Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington’s disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt cytoplasmic and nuclear inclusions in mammalian cells and primary neurons overexpressing mutant exon1 of the Htt protein. Our findings provide unique insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve the polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; the recruitment and accumulation of remodeled or dysfunctional membranous organelles, and the impairment of the protein quality control and degradation machinery. We also show that nuclear and cytoplasmic Htt inclusions exhibit distinct biochemical compositions and ultrastructural properties, suggesting different mechanisms of aggregation and toxicity.LMN

Associations of autozygosity with a broad range of human phenotypes

Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Search for dark matter produced in association with a pair of bottom quarks in proton-proton collisions at s= \sqrt{s} = 13 TeV

A search for dark matter (DM) particles produced in association with bottom quarks is presented. The analysis uses proton-proton collision data at a center-of-mass energy of $\sqrt{s}=$ 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The search is performed in the final state with large missing transverse momentum and a pair of jets originating from bottom quarks. No significant excess of data is observed with respect to the standard model expectation. Results are interpreted in the context of a type-II two-Higgs-doublet model with an additional light pseudoscalar (2HDM+a). An upper limit is set on the mass of the lighter pseudoscalar, excluding masses up to 260 GeV at 95% confidence level. This is the first search at the LHC to probe DM produced in association with two nonresonant bottom quarks in the 2HDM+a model. Sensitivity to the parameter space with the ratio of the vacuum expectation values of the two Higgs doublets, $\tan\beta$, greater than 15 is achieved, capitalizing on the enhancement of couplings between pseudoscalars and bottom quarks with high $\tan\beta$.A search for dark matter (DM) particles produced in association with bottom quarks is presented. The analysis uses proton-proton collision data at a center-of-mass energy of $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The search is performed in the final state with large missing transverse momentum and a pair of jets originating from bottom quarks. No significant excess of data is observed with respect to the standard model expectation. Results are interpreted in the context of a type-II two-Higgs-doublet model with an additional light pseudoscalar (2HDM+a). An upper limit is set on the mass of the lighter pseudoscalar, excluding masses up to 260 GeV at 95% confidence level. This is the first search at the LHC to probe DM produced in association with two nonresonant bottom quarks in the 2HDM+a model. Sensitivity to the parameter space with the ratio of the vacuum expectation values of the two Higgs doublets, $\tan\beta$, greater than 15 is achieved, capitalizing on the enhancement of couplings between pseudoscalars and bottom quarks with high $\tan\beta$

Search for nuclear modifications of B+^+ meson production in pPb collisions at sNN\sqrt{s_\mathrm{NN}} = 8.16 TeV

International audienceNuclear medium effects on B$^+$ meson production are studied using the binary-collision scaled cross section ratio between events of different multiplicities from proton-lead collisions. Data, collected by the CMS experiment in 2016 at a nucleon-nucleon center-of-mass energy of $\sqrt{s_\mathrm{NN}}$ = 8.16 TeV, corresponding to an integrated luminosity of 175 nb$^{-1}$, were used. The scaling factors in the ratio are determined using a novel approach based on the Z $\to$$\mu^+\mu^-$ cross sections measured in the same events. The scaled ratio for B$^+$ is consistent with unity for all event multiplicities, putting stringent constraints on nuclear modification for heavy flavor

Search for long-lived heavy neutral leptons in proton-proton collision events with a lepton-jet pair associated with a secondary vertex at s\sqrt{s} = 13 TeV

International audienceA search for long-lived heavy neutral leptons (HNLs) using proton-proton collision data corresponding to an integrated luminosity of 138 fb$^{-1}$ collected at $\sqrt{s}$ = 13 TeV with the CMS detector at the CERN LHC is presented. Events are selected with a charged lepton originating from the primary vertex associated with the proton-proton interaction, as well as a second charged lepton and a hadronic jet associated with a secondary vertex that corresponds to the semileptonic decay of a long-lived HNL. No excess of events above the standard model expectation is observed. Exclusion limits at 95% confidence level are evaluated for HNLs that mix with electron and/or muon neutrinos. Limits are presented in the mass range of 1-16.5 GeV, with excluded square mixing parameter values reaching as low as 2 $\times$ 10$^{-7}$. For masses above 11 GeV, the presented limits exceed all previous results in the semileptonic decay channel, and for some of the considered scenarios are the strongest to date

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Bottom quark energy loss and hadronization with B+^+ and Bs0^0_\mathrm{s} nuclear modification factors using pp and \PbPb collisions at sNN\sqrt{s_\mathrm{NN}} = 5.02 TeV

International audienceThe production cross sections of B$^0_\mathrm{s}$ and B$^+$ mesons are reported in proton-proton (pp) collisions recorded by the CMS experiment at the CERN LHC with a center-of-mass energy of 5.02 TeV. The data sample corresponds to an integrated luminosity of 302 pb$^{-1}$. The cross sections are based on measurements of the B$^0_\mathrm{s}$$\to$ J/$\psi(\mu^+\mu^-)\phi$(1020)(K$^+$K$^-$) and B$^+$$\to$ J/$\psi(\mu^+\mu^-)$K$^+$ decay channels. Results are presented in the transverse momentum ($p_\mathrm{T}$) range 7-50 GeV/$c$ and the rapidity interval $\lvert y \rvert$$\lt$ 2.4 for the B mesons. The measured $p_\mathrm{T}$-differential cross sections of B$^+$ and B$^0_\mathrm{s}$ in pp collisions are well described by fixed-order plus next-to-leading logarithm perturbative quantum chromodynamics calculations. Using previous PbPb collision measurements at the same nucleon-nucleon center-of-mass energy, the nuclear modification factors, $R_\mathrm{AA}$, of the B mesons are determined. For $p_\mathrm{T}$$\lt$ 10 GeV/$c$, both mesons are found to be suppressed in PbPb collisions (with $R_\mathrm{AA}$ values significantly below unity), with less suppression observed for the B$^0_\mathrm{s}$ mesons. In this $p_\mathrm{T}$ range, the $R_\mathrm{AA}$ values for the B$^+$ mesons are consistent with those for inclusive charged hadrons and D$^0$ mesons. Below 10 GeV/$c$, both B$^+$ and B$^0_\mathrm{s}$s are found to be less suppressed than either inclusive charged hadrons or D$^0$ mesons, with the B$^0_\mathrm{s}$$R_\mathrm{AA}$ value consistent with unity. The $R_\mathrm{AA}$ values found for the B$^+$ and B$^0_\mathrm{s}$ are compared to theoretical calculations, providing constraints on the mechanism of bottom quark energy loss and hadronization in the quark-gluon plasma, the hot and dense matter created in ultrarelativistic heavy ion collisions

Measurement of the ttˉ\mathrm{t\bar{t}}H and tH production rates in the H →\tobbˉ\mathrm{b\bar{b}} decay channel using proton-proton collision data at s\sqrt{s} = 13 TeV

International audienceAn analysis of the production of a Higgs boson (H) in association with a top quark-antiquark pair ($\mathrm{t\bar{t}}$H) or a single top quark (tH) is presented. The Higgs boson decay into a bottom quark-antiquark pair (H $\to$$\mathrm{b\bar{b}}$) is targeted, and three different final states of the top quark decays are considered, defined by the number of leptons (electrons or muons) in the event. The analysis utilises proton-proton collision data collected at the CERN LHC with the CMS experiment at $\sqrt{s}$ = 13 TeV in 2016-2018, which correspond to an integrated luminosity of 138 fb$^{-1}$. The observed $\mathrm{t\bar{t}}$H production rate relative to the standard model expectation is 0.33 $\pm$ 0.26 = 0.33 $\pm$ 0.17 (stat) $\pm$ 0.21 (syst). Additionally, the $\mathrm{t\bar{t}}$H production rate is determined in intervals of Higgs boson transverse momentum. An upper limit at 95% confidence level is set on the tH production rate of 14.6 times the standard model prediction, with an expectation of 19.3$^{+9.2}_{-6.0}$. Finally, constraints are derived on the strength and structure of the coupling between the Higgs boson and the top quark from simultaneous extraction of the $\mathrm{t\bar{t}}$H and tH production rates, and the results are combined with those obtained in other Higgs boson decay channels