A Mutation in the Borcs7 Subunit of the Lysosome Regulatory BORC Complex Results in Motor Deficits and Dystrophic Axonopathy in Mice

Lysosomes play a critical role in maintenance of the integrity of neuronal function, and mutations in genes that contribute to lysosome formation, transport, and activity are associated with neurodegenerative disorders. Recently, the multisubunit complex, BLOC-one-related complex (BORC), has been shown to be involved in positioning lysosomes within the cytoplasm, although the consequences of altered BORC function in adult animals have not been established. We show that a spontaneous truncation mutation in the mouse Borcs7 gene, identified through whole-genome sequencing followed by genetic complementation, results in progressive axonal dystrophy with dramatic impairment of motor function. Furthermore, mice homozygous for deletion of the entire Borcs7 coding sequence die shortly after birth, and neurons cultured from these animals show impaired centrifugal transport of lysosomes. This identifies BORCS7 as a central factor in axonal transport of lysosomes and a possible target for improving disease-related disturbances in this important function. BORC is a multisubunit complex that regulates lysosomal positioning. Snouwaert et al. report that a truncation mutation in Borcs7, a subunit of this complex, results in reduced lysosomal transport, progressive axonal dystrophy, and impaired motor function in mice. Loss of Borcs7 causes juxtanuclear clustering of neuronal lysosomes and perinatal mortality

Parity Violation Constraints Using Cosmic Microwave Background Polarization Spectra from 2006 and 2007 Observations by the QUaD Polarimeter

We constrain parity-violating interactions to the surface of last scattering using spectra from the QUaD experiment’s second and third seasons of observations by searching for a possible systematic rotation of the polarization directions of cosmic microwave background photons. We measure the rotation angle due to such a possible ‘‘cosmological birefringence’’ to be $0.55^{\circ} \pm 0.82^{\circ}$ (random) $\pm 0.5^{\circ}$ (systematic) using QUaD’s 100 and 150 GHz temperature-curl and gradient-curl spectra over the spectra over the multipole range 200 <$\ell$< 2000, consistent with null, and constrain Lorentz-violating interactions to <2 $\times$ 10$^ {-43}$ GeV (68% confidence limit). This is the best constraint to date on electrodynamic parity violation on cosmological scales.Astronom

Second and Third Season QUaD Cosmic Microwave Background Temperature and Polarization Power Spectra

We report results from the second and third seasons of observation with the QUaD experiment. Angular power spectra of the cosmic microwave background are derived for both temperature and polarization at both 100 GHz and 150 GHz, and as cross-frequency spectra. All spectra are subjected to an extensive set of jackknife tests to probe for possible systematic contamination. For the implemented data cuts and processing technique such contamination is undetectable. We analyze the difference map formed between the 100 and 150 GHz bands and find no evidence of foreground contamination in polarization. The spectra are then combined to form a single set of results which are shown to be consistent with the prevailing LCDM model. The sensitivity of the polarization results is considerably better than that of any previous experiment— for the first time multiple acoustic peaks are detected in the E-mode power spectrum at high significance

The QUAD Galactic Plane Survey 1: Maps and Analysis of Diffuse Emission

We present a survey of ~ 800 square degrees of the galactic plane observed with the QUaD telescope. The primary product of the survey are maps of Stokes I, Q and U parameters at 100 and 150 GHz, with spatial resolution 5 and 3.5 arcminutes respectively. Two regions are covered, spanning approximately 245 - 295° and 315 - 5° in galactic longitude l, and -4 < b < +4° in galactic latitude b. At 0:02° square pixel size, the median sensitivity is 74 and 107 kJy/sr at 100 GHz and 150 GHz respectively in I, and 98 and 120 kJy/sr for Q and U. In total intensity, we find an average spectral index of α = 2:35+-0:01(stat)+-0:02(sys) for |b| ≤1°, indicative of emission components other than thermal dust. A comparison to published dust, synchrotron and free-free models implies an excess of emission in the 100 GHz QUaD band, while better agreement is found at 150 GHz. A smaller excess is observed when comparing QUaD 100 GHz data to WMAP 5-year W band; in this case the excess is likely due to the wider bandwidth of QUaD. Combining the QUaD and WMAP data, a two-component spectral fit to the inner galactic plane (|b| ≤1°) yields mean spectral indices of αs = -0:32+-0:03 and αd = 2:84+-0:03; the former is interpreted as a combination of the spectral indices of synchrotron, free-free and dust, while the second is attributed largely to the thermal dust continuum. In the same galactic latitude range, the polarization data show a high degree of alignment perpendicular to the expected galactic magnetic field direction, and exhibit mean polarization fraction 1:38+-0:08(stat)+-0:1(sys)% at 100 GHz and 1:70+-0:06(stat)+-0:1(sys)% at 150 GHz. We find agreement in polarization fraction between QUaD 100 GHz and WMAP W band, the latter giving 1:1+-0:4%

Polarization Calibration of the QUaD Experiment

We describe the polarization calibration of the QUaD experiment, including determination of the polarization efficiency of the detectors and their orientation angles. QUaD is a millimeter-wavelength polarimeter that observed the Cosmic Microwave Background (CMB) from a site at the South Pole. The experiment comprises a 2.64 m Cassegrain telescope equipped with a cryogenically cooled receiver containing an array of 62 polarization-sensitive bolometers. The focal plane contains pixels at two different frequency bands, 100 GHz and 150 GHz, with angular resolutions of 5prime and 3farcm5, respectively. The high angular resolution allows observation of CMB temperature and polarization anisotropies over a wide range of scales. The instrument commenced operation in early 2005 and collected science data during three successive Austral winter seasons of observation

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase