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401.
  • Abdallah, J., et al. (författare)
  • Mechanical construction and installation of the ATLAS tile calorimeter
  • 2013
  • Ingår i: Journal of Instrumentation. - 1748-0221 .- 1748-0221. ; 8, s. T11001-
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper summarises the mechanical construction and installation of the Tile Calorimeter for the ATLAS experiment at the Large Hadron Collider in CERN, Switzerland. The Tile Calorimeter is a sampling calorimeter using scintillator as the sensitive detector and steel as the absorber and covers the central region of the ATLAS experiment up to pseudorapidities +/- 1.7. The mechanical construction of the Tile Calorimeter occurred over a period of about 10 years beginning in 1995 with the completion of the Technical Design Report and ending in 2006 with the installation of the final module in the ATLAS cavern. During this period approximately 2600 metric tons of steel were transformed into a laminated structure to form the absorber of the sampling calorimeter. Following instrumentation and testing, which is described elsewhere, the modules were installed in the ATLAS cavern with a remarkable accuracy for a structure of this size and weight.
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402.
  • Abdallah, J., et al. (författare)
  • The optical instrumentation of the ATLAS Tile Calorimeter
  • 2013
  • Ingår i: Journal of Instrumentation. - 1748-0221 .- 1748-0221. ; 8, s. P01005-
  • Tidskriftsartikel (refereegranskat)abstract
    • The Tile Calorimeter, covering the central region of the ATLAS experiment up to pseudorapidities of +/-1.7, is a sampling device built with scintillating tiles that alternate with iron plates. The light is collected in wave-length shifting (WLS) fibers and is read out with photomultipliers. In the characteristic geometry of this calorimeter the tiles lie in planes perpendicular to the beams, resulting in a very simple and modular mechanical and optical layout. This paper focuses on the procedures applied in the optical instrumentation of the calorimeter, which involved the assembly of about 460,000 scintillator tiles and 550,000 WLS fibers. The outcome is a hadronic calorimeter that meets the ATLAS performance requirements, as shown in this paper.
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403.
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404.
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405.
  • Walsh, Roddy, et al. (författare)
  • Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
  • 2021
  • Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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406.
  • Böhm, Johann, et al. (författare)
  • Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.
  • 2012
  • Ingår i: Human mutation. - 1098-1004. ; 33:6, s. 949-59
  • Tidskriftsartikel (refereegranskat)abstract
    • Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
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407.
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408.
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409.
  • Lahrouchi, Najim, et al. (författare)
  • Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
  • 2020
  • Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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