PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.

SUMMARY: PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates 'phenome scans', where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner ('PhenoScanner V2'), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. AVAILABILITY AND IMPLEMENTATION: PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.This work was supported by the UK Medical Research Council [G0800270; MR/L003120/1], the British Heart Foundation [SP/09/002; RG/13/13/30194; RG/18/13/33946], Pfizer [G73632], the European Research Council [268834], the European Commission Framework Programme 7 [HEALTH-F2-2012-279233], the National Institute for Health Research and Health Data Research UK (*). *The views expressed are those of the authors and not necessarily those of the NHS or the NIHR

Stabilnost amlodipin besilata i atenolola u jednoslojnim i dvoslojnim tabletama

Multi-drug tablets of amlodipine besylate and atenolol were prepared as either mono-layer (mixed matrix) or bi-layer tablets containing each drug in a separate layer by using similar excipients and processing. Each tablet batch was packed in strip and blister packs and kept under accelerated temperature and humidity conditions. The stability of two tablet and packaging types was compared by HPLC analysis after 0, 1, 3 and 4.5 months and expressed as the content of intact amlodipine and atenolol. The content of atenolol did not decline regardless of tablet and packaging type. Amlodipine content in bi-layer tablets decreased to about 95 and 88% when packed in strips and blisters, respectively. When prepared as mono-layer tablets, the content decreased to 72 and 32%, respectively. The study revealed that the bi-layer tablet formulation was more stable than the mono-layer type. Further, the stability was increased when the tablets were packed in aluminium strips as compared to PVC blisters.Tablete s amlodipinom i atenololom pripremljene su ili u obliku jednoslojne tablete (miješani matriks) ili kao dvoslojne tablete (lijekovi u zasebnim slojevima) koristeći slične pomoćne tvari i uvjete tabletiranja. Tablete su pakirane u dvije vrste pakiranja, aluminijske folije (strip) ili PVC (blister) i čuvane u uvjetima ubrzanog starenja. Stabilnost je određivana pomoću HPLC metode nakon 0, 1, 2, 3 i 4,5 mjeseci i izražena kao sadržaj intaktnog lijeka. Sadržaj atenolola nije se značajno promijenio bez obzira na tip tablete ili pakiranje. Sadržaj amlodipina u dvoslojnim tabletama smanjio se na 95 % (tablete u strip pakiranju) i 88 % (tablete u blister pakiranju). Istodobno, u jednoslojnom tipu kombiniranih tableta sadržaj se smanjio na 72 % (strip pakiranje) i 32 % (blister pakiranje). Rezultati pokazuju da su dvoslojne tablete s amlodipinom i atenololom stabilnije od jednoslojnih. Štoviše, pakiranje tableta u aluminijsku foliju u obliku strip pakiranja povećava njihovu stabilnost u usporedbi s PVC pakirnim materijalom (blister)

New Results from the Cryogenic Dark Matter Search Experiment

Using improved Ge and Si detectors, better neutron shielding, and increased counting time, the Cryogenic Dark Matter Search (CDMS) experiment has obtained stricter limits on the cross section of weakly interacting massive particles (WIMPs) elastically scattering from nuclei. Increased discrimination against electromagnetic backgrounds and reduction of neutron flux confirm WIMP-candidate events previously detected by CDMS were consistent with neutrons and give limits on spin-independent WIMP interactions which are >2X lower than previous CDMS results for high WIMP mass, and which exclude new parameter space for WIMPs with mass between 8-20 GeV/c^2.Comment: 4 pages, 4 figure

Low-threshold analysis of CDMS shallow-site data

Data taken during the final shallow-site run of the first tower of the Cryogenic Dark Matter Search (CDMS II) detectors have been reanalyzed with improved sensitivity to small energy depositions. Four ~224 g germanium and two ~105 g silicon detectors were operated at the Stanford Underground Facility (SUF) between December 2001 and June 2002, yielding 118 live days of raw exposure. Three of the germanium and both silicon detectors were analyzed with a new low-threshold technique, making it possible to lower the germanium and silicon analysis thresholds down to the actual trigger thresholds of ~1 keV and ~2 keV, respectively. Limits on the spin-independent cross section for weakly interacting massive particles (WIMPs) to elastically scatter from nuclei based on these data exclude interesting parameter space for WIMPs with masses below 9 GeV/c^2. Under standard halo assumptions, these data partially exclude parameter space favored by interpretations of the DAMA/LIBRA and CoGeNT experiments' data as WIMP signals, and exclude new parameter space for WIMP masses between 3 GeV/c^2 and 4 GeV/c^2.Comment: 18 pages, 12 figures, 5 table

Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype

© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X-linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. Methods: We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next-gen sequencing for defining the duplication breakpoint, PacBio sequencing of full-length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB- cells with lentiviral FANCB WT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. Results: We describe here an FA-B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154 bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology-mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild-type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. Conclusion: Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA-B patient described here

Exclusion limits on the WIMP-nucleon cross-section from the Cryogenic Dark Matter Search

The Cryogenic Dark Matter Search (CDMS) employs low-temperature Ge and Si detectors to search for Weakly Interacting Massive Particles (WIMPs) via their elastic-scattering interactions with nuclei while discriminating against interactions of background particles. For recoil energies above 10 keV, events due to background photons are rejected with >99.9% efficiency, and surface events are rejected with >95% efficiency. The estimate of the background due to neutrons is based primarily on the observation of multiple-scatter events that should all be neutrons. Data selection is determined primarily by examining calibration data and vetoed events. Resulting efficiencies should be accurate to about 10%. Results of CDMS data from 1998 and 1999 with a relaxed fiducial-volume cut (resulting in 15.8 kg-days exposure on Ge) are consistent with an earlier analysis with a more restrictive fiducial-volume cut. Twenty-three WIMP candidate events are observed, but these events are consistent with a background from neutrons in all ways tested. Resulting limits on the spin-independent WIMP-nucleon elastic-scattering cross-section exclude unexplored parameter space for WIMPs with masses between 10-70 GeV c^{-2}. These limits border, but do not exclude, parameter space allowed by supersymmetry models and accelerator constraints. Results are compatible with some regions reported as allowed at 3-sigma by the annual-modulation measurement of the DAMA collaboration. However, under the assumptions of standard WIMP interactions and a standard halo, the results are incompatible with the DAMA most likely value at >99.9% CL, and are incompatible with the model-independent annual-modulation signal of DAMA at 99.99% CL in the asymptotic limit.Comment: 40 pages, 49 figures (4 in color), submitted to Phys. Rev. D; v.2:clarified conclusions, added content and references based on referee's and readers' comments; v.3: clarified introductory sections, added figure based on referee's comment

Exclusion Limits on the WIMP-Nucleon Cross-Section from the First Run of the Cryogenic Dark Matter Search in the Soudan Underground Lab

The Cryogenic Dark Matter Search (CDMS-II) employs low-temperature Ge and Si detectors to seek Weakly Interacting Massive Particles (WIMPs) via their elastic scattering interactions with nuclei. Simultaneous measurements of both ionization and phonon energy provide discrimination against interactions of background particles. For recoil energies above 10 keV, events due to background photons are rejected with >99.99% efficiency. Electromagnetic events very near the detector surface can mimic nuclear recoils because of reduced charge collection, but these surface events are rejected with >96% efficiency by using additional information from the phonon pulse shape. Efficient use of active and passive shielding, combined with the the 2090 m.w.e. overburden at the experimental site in the Soudan mine, makes the background from neutrons negligible for this first exposure. All cuts are determined in a blind manner from in situ calibrations with external radioactive sources without any prior knowledge of the event distribution in the signal region. Resulting efficiencies are known to ~10%. A single event with a recoil of 64 keV passes all of the cuts and is consistent with the expected misidentification rate of surface-electron recoils. Under the assumptions for a standard dark matter halo, these data exclude previously unexplored parameter space for both spin-independent and spin-dependent WIMP-nucleon elastic scattering. The resulting limit on the spin-independent WIMP-nucleon elastic-scattering cross-section has a minimum of 4x10^-43 cm^2 at a WIMP mass of 60 GeV/c^2. The minimum of the limit for the spin-dependent WIMP-neutron elastic-scattering cross-section is 2x10^-37 cm^2 at a WIMP mass of 50 GeV/c^2.Comment: 37 pages, 42 figure