2,096 research outputs found

    Modelling uncertainties for measurements of the H → γγ Channel with the ATLAS Detector at the LHC

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    The Higgs boson to diphoton (H → γγ) branching ratio is only 0.227 %, but this final state has yielded some of the most precise measurements of the particle. As measurements of the Higgs boson become increasingly precise, greater import is placed on the factors that constitute the uncertainty. Reducing the effects of these uncertainties requires an understanding of their causes. The research presented in this thesis aims to illuminate how uncertainties on simulation modelling are determined and proffers novel techniques in deriving them. The upgrade of the FastCaloSim tool is described, used for simulating events in the ATLAS calorimeter at a rate far exceeding the nominal detector simulation, Geant4. The integration of a method that allows the toolbox to emulate the accordion geometry of the liquid argon calorimeters is detailed. This tool allows for the production of larger samples while using significantly fewer computing resources. A measurement of the total Higgs boson production cross-section multiplied by the diphoton branching ratio (σ × Bγγ) is presented, where this value was determined to be (σ × Bγγ)obs = 127 ± 7 (stat.) ± 7 (syst.) fb, within agreement with the Standard Model prediction. The signal and background shape modelling is described, and the contribution of the background modelling uncertainty to the total uncertainty ranges from 18–2.4 %, depending on the Higgs boson production mechanism. A method for estimating the number of events in a Monte Carlo background sample required to model the shape is detailed. It was found that the size of the nominal γγ background events sample required a multiplicative increase by a factor of 3.60 to adequately model the background with a confidence level of 68 %, or a factor of 7.20 for a confidence level of 95 %. Based on this estimate, 0.5 billion additional simulated events were produced, substantially reducing the background modelling uncertainty. A technique is detailed for emulating the effects of Monte Carlo event generator differences using multivariate reweighting. The technique is used to estimate the event generator uncertainty on the signal modelling of tHqb events, improving the reliability of estimating the tHqb production cross-section. Then this multivariate reweighting technique is used to estimate the generator modelling uncertainties on background V γγ samples for the first time. The estimated uncertainties were found to be covered by the currently assumed background modelling uncertainty

    Focusing a NIR adaptive optics imager, experience with GSAOI

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    The Gemini South Adaptive Optics Imager (GSAOI) to be used with the Multi-Conjugate Adaptive Optics (MCAO) system at Gemini South is currently in the final stages of assembly and testing. GSAOI uses a suite of 26 different filters, made from both BK7 and Fused Silica substrates. These filters, located in a non-collimated beam, work as active optical elements. The optical design was undertaken to ensure that both the filter substrates both focused longitudinally at the same point. During the testing of the instrument it was found that longitudinal focus was filter dependant. The methods used to investigate this are outlined in the paper. These investigations identified several possible causes for the focal shift including substrate material properties in cryogenic conditions and small amounts of residual filter power

    Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes

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    Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; \u3e5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with \u3e5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD

    Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing

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    Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells

    Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

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    This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands

    Genomic landscape of TP53-mutated myeloid malignancies

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    TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance

    Clonal architecture of secondary acute myeloid leukemia

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    BACKGROUND: The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS: We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS: Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS: Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.
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