Measurement of the tt production cross-section in the ⊤ + jets final state at √s = 7 TeV with the ATLAS detector at the LHC

This thesis contributes to the area of top physics with the measurement of the top pairs (t-tbar) production cross-section via strong interaction in proton-proton collisions at the LHC. The aim is to measure the t-tbar production cross-section in the semi-leptonic decay channel with in the final state a hadronically decaying tau lepton (t-tbar → τ + jets). This represents one of the most challenging experimental final state, due to the difficulty of reconstructing and identifying the hadronically decaying τ and due to the presence of more than one neutrino as the source of missing transverse energy (ETmiss ). The final state contains various additional jets, two of them originating from a b-quark. Jet reconstruction with precise jet energy scale estimation and efficient and well calibrated tagging of b-quark jets constitute other challenging experimental issues. The measurement is done using 2.05 fb-1 of LHC data produced at the center-of-mass energy of √s = 7 TeV, collected by the ATLAS detector during 2011. The cross-section is extracted with a profile likelihood fit of the transverse mass of the leptonically decaying W, combining the information of the 1-prong tau, 3-prong tau and electron channels. The cross-section in the tau and electron channel can vary independently. Systematic uncertainties are implemented as nuisance parameters in the fit and are constrained by the data improving the precision of the measurement. The result of the t-tbar → τ + jets cross-section measurement is : σ t-tbar→ τ +jets = 205 ± 11 (stat) ± 39 (syst) pb. It is compatible with the result of another measurement of the t-tbar → τ + jets cross-section at √s =7 TeV done with a with a sample of 1.7 fb-1 and based on a very different technique. Our measurement achieves a better precision with a relative error about 30% smaller. Both measurements are compatible with the theoretical calculation. We measured also the cross-section in the t-tbar → e + jets channel, which resulted in the value of σ t-tbar → e+jets = 178 ± 14 (stat+syst) pb , in good agreement with the ATLAS combined measurement in the electron and muon channels. The ratio of the t-tbar cross-section in the electron and the tau + jets channels is measured to be 0.86 +0.13 -0.11 compatible with 1 as expected in the Standard Model. As future perspective, we discussed possible improvements of the method developed in this thesis that could be achieved with a higher statistics sample like the 25 fb-1 of 8 TeV data.La presente tesis constituye una aportación a la área de la física del quark top proporcionando la medida de la sección eficaz de producción de pares top-antitop (t-tbar) vía interacción fuerte en colisiones protón-protón en el LHC. El objetivo de la tesis es él de medir la sección eficaz de producción de t-tbar en el canal de desintegración semi-leptónico con en el estado final un leptón tau que a su vez se desintegra de manera hadrónica (t-tbar → τ + jets). Este representa uno de los estados finales más desafiantes desde el punto de vista experimental, debido a la dificultad de reconstruir y identificar el leptón τ en su modo de desintegración hadrónico y debido también a la presencia de más de un neutrino como fuente de la energía transversa faltante (ETmiss ). Además, el estado final consta de otros jets, dos de los cuales producidos por quarks de tipo b. La reconstrucción de los jets con una estimación precisa de su escala de energía y la puesta a punto de un método para etiquetar los jets de tipo b (b-tagging) que sea eficiente y bien calibrado, constituyen otro desafío experimental. La medida está hecha con 2.05 fb-1 de datos del LHC producidos a la energía de centro de masa de √s = 7 TeV y coleccionados por el detector ATLAS durante el 2011. La sección eficaz está extraída con un profile likelihood fit de la masa transversa del bosón W que se desintegra leptónicamente, combinando la información de los canales de tau 1-prong y 3-prong y de electrón. La sección eficaz de los canales de tau se deja variar de manera independiente con respecto a la sección eficaz del canal de electrón. Los errores sistemáticos están implementados como nuisance parameters en el fit y están constreñidos por los datos: de tal manera se obtiene una mejora en la precisión de la medida. El resultado de la medida de la sección eficaz del proceso t-tbar → τ + jet es: σ t-tbar→ τ +jets = 205 ± 11 (stat) ± 39 (syst) pb. Este resultado es compatible con él de otra medida de sección eficaz del mismo estado final a √s =7 TeV hecho con una muestra de 1.7 fb-1 y basado en un procedimiento muy distinto. Nuestra medida alcanza una mejor precisión con un error relativo un 30% aproximadamente más bajo. Por otra parte, ambas medidas son compatibles con el valor calculado teóricamente. Hemos medido también la sección eficaz del canal t-tbar → e + jets, la cual resulta: σ t-tbar → e+jets = 178 ± 14 (stat+syst) pb , en buen acuerdo con la medida combinada de ATLAS en los canales de electrón y muón. El ratio de la sección eficaz de t-tbar en el canal de electrón y de tau resulta ser 0.86 +0.13 -0.11 , lo cual es compatible con 1, como se espera en el Modelo Estándard. Con respecto a las perspectivas para el futuro, se ha discutido una posible mejora del método desarrollado en esta tesis que se podría conseguir con una muestra con estadística más elevada, por ejemplo la muestra de 25 fb-1 de datos producidos a la energía de centro de masa de 8 TeV

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Search for pair and single production of new heavy quarks that decay to a Z boson and a third-generation quark in pp collisions at √s = 8TeV with the ATLAS detector

A search is presented for the production of new heavy quarks that decay to a Z boson and a third-generation Standard Model quark. In the case of a new charge +2/3 quark (T), the decay targeted is T -> Zt, while the decay targeted for a new charge -1/3 quark (B) is B -> Zb. The search is performed with a dataset corresponding to 20.3 fb(-1) of p p collisions at root s = 8TeV recorded in 2012 with the ATLAS detector at the CERN Large Hadron Collider. Selected events contain a high transverse momentum Z boson candidate reconstructed from a pair of oppositely charged same-flavor leptons (electrons or muons), and are analyzed in two channels defined by the absence or presence of a third lepton. Hadronic jets, in particular those with properties consistent with the decay of a b-hadron, are also required to be present in selected events. Different requirements are made on the jet activity in the event in order to enhance the sensitivity to either heavy quark pair production mediated by the strong interaction, or single production mediated by the electroweak interaction. No significant excess of events above the Standard Model expectation is observed, and lower limits are derived on the mass of vector-like T and B quarks under various branching ratio hypotheses, as well as upper limits on the magnitude of electroweak coupling parameters

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA\xe2\x80\x99s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration

Measurement of the t t production cross-section in the + jets nal state at ps = 7 TeV with the ATLAS detector at the LHC

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