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

Transverse momentum spectra and nuclear modification factors of charged particles in Xe–Xe collisions at sNN=5.44TeV

Transverse momentum (pT) spectra of charged particles at mid-pseudorapidity in Xe–Xe collisions at sNN=5.44TeV measured with the ALICE apparatus at the Large Hadron Collider are reported. The kinematic range 0.15<pT<50GeV/c and |η|<0.8 is covered. Results are presented in nine classes of collision centrality in the 0–80% range. For comparison, a pp reference at the collision energy of s=5.44 TeV is obtained by interpolating between existing pp measurements at s=5.02 and 7 TeV. The nuclear modification factors in central Xe–Xe collisions and Pb–Pb collisions at a similar center-of-mass energy of sNN=5.02 TeV, and in addition at 2.76 TeV, at analogous ranges of charged particle multiplicity density 〈dNch/dη〉 show a remarkable similarity at pT>10 GeV/c. The centrality dependence of the ratio of the average transverse momentum 〈pT〉 in Xe–Xe collisions over Pb–Pb collision at s=5.02 TeV is compared to hydrodynamical model calculations. © 2018 The Autho

Anisotropic flow in Xe–Xe collisions at sNN=5.44 TeV

The first measurements of anisotropic flow coefficients vn for mid-rapidity charged particles in Xe–Xe collisions at sNN=5.44 TeV are presented. Comparing these measurements to those from Pb–Pb collisions at sNN=5.02 TeV, v2 is found to be suppressed for mid-central collisions at the same centrality, and enhanced for central collisions. The values of v3 are generally larger in Xe–Xe than in Pb–Pb at a given centrality. These observations are consistent with expectations from hydrodynamic predictions. When both v2 and v3 are divided by their corresponding eccentricities for a variety of initial state models, they generally scale with transverse density when comparing Xe–Xe and Pb–Pb, with some deviations observed in central Xe–Xe and Pb–Pb collisions. These results assist in placing strong constraints on both the initial state geometry and medium response for relativistic heavy-ion collisions. © 2018 European Organization for Nuclear Researc

Production of the rho(770)(0) meson in pp and Pb-Pb collisions at root S-NN=2.76 TeV

The production of the \u3c1(770)0 meson has been measured at midrapidity (|y|<0.5) in pp and centrality differential Pb-Pb collisions at sNN= 2.76 TeV with the ALICE detector at the Large Hadron Collider. The particles have been reconstructed in the \u3c1(770)0\u2192\u3c0+\u3c0- decay channel in the transverse-momentum (pT) range 0.5-11 GeV/c. A centrality-dependent suppression of the ratio of the integrated yields 2\u3c1(770)0/(\u3c0++\u3c0-) is observed. The ratio decreases by 3c40% from pp to central Pb-Pb collisions. A study of the pT-differential 2\u3c1(770)0/(\u3c0++\u3c0-) ratio reveals that the suppression occurs at low transverse momenta, pT<2 GeV/c. At higher momentum, particle ratios measured in heavy-ion and pp collisions are consistent. The observed suppression is very similar to that previously measured for the K 17(892)0/K ratio and is consistent with EPOS3 predictions that may imply that rescattering in the hadronic phase is a dominant mechanism for the observed suppression

Transverse momentum spectra and nuclear modification factors of charged particles in pp, p-Pb and Pb-Pb collisions at the LHC

We report the measured transverse momentum (pT) spectra of primary charged particles from pp, p-Pb and Pb-Pb collisions at a center-of-mass energy sNN=5.02 TeV in the kinematic range of 0.15 < pT< 50 GeV/c and |η| < 0.8. A significant improvement of systematic uncertainties motivated the reanalysis of data in pp and Pb-Pb collisions at sNN=2.76 TeV, as well as in p-Pb collisions at sNN=5.02 TeV, which is also presented. Spectra from Pb-Pb collisions are presented in nine centrality intervals and are compared to a reference spectrum from pp collisions scaled by the number of binary nucleon-nucleon collisions. For central collisions, the pT spectra are suppressed by more than a factor of 7 around 6–7 GeV/c with a significant reduction in suppression towards higher momenta up to 30 GeV/c. The nuclear modification factor RpPb, constructed from the pp and p-Pb spectra measured at the same collision energy, is consistent with unity above 8 GeV/c. While the spectra in both pp and Pb-Pb collisions are substantially harder at sNN=5.02 TeV compared to 2.76 TeV, the nuclear modification factors show no significant collision energy dependence. The obtained results should provide further constraints on the parton energy loss calculations to determine the transport properties of the hot and dense QCD matter.[Figure not available: see fulltext.]. © 2018, The Author(s)