Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle

Background: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of alpha-dystroglycan. Overexpression of LARGE induces hyperglycosylation of alpha-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored.Methodology/Principal Findings: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with alpha-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage.Conclusions/Significance: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and alpha-dystroglycan hyperglycosylation in muscle should be safe

Discovering new two-dimensional topological insulators from computational screening

We have performed a computational screening of topological two-dimensional (2D) materials from the Computational 2D Materials Database (C2DB) employing density functional theory. A full \textit{ab initio} scheme for calculating hybrid Wannier functions directly from the Kohn-Sham orbitals has been implemented and the method was used to extract $\mathbb{Z}_2$ indices, Chern numbers and Mirror Chern numbers of 3331 2D systems including both experimentally known and hypothetical 2D materials. We have found a total of 46 quantum spin Hall insulators, 7 quantum anomalous Hall insulators and 9 crystalline topological insulators that are all predicted to be dynamically stable. Roughly one third of these were known prior to the screening. The most interesting of the novel topological insulators are investigated in more detail. We show that the calculated topological indices of the quantum anomalous Hall insulators are highly sensitive to the approximation used for the exchange-correlation functional and reliable predictions of the topological properties of these materials thus require methods beyond density functional theory. We also performed $GW$ calculations, which yield a gap of 0.65 eV for the quantum spin Hall insulator PdSe$_2$ in the MoS$_2$ crystal structure. This is significantly higher than any known 2D topological insulator and three times larger than the Kohn-Sham gap.Comment: 12 page

Unconventional Metallic Magnetism in LaCrSb{3}

Neutron-diffraction measurements in LaCrSb{3} show a coexistence of ferromagnetic and antiferromagnetic sublattices below Tc=126 K, with ordered moments of 1.65(4) and 0.49(4) Bohr magnetons per formula unit, respectively (T=10 K), and a spin reorientation transition at ~95 K. No clear peak or step was observed in the specific heat at Tc. Coexisting localized and itinerant spins are suggested.Comment: PRL, in pres

APE Results of Hadron Masses in Full QCD Simulations

We present numerical results obtained in full QCD with 2 flavors of Wilson fermions. We discuss the relation between the phase of Polyakov loops and the {\bf sea} quarks boundary conditions. We report preliminary results about the HMC autocorrelation of the hadronic masses, on a $16^3 \times 32$ lattice volume, at $\beta=5.55$ with $k_{sea}=0.1570$.Comment: 3 pages, compressed ps-file (uufiles), Contribution to Lattice 9

Detection of possible factors favouring the evolution of migraine without aura into chronic migraine

In a minority of cases, the natural history of migraine without aura (MO) is characterised over time by its evolution into a form of chronic migraine (CM). In order to detect the possible factors predicting this negative evolution of MO, we searched in our Headache Centre files for all clinical records that met the following criteria: (a) first visit between 1976 and 1998; (b) diagnosis of MO or of common migraine at the first observation, with or without association with other primary headache types; (c) <15 days per month of migraine at the first observation; and (d) at least one follow-up visit at least 10 years after the first visit. The patients thus identified were then divided into two groups based on a favourable/steady evolution (Group A: n = 243, 195 women and 48 men) or an unfavourable evolution (Group B: n = 72, 62 women and 10 men) of their migraine over time. In the two groups, we compared various clinical parameters that were present at the first observation or emerged at the subsequent follow-up visits. The parameters that were statistically significantly more frequent in Group B--and can therefore be considered possible negative prognostic factors--were: (a) ≥ 10 days per month of migraine at the first observation; (b) presence of depression at the first visit in males; and (c) onset of depression or arterial hypertension after the first observation but before transformation to CM in females. Based on these findings, in MO patients the high frequency of migraine attacks, comorbidity with depression, and the tendency to develop arterial hypertension should require particular attention and careful management to prevent evolution into CM

K-edge X-ray absorption spectra in transition metal oxides beyond the single particle approximation: shake-up many body effects

The near edge structure (XANES) in K-edge X-ray absorption spectroscopy (XAS) is a widely used tool for studying electronic and local structure in materials. The precise interpretation of these spectra with the help of calculations is hence of prime importance, especially for the study of correlated materials which have a complicated electronic structure per se. The single particle approach, for example, has generally limited itself to the dominant dipolar cross-section. It has long been known however that effects beyond this approach should be taken into account, both due to the inadequacy of such calculations when compared to experiment and the presence of shake-up many-body satellites in core-level photoemission spectra of correlated materials. This effect should manifest itself in XANES spectra and the question is firstly how to account for it theoretically and secondly how to verify it experimentally. By using state-of-the-art first principles electronic structure calculations and 1s photoemission measurements we demonstrate that shake-up many-body effects are present in K-edge XAS dipolar spectra of NiO, CoO and CuO at all energy scales. We show that shake-up effects can be included in K-edge XAS spectra in a simple way by convoluting the single-particle first-principles calculations including core-hole effects with the 1s photoemission spectra. We thus describe all features appearing in the XAS dipolar cross-section of NiO and CoO and obtain a dramatic improvement with respect to the single-particle calculation in CuO. These materials being prototype correlated magnetic oxides, our work points to the presence of shake-up effects in K-edge XANES of most correlated transition metal compounds and shows how to account for them, paving the way to a precise understanding of their electronic structure.Comment: 6 pages, 4 picture

Enhanced Optical 13C Hyperpolarization in Diamond Treated by High-Temperature Rapid Thermal Annealing

Methods of optical dynamic nuclear polarization open the door to the replenishable hyperpolarization of nuclear spins, boosting their nuclear magnetic resonance/imaging signatures by orders of magnitude. Nanodiamond powder rich in negatively charged nitrogen vacancy defect centers has recently emerged as one such promising platform, wherein 13C nuclei can be hyperpolarized through the optically pumped defects completely at room temperature. Given the compelling possibility of relaying this 13C polarization to nuclei in external liquids, there is an urgent need for the engineered production of highly “hyperpolarizable” diamond particles. Here, a systematic study of various material dimensions affecting optical 13C hyperpolarization in diamond particles is reported on. It is discovered surprisingly that diamond annealing at elevated temperatures ∼1720 °C has remarkable effects on the hyperpolarization levels enhancing them by above an order of magnitude over materials annealed through conventional means. It is demonstrated these gains arise from a simultaneous improvement in NV− electron relaxation/coherence times, as well as the reduction of paramagnetic content, and an increase in 13C relaxation lifetimes. This work suggests methods for the guided materials production of fluorescent, 13C hyperpolarized, nanodiamonds and pathways for their use as multimodal (optical and magnetic resonance) imaging and hyperpolarization agents

Low Temperature Solution-Phase Deposition of SnS Thin Films

The solution-phase deposition of inorganic semiconductors is a promising, scalable method for the manufacture of thin film photovoltaics. Deposition of photovoltaic materials from molecular or colloidal inks offers the possibility of inexpensive, rapid, high-throughput thin film fabrication through processes such as spray coating. For example, CdTe, Cu(In,Ga)(S,Se)_2 (CIGS), and CH_3NH_3Pb(Cl,I)_3 perovskite-based thin film solar cells have been previously deposited using solution-based processes. Inks have also recently been developed for the solution deposition of Cu_2ZnSn(S,Se)_4 (CZTS) and FeS_2 (iron pyrite) absorber layers for thin film solar applications, in order to provide sustainable alternatives to materials that contain environmentally harmful heavy metals (e.g., Cd, Pb) and/or scarce elements (e.g., Te, In)

Progress and status of APEmille

We report on the progress and status of the APEmille project: a SIMD parallel computer with a peak performance in the TeraFlops range which is now in an advanced development phase. We discuss the hardware and software architecture, and present some performance estimates for Lattice Gauge Theory (LGT) applications.Comment: Talk presented at LATTICE97, 3 pages, Late