[Show abstract][Hide abstract]ABSTRACT: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
[Show abstract][Hide abstract]ABSTRACT: This work is on the Physics of the B Factories. Part A of this book contains
a brief description of the SLAC and KEK B Factories as well as their detectors,
BaBar and Belle, and data taking related issues. Part B discusses tools and
methods used by the experiments in order to obtain results. The results
themselves can be found in Part C.
Please note that version 3 on the archive is the auxiliary version of the
Physics of the B Factories book. This uses the notation alpha, beta, gamma for
the angles of the Unitarity Triangle. The nominal version uses the notation
phi_1, phi_2 and phi_3. Please cite this work as Eur. Phys. J. C74 (2014) 3026.
Full-text · Article · Nov 2014 · European Physical Journal C
[Show abstract][Hide abstract]ABSTRACT: Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.
Full-text · Article · Jun 2013 · The American Journal of Human Genetics
[Show abstract][Hide abstract]ABSTRACT: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
Full-text · Article · Mar 2012 · New England Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: We report the result of a search for the rare decay B0→γγ in 426 fb-1 of data, corresponding to 226×106 B0B̅ 0 pairs, collected on the Υ(4S) resonance at the PEP-II asymmetric-energy e+e- collider using the BABAR detector. We use a maximum likelihood fit to extract the signal yield and observe 21-12+13 signal events with a statistical significance of 1.8σ. This corresponds to a branching fraction B(B0→γγ)=(1.7±1.1(stat.)±0.2(syst.))×10-7. Based on this result, we set a 90% confidence level upper limit of B(B0→γγ)<3.2×10-7.
[Show abstract][Hide abstract]ABSTRACT: We report a Dalitz-plot analysis of the charmless hadronic decays of charged B mesons to the final state K±π∓π±. Using a sample of 226.0±2.5 million BB̅ pairs collected by the BABAR detector, we measure the magnitudes and phases of the intermediate resonant and nonresonant amplitudes for both charge-conjugate decays. We present measurements of the corresponding branching fractions and their charge asymmetries that supersede those of previous BABAR analyses. We find the charge asymmetries to be consistent with zero.
Full-text · Article · Jan 2009 · Physical Review D
[Show abstract][Hide abstract]ABSTRACT: We present a measurement of the partial branching fractions and mass spectra of the exclusive radiative penguin processes B-->Kpipigamma in the range m(Kpipi)<1.8 GeV/c(2). We reconstruct four final states: K(+)pi(-)pi(+)gamma, K(+)pi(-)pi(0)gamma, K(S)(0)pi(-)pi(+)gamma, and K(S)(0)pi(+)pi(0)gamma, where K(S)(0)-->pi(+)pi(-). Using 232 x 10(6) e(+)e(-)-->BB events recorded by the BABAR experiment at the SLAC PEP-II asymmetric-energy storage ring, we measure the branching fractions B(B(+)-->K(+)pi(-)pi(+)gamma)=[2.95+/-0.13(stat)+/-0.20(syst)] x 10(-5), B(B(0)-->K(+)pi(-)pi(0)gamma)=[4.07+/-0.22(stat)+/-0.31(syst)] x 10(-5), B(B(0)-->K(0)pi(+)pi(-)gamma)=[1.85+/-0.21(stat)+/-0.12(syst)] x 10(-5), and B(B(+)-->K(0)pi(+)pi(0)gamma)=[4.56+/-0.42(stat)+/-0.31(syst)] x 10(-5).
Full-text · Article · May 2007 · Physical Review Letters
[Show abstract][Hide abstract]ABSTRACT: We report on a study of inclusive B- and B̅ 0 meson decays to D0X, D̅ 0X, D+X, D-X, Ds+X, Ds-X, Λc+X, Λ̅ c-X, based on a sample of 231×106 BB̅ events recorded with the BABAR detector at the Υ(4S) resonance. Events are selected by completely reconstructing one B and searching for a reconstructed charm particle in the rest of the event. From the measured branching fractions of these decays, we infer the number of charm and anticharm particles per B̅ decay, separately for charged and neutral parents. We derive the total charm yield per B- decay, nc-=1.208±0.023±0.040-0.029+0.035, and per B̅ 0 decay, nc0=1.203±0.030±0.034-0.035+0.044 where the first uncertainty is statistical, the second is systematic, and the third reflects the charm branching-fraction uncertainties. We also present the charm momentum distributions measured in the B̅ rest frame.
Full-text · Article · Apr 2007 · Physical Review D
[Show abstract][Hide abstract]ABSTRACT: Using 230.2 fb-1 of e+e- annihilation data collected with the BABAR detector at and near the peak of the Upsilon(4S) resonance, 489+/-55 events containing the pure leptonic decay Ds+-->micro;+numicro have been isolated in charm-tagged events. The ratio of partial widths Gamma(D+-->micro+numicro)/Gamma(Ds+-->phipi+) is measured to be 0.143+/-0.018+/-0.006 allowing a determination of the pseudoscalar decay constant fDs=(283+/-17+/-7+/-14) MeV. The errors are statistical, systematic, and from the Ds+-->phipi+ branching ratio, respectively.
[Show abstract][Hide abstract]ABSTRACT: BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B(12) and vitamin B(6), it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. AIM: To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B(6) 25 mg, B(12) 500 microg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye.
DESIGN: A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial.
SETTING: One hundred and four medical centres in 20 countries on five continents.
SUBJECTS: Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (<7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye).
RANDOMISATION: Randomisation and data collection are performed by means of a central telephone service or secure internet site.
INTERVENTION: One tablet daily of either placebo or B vitamins (folic acid 2 mg, B(6) 25 mg, B(12) 500 mug).
PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. SECONDARY OUTCOMES: TIA, unstable angina, revascularisation procedures, dementia, depression.
STATISTICAL POWER: With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6.8%/year), applying a two-tailed level of significance of 5%.
Full-text · Article · Feb 2007 · International Journal of Stroke