Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells

Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. © 2012 Liberman et al.Fil:Liberman, A.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Castro, C.N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Druker, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Search for new phenomena in final states with photons, jets and missing transverse momentum in pp collisions at s \sqrt{s} = 13 TeV with the ATLAS detector

International audienceA search for new phenomena has been performed in final states with at least one isolated high-momentum photon, jets and missing transverse momentum in proton–proton collisions at a centre-of-mass energy of $\sqrt{s}$ = 13 TeV. The data, collected by the ATLAS experiment at the CERN LHC, correspond to an integrated luminosity of 139 fb$^{−1}$. The experimental results are interpreted in a supersymmetric model in which pair-produced gluinos decay into neutralinos, which in turn decay into a gravitino, at least one photon, and jets. No significant deviations from the predictions of the Standard Model are observed. Upper limits are set on the visible cross section due to physics beyond the Standard Model, and lower limits are set on the masses of the gluinos and neutralinos, all at 95% confidence level. Visible cross sections greater than 0.022 fb are excluded and pair-produced gluinos with masses up to 2200 GeV are excluded for most of the NLSP masses investigated.[graphic not available: see fulltext

Search for resonant and non-resonant Higgs boson pair production in the bb‾τ+τ− b\overline{b}{\tau}^{+}{\tau}^{-} decay channel using 13 TeV pp collision data from the ATLAS detector

International audienceA search for Higgs boson pair production in events with two b-jets and two τ-leptons is presented, using a proton–proton collision dataset with an integrated luminosity of 139 fb$^{−1}$ collected at $\sqrt{s}$ = 13 TeV by the ATLAS experiment at the LHC. Higgs boson pairs produced non-resonantly or in the decay of a narrow scalar resonance in the mass range from 251 to 1600 GeV are targeted. Events in which at least one τ-lepton decays hadronically are considered, and multivariate discriminants are used to reject the backgrounds. No significant excess of events above the expected background is observed in the non-resonant search. The largest excess in the resonant search is observed at a resonance mass of 1 TeV, with a local (global) significance of 3.1σ (2.0σ). Observed (expected) 95% confidence-level upper limits are set on the non-resonant Higgs boson pair-production cross-section at 4.7 (3.9) times the Standard Model prediction, assuming Standard Model kinematics, and on the resonant Higgs boson pair-production cross-section at between 21 and 900 fb (12 and 840 fb), depending on the mass of the narrow scalar resonance.[graphic not available: see fulltext