Mitogen Activated Protein Kinase Phosphatase-1 Prevents the Development of Tactile Sensitivity In a Rodent Model of Neuropathic Pain

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression. We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs) as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide). Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38

Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

<p>Abstract</p> <p>Background</p> <p>Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.</p> <p>Results</p> <p>JWH015 (a CBR2 agonist) increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2 in LPS-stimulated primary microglia. These effects resulted in a significant reduction of tumor necrosis factor-α (TNF) expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors. We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia.</p> <p>Conclusion</p> <p>Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.</p

Search for a new resonance decaying to a W or Z boson and a Higgs boson in the ll/lv/vv + bb final states with the ATLAS detector

A search for a new resonance decaying to a W or Z boson and a Higgs boson in the ll/lv/vv + bb final states is performed using 20.3 fb −1 of pp collision data recorded at √ s = 8 TeV with the ATLAS detector at the Large Hadron Collider. The search is conducted by examining the W H / Z H invariant mass distribution for a localized excess. No significant deviation from the Standard Model background prediction is observed. The results are interpreted in terms of constraints on the Minimal Walking Technicolor model and on a simplified approach based on a phenomenological Lagrangian of Heavy Vector Triplets

Search for heavy long-lived multi-charged particles in pp collisions at √s = 8 TeV using the ATLAS detector

A search for heavy long-lived multi-charged particles is performed using the ATLAS detector at the LHC. Data collected in 2012 at s√ = 8 TeV from pp collisions corresponding to an integrated luminosity of 20.3 fb−1 are examined. Particles producing anomalously high ionisation, consistent with long-lived massive particles with electric charges from |q|=2e to |q|=6e are searched for. No signal candidate events are observed, and 95% confidence level cross-section upper limits are interpreted as lower mass limits for a Drell–Yan production model. The mass limits range between 660 and 785 GeV

Measurements of long-range azimuthal anisotropies and associated Fourier coefficients for pp collisions at √s=5.02 and 13 TeV and p+Pb collisions at √sNN=5.02 TeV with the ATLAS detector

ATLAS measurements of two-particle correlations are presented for √s=5.02 and 13 TeV ppcollisions and for √sNN=5.02 TeV p+Pb collisions at the LHC. The correlation functions are measured as a function of relative azimuthal angle Δϕ, and pseudorapidity separation Δη, using charged particles detected within the pseudorapidity interval |η|2, is studied using a template fitting procedure to remove a “back-to-back” contribution to the correlation function that primarily arises from hard-scattering processes. In addition to the elliptic, cos (2Δϕ), modulation observed in a previous measurement, the pp correlation functions exhibit significant cos (3Δϕ) and cos (4Δϕ) modulation. The Fourier coefficients vn, n associated with the cos (nΔϕ) modulation of the correlation functions for n=2–4 are measured as a function of charged-particle multiplicity and charged-particle transverse momentum. The Fourier coefficients are observed to be compatible with cos (nϕ) modulation of per-event single-particle azimuthal angle distributions. The single-particle Fourier coefficients vn are measured as a function of charged-particle multiplicity, and charged-particle transverse momentum for n=2–4. The integrated luminosities used in this analysis are, 64nb−1 for the √s=13 TeV pp data, 170 nb−1 for the √ s = 5.02 TeV pp data, and 28 nb−1 for the √sNN = 5.02 TeV p+Pb data

Study of the spin and parity of the Higgs boson in diboson decays with the ATLAS detector

Studies of the spin, parity and tensor couplings of the Higgs boson in the H→ZZ∗→4ℓ, H→WW∗→eνμν and H→γγ decay processes at the LHC are presented. The investigations are based on 25fb−1 of pp collision data collected by the ATLAS experiment at √s=7 TeV and √s=8 TeV. The Standard Model (SM) Higgs boson hypothesis, corresponding to the quantum numbers JP=0+, is tested against several alternative spin scenarios, including non-SM spin-0 and spin-2 models with universal and non-universal couplings to fermions and vector bosons. All tested alternative models are excluded in favour of the SM Higgs boson hypothesis at more than 99.9 % confidence level. Using the H → ZZ∗ → 4ℓ and H → WW∗ → eνμν decays, the tensor structure of the interaction between the spin-0 boson and the SM vector bosons is also investigated. The observed distributions of variables sensitive to the non-SM tensor couplings are compatible with the SM predictions and constraints on the non-SM couplings are derived

Search for high-mass diboson resonances with boson-tagged jets in proton-proton collisions at √s=8 TeV with the ATLAS detector

A search is performed for narrow resonances decaying into WW, WZ, or ZZ boson pairs using 20.3 fb−1 of proton-proton collision data at a centre-of-mass energy of √s=8 TeV recorded with the ATLAS detector at the Large Hadron Collider. Diboson resonances with masses in the range from 1.3 to 3.0 TeV are sought after using the invariant mass distribution of dijets where both jets are tagged as a boson jet, compatible with a highly boosted W or Z boson decaying to quarks, using jet mass and substructure properties. The largest deviation from a smoothly falling background in the observed dijet invariant mass distribution occurs around 2 TeV in the WZ channel, with a global significance of 2.5 standard deviations. Exclusion limits at the 95% confidence level are set on the production cross section times branching ratio for the WZ final state of a new heavy gauge boson, W′, and for the WW and ZZ final states of Kaluza-Klein excitations of the graviton in a bulk Randall-Sundrum model, as a function of the resonance mass. W′ bosons with couplings predicted by the extended gauge model in the mass range from 1.3 to 1.5 TeV are excluded at 95% confidence level

Search for low-scale gravity signatures in multi-jet final states with the ATLAS detector at √s=8 TeV

A search for evidence of physics beyond the Standard Model in final states with multiple high-transverse-momentum jets is performed using 20.3 fb−1 of proton-proton collision data at √s=8 TeV recorded by the ATLAS detector at the LHC. No significant excess of events beyond Standard Model expectations is observed, and upper limits on the visible cross sections for non-Standard Model production of multi-jet final states are set. A wide variety of models for black hole and string ball production and decay are considered, and the upper limit on the cross section times acceptance is as low as 0.16 fb at the 95% confidence level. For these models, excluded regions are also given as function of the main model parameters

Search for additional heavy neutral Higgs and gauge bosons in the ditau final state produced in 36 fb−1 of pp collisions at √s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons and Z′ bosons is performed using a data sample corresponding to an integrated luminosity of 36.1 fb−1 from proton-proton collisions at √s=13 TeV recorded by the ATLAS detector at the LHC during 2015 and 2016. The heavy resonance is assumed to decay to τ+τ− with at least one tau lepton decaying to final states with hadrons and a neutrino. The search is performed in the mass range of 0.2-2.25 TeV for Higgs bosons and 0.2-4.0 TeV for Z′ bosons. The data are in good agreement with the background predicted by the Standard Model. The results are interpreted in benchmark scenarios. In the context of the hMSSM scenario, the data exclude tan β > 1.0 for mA= 0.25 TeV and tan β > 42 for mA=1.5 TeV at the 95% confidence level. For the Sequential Standard Model, ZSSM′ with mZ′< 2.42 TeV is excluded at 95% confidence level, while Z NU′ with mZ ′ < 2.25 TeV is excluded for the non-universal G(221) model that exhibits enhanced couplings to third-generation fermions

Probing the W tb vertex structure in t-channel single-top-quark production and decay in pp collisions at s√=8 TeV with the ATLAS detector

To probe the W tb vertex structure, top-quark and W -boson polarisation observables are measured from t-channel single-top-quark events produced in proton-proton collisions at a centre-of-mass energy of 8 TeV. The dataset corresponds to an integrated luminosity of 20.2 fb−1, recorded with the ATLAS detector at the LHC. Selected events contain one isolated electron or muon, large missing transverse momentum and exactly two jets, with one of them identified as likely to contain a b-hadron. Stringent selection requirements are applied to discriminate t-channel single-top-quark events from background. The polarisation observables are extracted from asymmetries in angular distributions measured with respect to spin quantisation axes appropriately chosen for the top quark and the W boson. The asymmetry measurements are performed at parton level by correcting the observed angular distributions for detector effects and hadronisation after subtracting the background contributions. The measured top-quark and W -boson polarisation values are in agreement with the Standard Model predictions. Limits on the imaginary part of the anomalous coupling gR are also set from model-independent measurements.We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS, CEA-DSM/IRFU, France; SRNSF, Georgia; BMBF, HGF, and MPG, Germany; GSRT, Greece; RGC, Hong Kong SAR, China; ISF, I-CORE and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT, Portugal; MNE/IFA, Romania; MES of Russia and NRC KI, Russian Federation; JINR; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZS, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom; DOE and NSF, United States of America. In addition, individual groups and members have received support from BCKDF, the Canada Council, CANARIE, CRC, Compute Canada, FQRNT, and the Ontario Innovation Trust, Canada; EPLANET, ERC, ERDF, FP7, Horizon 2020 and Marie Sklodowska-Curie Actions, European Union; Investissements d'Avenir Labex and Idex, ANR, Region Auvergne and Fondation Partager le Savoir, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek NSRF; BSF, GIF and Minerva, Israel; BRF, Norway; CERCA Programme Generalitat de Catalunya, Generalitat Valenciana, Spain; the Royal Society and Leverhulme Trust, United Kingdom.The crucial computing support from all WLCG partners is acknowledged gratefully, in particular from CERN, the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF (Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF (Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (UK) and BNL (USA), the Tier-2 facilities worldwide and large non-WLCG resource providers. Major contributors of computing resoinfo:eu-repo/semantics/publishedVersio