Improving Binding Specificity of Pharmacological Chaperones That Target Mutant Superoxide Dismutase-1 Linked to Familial Amyotrophic Lateral Sclerosis Using Computational Methods

We recently described a set of drug-like molecules obtained from an in silico screen that stabilize mutant superoxide dismutase-1 (SOD-1) linked to familial amyotrophic lateral sclerosis (ALS) against unfolding and aggregation but exhibited poor binding specificity toward SOD-1 in presence of blood plasma. A reasonable but not a conclusive model for the binding of these molecules was proposed on the basis of restricted docking calculations and site-directed mutagenesis of key residues at the dimer interface. A set of hydrogen bonding constraints obtained from these experiments were used to guide docking calculations with compound library around the dimer interface. A series of chemically unrelated hits were predicted, which were experimentally tested for their ability to block aggregation. At least six of the new molecules exhibited high specificity of binding toward SOD-1 in the presence of blood plasma. These molecules represent a new class of molecules for further development into clinical candidates

Magnetic relaxation in finite two-dimensional nanoparticle ensembles

We study the slow phase of thermally activated magnetic relaxation in finite two-dimensional ensembles of dipolar interacting ferromagnetic nanoparticles whose easy axes of magnetization are perpendicular to the distribution plane. We develop a method to numerically simulate the magnetic relaxation for the case that the smallest heights of the potential barriers between the equilibrium directions of the nanoparticle magnetic moments are much larger than the thermal energy. Within this framework, we analyze in detail the role that the correlations of the nanoparticle magnetic moments and the finite size of the nanoparticle ensemble play in magnetic relaxation.Comment: 21 pages, 4 figure

Optical, magneto-optical properties and fiber-drawing ability of tellurite glasses in the TeO2-ZnO-BaO ternary system

The presented work is focused on the optical and magneto-optical characterization of TeO2-ZnO-BaO (TZB) tellurite glasses. We investigated the refractive index and extinction coefficient dispersion by spectroscopic ellipsometry from ultraviolet, 0.193 um, up to mid infrared, 25 um spectral region. Studied glasses exhibited large values of linear (n632 = 1.91-2.09) and non-linear refractive index (n2 = 1.20-2.67x10-11 esu), Verdet constant (V632 = 22-33 radT-1m-1) and optical band gap energy (Eg = 3.7-4.1 eV). The materials characterization revealed that BaO substitution by ZnO leads (at constant content of TeO2) to an increase in linear and nonlinear refractive index as well as Verdet constant while the optical band gap energy decreases. Fiber drawing ability of TeO2-ZnO-BaO glassy system has been demonstrated on 60TeO2-20ZnO-20BaO glass with presented mid infrared attenuation coefficient. Specific parameters such as dispersion and single oscillator energy, Abbe number, and first-/ third-order optical susceptibility are enclosed together with the values of magneto-optic anomaly derived from the calculation of measured dispersion of the refractive index

Chemical composition of air masses transported from Asia to the U.S. West coast during ITCT 2K2: Fossil fuel combustion versus biomass-burning signatures

As part of the Intercontinental Transport and Chemical Transformation experiment in 2002 (ITCT 2K2), a National Oceanic and Atmospheric Administration (NOAA) WP-3D research aircraft was used to study the long-range transport of Asian air masses toward the west coast of North America. During research flights on 5 and 17 May, strong enhancements of carbon monoxide (CO) and other species were observed in air masses that had been transported from Asia. The hydrocarbon composition of the air masses indicated that the highest CO levels were related to fossil fuel use. During the flights on 5 and 17 May and other days, the levels of several biomass-buming indicators increased with altitude. This was true for acetonitrile (CH3CN), methyl chloride (CH3Cl), the ratio of acetylene (C2H2) to propane (C3H8), and, on May 5, the percentage of particles measured by the particle analysis by laser mass spectrometry (PALMS) instrument that were attributed to biomass burning based on their carbon and potassium content. An ensemble of back-trajectories, calculated from the U.S. west coast over a range of latitudes and altitudes for the entire ITCT 2K2 period, showed that air masses from Southeast Asia and China were generally observed at higher altitudes than air from Japan and Korea. Emission inventories estimate the contribution of biomass burning to the total emissions to be low for Japan and Korea, higher for China, and the highest for Southeast Asia. Combined with the origin of the air masses versus altitude, this qualitatively explains the increase with altitude, averaged over the whole ITCT 2K2 period, of the different biomass-burning indicators. Copyright 2004 by the American Geophysical Union

Gas-phase chemical characteristics of Asian emission plumes observed during ITCT 2K2 over the eastern North Pacific Ocean

The gas-phase chemical characteristics of emission plumes transported from Asia across the Pacific Ocean observed during the Intercontinental Transport and Chemical Transformation experiment in 2002 (ITCT 2K2) are described. Plumes measured in the troposphere from an aircraft were separated from the background air in data analysis using 1-s measurements of carbon monoxide (CO), total reactive nitrogen (NOy), and other gasphase species along with back trajectory analysis. On the basis of these measurements, Asian transport plumes with CO mixing ratios greater than 150 ppbv were observed on seven flights. Correlations between 1-s observations of CO, ozone (O3), and NOy are used to characterize the plumes. The NOy/CO ratios were similar in each plume and significantly lower than those derived from estimated Asian emission ratios, indicating substantial removal of soluble NOy species during transport. Observations of nitric oxide (NO), nitrogen dioxide (NO2) nitric acid (HNO3) peroxyacetyl nitrate (PAN), peroxypropionyl nitrate (PPN), and alkyl nitrates are used with the NOy measurements to further distinguish the transport plumes by their NOy partitioning. NOy was primarily in the form of PAN in plumes that were transported in cold high-latitude and high-altitude regions, whereas in plumes transported in warmer, lower latitude and altitude regions, NOy was mainly HNO3. Additional gas-phase species enhanced in these plumes include sulfuric acid, methanol, acetone, propane, and ethane. The O3/CO ratio varied among the plumes and was affected by the mixing of anthropogenic and stratospheric influences. The complexity of this mixing prevents the determination of the relative contribution of anthropogenic and stratospheric influences to the observed O3 levels. Copyright 2004 by the American Geophysical Union

Measurements of neutrino oscillation in appearance and disappearance channels by the T2K experiment with 6.6 x 10(20) protons on target

111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee commentsWe thank the J-PARC staff for superb accelerator performance and the CERN NA61/SHINE Collaboration for providing valuable particle production data. We acknowledge the support of MEXT, Japan; NSERC, NRC, and CFI, Canada; CEA and CNRS/IN2P3, France; DFG, Germany; INFN, Italy; National Science Centre (NCN), Poland; RSF, RFBR and MES, Russia; MINECO and ERDF funds, Spain; SNSF and SER, Switzerland; STFC, UK; and the U. S. Deparment of Energy, USA. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, GridPP, UK, and the Emerald High Performance Computing facility in the Centre for Innovation, UK. In addition, participation of individual researchers and institutions has been further supported by funds from ERC (FP7), EU; JSPS, Japan; Royal Society, UK; and DOE Early Career program, USA

Measurement of the electron neutrino charged-current interaction rate on water with the T2K ND280 pi(0) detector

10 pages, 6 figures, Submitted to PRDhttp://journals.aps.org/prd/abstract/10.1103/PhysRevD.91.112010© 2015 American Physical Society11 pages, 6 figures, as accepted to PRD11 pages, 6 figures, as accepted to PRD11 pages, 6 figures, as accepted to PR

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Fungal root endophyte associations of plants endemic to the Pamir Alay Mountains of Central Asia

The fungal root endophyte associations of 16 species from 12 families of plants endemic to the Pamir Alay Mountains of Central Asia are presented. The plants and soil samples were collected in Zeravshan and Hissar ranges within the central Pamir Alay mountain system. Colonization by arbuscular mycorrhizal fungi (AMF) was found in 15 plant species; in 8 species it was of the Arum type and in 4 of the Paris type, while 3 taxa revealed intermediate arbuscular mycorrhiza (AM) morphology. AMF colonization was found to be absent only in Matthiola integrifolia, the representative of the Brassicaceae family. The AM status and morphology are reported for the first time for all the species analyzed and for the genera Asyneuma, Clementsia, and Eremostachys. Mycelia of dark septate endophytes (DSE) accompanied the AMF colonization in ten plant species. The frequency of DSE occurrence in the roots was low in all the plants, with the exception of Spiraea baldschuanica. However, in the case of both low and higher occurrence, the percentage of DSE root colonization was low. Moreover, the sporangia of Olpidium spp. were sporadically found inside the root epidermal cells of three plant species. Seven AMF species (Glomeromycota) found in the trap cultures established with soils surrounding roots of the plants being studied were reported for the first time from this region of Asia. Our results provide information that might well be of use to the conservation and restoration programmes of these valuable plant species. The potential application of beneficial root-inhabiting fungi in active plant protection projects of rare, endemic and endangered plants is discussed

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space