the radius of the neutron distribution (R-n). The result A(PV) = 0.656 +/- 0.060(stat) +/- 0.014(syst) ppm corresponds to a difference between the radii of the neutron and proton distributions R-n - R-p = 0.33(-0.18)(+0.16) fm and provides the first electroweak observation of the neutron skin which is expected in a heavy, neutron-rich nucleus

Modulated Amplitude Waves in Bose-Einstein Condensates

We analyze spatio-temporal structures in the Gross-Pitaevskii equation to study the dynamics of quasi-one-dimensional Bose-Einstein condensates (BECs) with mean-field interactions. A coherent structure ansatz yields a parametrically forced nonlinear oscillator, to which we apply Lindstedt's method and multiple-scale perturbation theory to determine the dependence of the intensity of periodic orbits (``modulated amplitude waves'') on their wave number. We explore BEC band structure in detail using Hamiltonian perturbation theory and supporting numerical simulations.Comment: 5 pages, 4 figs, revtex, final form of paper, to appear in PRE (forgot to include \bibliography command in last update, so this is a correction of that; the bibliography is hence present again

Analysis of new control applications

This document reports the results of the activities performed during the first year of the CRUTIAL project, within the Work Package 1 "Identification and description of Control System Scenarios". It represents the outcome of the analysis of new control applications in the Power System and the identification of critical control system scenarios to be explored by the CRUTIAL project

The Unified Method: I Non-Linearizable Problems on the Half-Line

Boundary value problems for integrable nonlinear evolution PDEs formulated on the half-line can be analyzed by the unified method introduced by one of the authors and used extensively in the literature. The implementation of this general method to this particular class of problems yields the solution in terms of the unique solution of a matrix Riemann-Hilbert problem formulated in the complex $k$-plane (the Fourier plane), which has a jump matrix with explicit $(x,t)$-dependence involving four scalar functions of $k$, called spectral functions. Two of these functions depend on the initial data, whereas the other two depend on all boundary values. The most difficult step of the new method is the characterization of the latter two spectral functions in terms of the given initial and boundary data, i.e. the elimination of the unknown boundary values. For certain boundary conditions, called linearizable, this can be achieved simply using algebraic manipulations. Here, we present an effective characterization of the spectral functions in terms of the given initial and boundary data for the general case of non-linearizable boundary conditions. This characterization is based on the analysis of the so-called global relation, on the analysis of the equations obtained from the global relation via certain transformations leaving the dispersion relation of the associated linearized PDE invariant, and on the computation of the large $k$ asymptotics of the eigenfunctions defining the relevant spectral functions.Comment: 39 page

Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation

Background: Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date. Methods: We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2 +/\ue2 ' HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2 \ue2 '/\ue2 ' murine fibroblasts. Results: We found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells. Conclusion: Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2 +/- cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants