Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ

Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3) : a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Altres ajuts: Canadian Institutes of Health Research (CIHR, FDN-143302); General Research Fund (14104419), Research Grant Council, Hong Kong SAR, China; National Health and Medical Research Council, Funding Schemes (NHMRC Project Grant 1162362), Australia; McMaster University Department of Medicine Career Research Award and a Physicians' Services Incorporated (PSI) Foundation Mid-Career Clinical Research Award.Background: For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods: The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion: Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration: ClinicalTrials.gov NCT03505723. Registered on 23 April 2018

A phylogenetic classification of the world’s tropical forests

Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition and dynamics. Such understanding will enable anticipation of region specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present the first classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (1) Indo-Pacific, (2) Subtropical, (3) African, (4) American, and (5) Dry forests. Our results do not support the traditional Neo- versus Palaeo-tropical forest division, but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar and India. Additionally, a northern hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern hemisphere forests

Search for resonances in the mass spectrum of muon pairs produced in association with b quark jets in proton-proton collisions at root 8 and 13 TeV

A search for resonances in the mass range 12-70 GeV produced in association with a b quark jet and a second jet, and decaying to a muon pair, is reported. The analysis is based on data from proton-proton collisions at center-of-mass energies of 8 and 13 TeV, collected with the CMS detector at the LHC and corresponding to integrated luminosities of 19.7 and 35.9 fb(-1), respectively. The search is carried out in two mutually exclusive event categories. Events in the first category are required to have a b quark jet in the central region (|| 2.4) and at least one jet in the forward region (|| > 2.4). Events in the second category are required to have two jets in the central region, at least one of which is identified as a b quark jet, no jets in the forward region, and low missing transverse momentum. An excess of events above the background near a dimuon mass of 28 GeV is observed in the 8 TeV data, corresponding to local significances of 4.2 and 2.9 standard deviations for the first and second event categories, respectively. A similar analysis conducted with the 13 TeV data results in a mild excess over the background in the first event category corresponding to a local significance of 2.0 standard deviations, while the second category results in a 1.4 standard deviation deficit. The fiducial cross section measurements and 95% confidence level upper limits on those for a resonance consistent with the 8 TeV excess are provided at both collision energies

Search for top squark pair production in pp collisions at root s=13 TeV using single lepton events

Peer reviewe

Jet properties in PbPb and pp collisions at sN N=5.02 \sqrt{s_{\mathrm{N}\;\mathrm{N}}}=5.02 TeV

Modifications of the properties of jets in PbPb collisions, relative to those in pp collisions, are studied at a nucleon-nucleon center-of-mass energy of s NN − − − − √ =5.02 sNN=5.02 TeV via correlations of charged particles with the jet axis in relative pseudorapidity (Δη), relative azimuth (Δϕ), and relative angular distance from the jet axis Δr=(Δη) 2 +(Δϕ) 2 − − − − − − − − − − − − √ Δr=(Δη)2+(Δϕ)2 . This analysis uses data collected with the CMS detector at the LHC, corresponding to integrated luminosities of 404 μb−1 and 27.4 pb−1 for PbPb and pp collisions, respectively. Charged particle number densities, jet fragmentation functions, and jet shapes are presented as a function of PbPb collision centrality and charged-particle track transverse momentum, providing a differential description of jet modifications due to interactions with the quark-gluon plasma

Evidence for associated production of a Higgs boson with a top quark pair in final states with electrons, muons, and hadronically decaying τ leptons at s=13 \sqrt{s}=13 TeV

Results of a search for the standard model Higgs boson produced in association with a top quark pair (tt¯H) in final states with electrons, muons, and hadronically decaying τ leptons are presented. The analyzed data set corresponds to an integrated luminosity of 35.9 fb−1 recorded in proton-proton collisions at s√=13 TeV by the CMS experiment in 2016. The sensitivity of the search is improved by using matrix element and machine learning methods to separate the signal from backgrounds. The measured signal rate amounts to 1.23 − 0.43 + 0.45 times the production rate expected in the standard model, with an observed (expected) significance of 3.2σ (2.8σ), which represents evidence for tt¯H production in those final states. An upper limit on the signal rate of 2.1 times the standard model production rate is set at 95% confidence level

Measurement of exclusive Upsilon photoproduction from protons in pPb collisions at root sNN=5.02 Tev

An Erratum to this article was published on 20 April 2022: https://doi.org/10.1140/epjc/s10052-022-10276-2The exclusive photoproduction of (nS) meson states from protons, (nS) p (with n = 1, 2, 3), is studied in ultraperipheral pPb collisions at a centre-of-mass energy per nucleon pair of The measurement is performed using the decay mode, with data collected by the CMS experiment corresponding to an integrated luminosity of 32.6 nb(-1). Differential cross sections as functions of the nS) transverse momentum squared and rapidity y, are presented. The 1S) photoproduction cross section is extracted in the rapidity range < 2.2, which corresponds to photon-proton centre-of-mass energies in the range 91 W < 826 GeV. The data are compared to theoretical predictions based on perturbative quantum chromodynamics and to previous measurements.Peer reviewe

Search for high-mass resonances in dilepton final states in proton-proton collisions at root s=13 TeV

A search is presented for new high-mass resonances decaying into electron or muon pairs. The search uses proton-proton collision data at a centre-of-mass energy of 13TeV collected by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 36 fb(-1). Observations are in agreement with standard model expectations. Upper limits on the product of a new resonance production cross section and branching fraction to dileptons are calculated in a model-independent manner. This permits the interpretation of the limits in models predicting a narrow dielectron or dimuon resonance. A scan of different intrinsic width hypotheses is performed. Limits are set on the masses of various hypothetical particles. For the Z(SSM)' (Z(psi)') particle, which arises in the sequential standard model (superstring-inspired model), a lower mass limit of 4.50 (3.90) TeV is set at 95% confidence level. The lightest Kaluza-Klein graviton arising in the Randall-Sundrum model of extra dimensions, with coupling parameters k/(M) over bar (Pl) of 0.01, 0.05, and 0.10, is excluded at 95% con fi dence level below 2.10, 3.65, and 4.25TeV, respectively. In a simpli fi ed model of dark matter production via a vector or axial vector mediator, limits at 95% con fi dence level are obtained on the masses of the dark matter particle and its mediator.Peer reviewe