Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.Genetics of disease, diagnosis and treatmen

Search for new Higgs bosons via same-sign top quark pair production in association with a jet in proton-proton collisions at s=13TeV

A search is presented for new Higgs bosons in proton-proton (pp) collision events in which a same-sign top quark pair is produced in association with a jet, via the pp→tH/A→ttc‾ and pp→tH/A→ttu‾ processes. Here, H and A represent the extra scalar and pseudoscalar boson, respectively, of the second Higgs doublet in the generalized two-Higgs-doublet model (g2HDM). The search is based on pp collision data collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 138fb−1. Final states with a same-sign lepton pair in association with jets and missing transverse momentum are considered. New Higgs bosons in the 200–1000 GeV mass range and new Yukawa couplings between 0.1 and 1.0 are targeted in the search, for scenarios in which either H or A appear alone, or in which they coexist and interfere. No significant excess above the standard model prediction is observed. Exclusion limits are derived in the context of the g2HDM

Portable Acceleration of CMS Computing Workflows with Coprocessors as a Service

Computing demands for large scientific experiments, such as the CMS experiment at the CERN LHC, will increase dramatically in the next decades. To complement the future performance increases of software running on central processing units (CPUs), explorations of coprocessor usage in data processing hold great potential and interest. Coprocessors are a class of computer processors that supplement CPUs, often improving the execution of certain functions due to architectural design choices. We explore the approach of Services for Optimized Network Inference on Coprocessors (SONIC) and study the deployment of this as-a-service approach in large-scale data processing. In the studies, we take a data processing workflow of the CMS experiment and run the main workflow on CPUs, while offloading several machine learning (ML) inference tasks onto either remote or local coprocessors, specifically graphics processing units (GPUs). With experiments performed at Google Cloud, the Purdue Tier-2 computing center, and combinations of the two, we demonstrate the acceleration of these ML algorithms individually on coprocessors and the corresponding throughput improvement for the entire workflow. This approach can be easily generalized to different types of coprocessors and deployed on local CPUs without decreasing the throughput performance. We emphasize that the SONIC approach enables high coprocessor usage and enables the portability to run workflows on different types of coprocessors

Search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state in proton-proton collisions at s=13TeV

A search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state is presented. The analysis is based on proton-proton collision data recorded by the CMS detector in 2016–2018 at a centre-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 138fb−1. The search is sensitive to resonances with masses between 1.3 and 6TeV, decaying to bosons that are highly Lorentz-boosted such that each of the bosons forms a single large-radius jet. Machine learning techniques are employed to identify such jets. No significant excess over the estimated standard model background is observed. A maximum local significance of 3.6 standard deviations, corresponding to a global significance of 2.3 standard deviations, is observed at masses of 2.1 and 2.9 TeV. In a heavy vector triplet model, spin-1 Z′ and W′ resonances with masses below 4.8TeV are excluded at the 95% confidence level (CL). These limits are the most stringent to date. In a bulk graviton model, spin-2 gravitons and spin-0 radions with masses below 1.4 and 2.7TeV, respectively, are excluded at 95% CL. Production of heavy resonances through vector boson fusion is constrained with upper cross section limits at 95% CL as low as 0.1fb

Measurement of the tt¯ charge asymmetry in events with highly Lorentz-boosted top quarks in pp collisions at s=13 TeV

The measurement of the charge asymmetry in top quark pair events with highly Lorentz-boosted top quarks decaying to a single lepton and jets is presented. The analysis is performed using proton-proton collisions at s=13TeV with the CMS detector at the LHC and corresponding to an integrated luminosity of 138 fb−1. The selection is optimized for top quarks produced with large Lorentz boosts, resulting in nonisolated leptons and overlapping jets. The top quark charge asymmetry is measured for events with a tt¯ invariant mass larger than 750 GeV and corrected for detector and acceptance effects using a binned maximum likelihood fit. The measured top quark charge asymmetry of (0.42−0.69+0.64)% is in good agreement with the standard model prediction at next-to-next-to-leading order in quantum chromodynamic perturbation theory with next-to-leading-order electroweak corrections. The result is also presented for two invariant mass ranges, 750–900 and >900GeV

Study of azimuthal anisotropy of ϒ(1S) mesons in pPb collisions at sNN = 8.16 TeV

The azimuthal anisotropy of Image 1 mesons in high-multiplicity proton-lead collisions is studied using data collected by the CMS experiment at a nucleon-nucleon center-of-mass energy of 8.16TeV. The Image 1 mesons are reconstructed using their dimuon decay channel. The anisotropy is characterized by the second Fourier harmonic coefficients, found using a two-particle correlation technique, in which the Image 1 mesons are correlated with charged hadrons. A large pseudorapidity gap is used to suppress short-range correlations. Nonflow contamination from the dijet background is removed using a low-multiplicity subtraction method, and the results are presented as a function of Image 1 transverse momentum. The azimuthal anisotropies are smaller than those found for charmonia in proton-lead collisions at the same collision energy, but are consistent with values found for Image 1 mesons in lead-lead interactions at a nucleon-nucleon center-of-mass energy of 5.02 TeV

Measurements of azimuthal anisotropy of nonprompt D0 mesons in PbPb collisions at sNN=5.02TeV

Measurements of the elliptic (v2) and triangular (v3) azimuthal anisotropy coefficients are presented for Image 1 mesons produced in Image 2 hadron decays (nonprompt Image 1 mesons) in lead-lead collisions at sNN=5.02TeV. The results are compared with previously published charm meson anisotropies measured using prompt Image 1 mesons. The data were collected with the CMS detector in 2018 with an integrated luminosity of 0.58nb−1. Azimuthal anisotropy is sensitive to the interactions of quarks with the hot and dense medium created in heavy ion collisions. Comparing results for prompt and nonprompt Image 1 mesons can assist in understanding the mass dependence of these interactions. The nonprompt results show lower magnitudes of v2 and v3 and weaker dependences on the meson transverse momentum and collision centrality than those found for prompt Image 1 mesons. The results are in agreement with theoretical predictions that include a mass dependence in the interactions of quarks with the medium