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An inclusive search for anomalous Higgs boson production in the diphoton decay channel and in association with at least one jet is presented, using LHC proton-proton collision data collected by the CMS experiment at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 35.9 fb(-1). The razor variables M-R and R-2, as well as the momentum and mass resolution of the diphoton system, are used to categorize events into different search regions. The search result is interpreted in the context of strong and electroweak production of supersymmetric particles. We exclude bottom squark pair-production with masses below 450 GeV for bottom squarks decaying to a bottom quark, a Higgs boson, and the lightest supersymmetric particle (LSP) for LSP masses below 250 GeV. For wino-like chargino-neutralino production, we exclude charginos with mass below 170 GeV for LSP masses below 25 GeV. In the GMSB scenario, we exclude charginos with mass below 205 GeV for neutralinos decaying to a Higgs boson and a goldstino LSP with 100% branching fraction. C) 2018 The Author(s). Published by Elsevier B.V.

For almost any given human-tropic virus, bacterium, fungus, or parasite, the clinical outcome of primary infection is enormously variable, ranging from asymptomatic to lethal infection. This variability has long been thought to be largely determined by the germline genetics of the human host, and this is increasingly being demonstrated to be the case. The number and diversity of known inborn errors of immunity is continually increasing, and we focus here on autosomal and X-linked recessive traits underlying complete deficiencies of the encoded protein. Schematically, four types of infectious phenotype have been observed in individuals with such deficiencies, each providing information about the redundancy of the corresponding human gene, in terms of host defense in natural conditions. The lack of a protein can confer vulnerability to a broad range of microbes in most, if not all patients, through the disruption of a key immunological component. In such cases, the gene concerned is of low redundancy. However, the lack of a protein may also confer vulnerability to a narrow range of microbes, sometimes a single pathogen, and not necessarily in all patients. In such cases, the gene concerned is highly redundant. Conversely, the deficiency may be apparently neutral, conferring no detectable predisposition to infection in any individual. In such cases, the gene concerned is completely redundant. Finally, the lack of a protein may, paradoxically, be advantageous to the host, conferring resistance to one or more infections. In such cases, the gene is considered to display beneficial redundancy. These findings reflect the current state of evolution of humans and microbes, and should not be considered predictive of redundancy, or of a lack of redundancy, in the distant future. Nevertheless, these observations are of potential interest to present-day biologists testing immunological hypotheses experimentally and physicians managing patients with immunological or infectious conditions.

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell-driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases.

Early co-transcriptional events during eukaryotic ribosome assembly result in the formation of precursors of the small (40S) and large (60S) ribosomal subunits1. A multitude of transient assembly factors regulate and chaperone the systematic folding of pre-ribosomal RNA subdomains. However, owing to a lack of structural information, the role of these factors during early nucleolar 60S assembly is not fully understood. Here we report cryo-electron microscopy (cryo-EM) reconstructions of the nucleolar pre-60S ribosomal subunit in different conformational states at resolutions of up to 3.4 angstrom. These reconstructions reveal how steric hindrance and molecular mimicry are used to prevent both premature folding states and binding of later factors. This is accomplished by the concerted activity of 21 ribosome assembly factors that stabilize and remodel pre-ribosomal RNA and ribosomal proteins. Among these factors, three Brix-domain proteins and their binding partners form a ring-like structure at ribosomal RNA (rRNA) domain boundaries to support the architecture of the maturing particle. The existence of mutually exclusive conformations of these pre-60S particles suggests that the formation of the polypeptide exit tunnel is achieved through different folding pathways during subsequent stages of ribosome assembly. These structures rationalize previous genetic and biochemical data and highlight the mechanisms that drive eukaryotic ribosome assembly in a unidirectional manner.

A search is reported for heavy resonances decaying into e mu final states in proton-proton collisions recorded by the CMS experiment at the CERN LHC at root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The search focuses on resonance masses above 200 GeV. With no evidence found for physics beyond the standard model in the e mu mass spectrum, upper limits are set at 95% confidence level on the product of the cross section and branching fraction for this lepton-flavor violating signal. Based on these results, resonant tau sneutrino production in R-parity violating supersymmetric models is excluded for masses below 1.7 TeV, for couplings lambda(132) = lambda(231) = lambda(311) = 0.01. Heavy Z' gauge bosons with lepton-flavor violating transitions are excluded for masses up to 4.4 TeV. The eit mass spectrum is also interpreted in terms of non-resonant contributions from quantum black-hole production in models with one to six extra spatial dimensions, and lower mass limits are found between 3.6 and 5.6 TeV. In all interpretations used in this analysis, the results of this search improve previous limits by about 1 TeV. These limits correspond to the most sensitive values obtained at colliders.

Impacts of steroid stress hormones on the brain have provided multiple opportunities for linking specific molecular phenomena to behavioral state. The negative impacts of stress on female reproductive biological processes have been documented thoroughly at the endocrine and behavioral levels. More recently, a '3-hit' theory of autism has identified early stress as one of the hits. The multiple biochemical effects of endotoxin (lipopolysaccharide, LPS) indicated that it would serve as a powerful maternal immune activator. The prenatal exposure to LPS coupled with the other two 'hits% an autism-related mutation and the Y chromosome - - heightened certain autism -like signs in mouse behavior.

Transcriptional pausing by RNA polymerases (RNAPs) is a key mechanism to regulate gene expression in all kingdoms of life and is a prerequisite for transcription termination. The essential bacterial transcription factor NusA stimulates both pausing and termination of transcription, thus playing a central role. Here, wereport single-particle electron cryo-microscopy reconstructions of NusA bound to paused E. coli RNAP elongation complexes with and without a pause-enhancing hairpin in the RNA exit channel. The structures reveal four interactions between NusA and RNAP that suggest how NusA stimulates RNA folding, pausing, and termination. An asymmetric translocation intermediate of RNA and DNA converts the active site of the enzyme into an inactive state, providing a structural explanation for the inhibition of catalysis. Comparing RNAP at different stages of pausing provides insights on the dynamic nature of the process and the role of NusA as a regulatory factor.

Gram-positive bacteria homeostasis and antibiotic resistance mechanisms are dependent on the intricate architecture of the cell wall, where amidated peptidoglycan plays an important role. The amidation reaction is carried out by the bi-enzymatic complex MurT-GatD, for which biochemical and structural information is very scarce. In this work, we report the first crystal structure of the glutamine amidotransferase member of this complex, GatD from Staphylococcus aureus, at 1.85 angstrom resolution. A glutamine molecule is found close to the active site funnel, hydrogen-bonded to the conserved R128. In vitro functional studies using H-1-NMR spectroscopy showed that S. aureus MurT-GatD complex has glutaminase activity even in the absence of lipid II, the MurT substrate. In addition, we produced R128A, C94A and H189A mutants, which were totally inactive for glutamine deamidation, revealing their essential role in substrate sequestration and catalytic reaction. GatD from S. aureus and other pathogenic bacteria share high identity to enzymes involved in cobalamin biosynthesis, which can be grouped in a new sub-family of glutamine amidotransferases. Given the ubiquitous presence of GatD, these results provide significant insights into the molecular basis of the so far undisclosed amidation mechanism, contributing to the development of alternative therapeutics to fight infections.

A statistical combination of several searches for the electroweak production of charginos and neutralinos is presented. All searches use proton-proton collision data at A root s = 13 TeV, recorded with the CMS detector at the LHC in 2016 and corresponding to an integrated luminosity of 35.9 fb(-1). In addition to the combination of previous searches, a targeted analysis requiring three or more charged leptons (electrons or muons) is presented, focusing on the challenging scenario in which the difference in mass between the two least massive neutralinos is approximately equal to the mass of the Z boson. The results are interpreted in simplified models of chargino-neutralino or neutralino pair production. For chargino-neutralino production, in the case when the lightest neutralino is massless, the combination yields an observed (expected) limit at the 95% confidence level on the chargino mass of up to 650 (570) GeV, improving upon the individual analysis limits by up to 40 GeV. If the mass difference between the two least massive neutralinos is approximately equal to the mass of the Z boson in the chargino-neutralino model, the targeted search requiring three or more leptons obtains observed and expected exclusion limits of around 225 GeV on the second neutralino mass and 125 GeV on the lightest neutralino mass, improving the observed limit by about 60 GeV in both masses compared to the previous CMS result. In the neutralino pair production model, the combined observed (expected) exclusion limit on the neutralino mass extends up to 650-750 (550-750) GeV, depending on the branching fraction assumed. This extends the observed exclusion achieved in the individual analyses by up to 200 GeV. The combined result additionally excludes some intermediate gaps in the mass coverage of the individual analyses.

Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, but it remains unclear how they are regulated. Here, we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury rather than a prothrombotic phenotype. This is a consequence of multiple negative feedback mechanisms, including downregulation of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemi-ITAM-containing receptors glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-chain and CLEC-2, respectively and upregulation of the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B and its interaction with the tyrosine phosphatases Shp1 and Shp2. Results from an analog-sensitive Csk mouse model demonstrate the unconventional role of SFKs in activating ITIM signaling. This study establishes Csk and CD148 as critical molecular switches controlling the thrombotic and hemostatic capacity of platelets and reveals cell-intrinsic mechanisms that prevent pathological thrombosis from occurring.