Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors

Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 mu g/ml, which represents good starting point for development of novel antibacterials. Graphical abstractPeer reviewe

Human Coronavirus Virulence Motifs and Virulence

Trabajo presentado en el XIV International Nidovirus Symposium (Nido2017), celebrado en Kansas City, Missouri (Estados Unidos), del 4 al 9 de junio de 2017We have shown that SARS-CoV E protein is a virulence factor that includes at least two virulence motifs: its ion channel (IC) activity encoded within the transmembrane domain and a PDZ binding motif (PBM) located at its carboxy-terminus. We showed that E protein pathogenicity was caused by the activation of different host signaling pathways. One of them was the activation of inflammasome, a process mediated by the conductance of Ca++ byEprotein IC activity, leading to an increased expression of IL-1beta, TNF-alpha and IL-6 levels. Another signaling pathway implied the activation of a proinflammatory response mediated by NF-kB activation. This activation was a consequence of E protein-syntenin binding mediated by PBM-PDZ interactions. This binding caused an increase of p38MAPK phosphorylation promoting the induction of acute respiratory distress syndrome (ARDS), edema and death of mice infected with a mouse adapted SARS-CoV. The relevance of p38 MAPK activation after infection with the mouse adapted SARS-CoV was confirmed by the protection of mice in the presence of an inhibitor of p38 MAPK, but not in its absence. These results illustrated the identification of an efficient coronavirus (CoV) antiviral. The presence of a virulence factor such as the PBM motif in E protein allows the virus to interact with more than 400 cell proteins containing PDZ motifs, conferring the virus the potential to control a high number of cell-signaling pathways increasing its replication and virulence. In fact, we are analyzing the proteome of the viral PBM-cellular PDZ interactions using system biology approaches. Frequently, the ARDS caused by lung infection with mild respiratory viruses is resolved before it evolves to serious edema. In contrast, after SARS-CoV infection frequently this resolution does not take place. We have shown the binding of E protein to a main mediator of edema resolution, the Na+ /K+ ATPase, and proposed that this may be one of the procedures by which edema recovery is prevented after SARS-CoV infection, either by inhibition of Na+ /K+ ATPase activity or by relocating this enzyme to another subcellular compartment. Deadly human CoVs as SARS- and MERS-CoVs have at least two viral proteins with IC activity and PBM motifs. Studies on the relevance of E and 3a SARS-CoV proteins in replication and virulence, and the interdependence among them have shown that the presence in the virus of at least E or 3a proteins was needed for virus viability. In fact, we have shown that the complementation between E and 3a proteins is mediated by the PBM motifs located at the carboxy-terminus of these proteins. Our studies on the interaction of SARS-CoV and MERS-CoV with the host, and the engineering of reverse genetics systems for each of these viruses, led us to the development of genetically stable vaccine candidates that provided full-protection against the challenge with the homologous virulent virus using mice models

Nonfucosylation of an anti-TIGIT antibody enhances FcγR engagement, driving innate immune activation and antitumor activity

TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fcγ receptor (FcγR) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased FcγR interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that FcγRIIIa binding with decreased FcγRIIb binding favorably activates APCs and enhances tumor-specific CD8+ T cell responses. The anti-TIGIT mAbs with intact FcγR interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody–drug conjugate. These findings highlight the importance of the anti-TIGIT mAb’s Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone

No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial

Exercise modulates both brown adipose tissue (BAT)metabolismand white adipose tissue (WAT) browning in murine models. Whether this is true in humans, however, has remained unknown. An unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129) was therefore conducted to study the effects of a 24-week supervised exercise intervention, combining endurance and resistance training, on BAT volume and activity (primary outcome). The study was carried out in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada (Spain). One hundred and forty-five young sedentary adults were assigned to either (i) a control group (no exercise, n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 48), or (iii) a vigorous intensity exercise group (VIG-EX n = 43) by unrestricted randomization. No relevant adverse events were recorded. 97 participants (34 men, 63 women) were included in the final analysis (Control; n = 35, MOD-EX; n=31, and VIG-EX; n=31).We observed no changes in BAT volume (Δ Control: −22.2 ± 52.6ml; Δ MOD-EX: −15.5 ± 62.1ml, Δ VIG-EX: −6.8 ± 66.4 ml; P = 0.771) or 18F-fluorodeoxyglucose uptake (SUVpeak Δ Control: −2.6 ± 3.1ml; Δ MOD-EX: −1.2 ± 4.8, Δ VIG-EX: −2.2 ± 5.1; p = 0.476) in either the control or the exercise groups. Thus, we did not find any evidence of an exercise-induced change on BAT volume or activity in young sedentary adults.Spanish Government PI13/01393Retos de la Sociedad DEP2016-79512-R PTA-12264IEuropean CommissionSpanish Government FPU13/04365 FPU14/04172 FPU15/04059 FPU16/03653 FPU19/01609Consejo Nacional de Ciencia y Tecnologia (CONACyT) 440575Fundacion Iberoamericana de Nutricion (FINUT)Redes Tematicas de Investigacion Cooperativa RETIC Red SAMID RD16/0022AstraZenecaUniversity of Granada Plan Propio de Investigacion 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES)Plan Propio de Investigacion 2018 -Programa Contratos-PuentePrograma Perfecionamiento de DoctoresJunta de Andalucia Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGRJunta de Andalucia P18-RT-4455Fundacion Alfonso Martin EscuderoMaria Zambrano fellowship by the Ministerio de Universidades y la Union Europea-NextGenerationEU RR_C_2021_04Novo Nordisk FoundationNovocure Limited NNF18OC003239

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of √s=7 TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV

Catalytic abatement of trichloroethylene over Mo and/or W-based bronzes

[EN] In this paper we present the results of the synthesis, characterization and catalytic behaviour of Mo(W)¿Nb¿V¿O mixed metal oxides bronzes for the catalytic oxidation of trichloroethylene. The catalysts were prepared hydrothermally with different Mo/W/Nb/V/P atomic ratio and heat-treated at 500 and 700 °C. They were characterized by several techniques as N2-adsorption, X-ray diffraction, FTIR, SEM-EDS, temperature programmed desorption, temperature programmed reduction, UV¿vis, Fourier transformed infrared spectroscopy of adsorbed pyridine and 18O/16O isotope exchange. X-ray diffraction patterns (XRD) of samples heat-treated at 500 °C suggest the presence of a semi-crystalline material with a diffraction peak at ca. 2¿ = 22.2°, while XRD patterns of samples heat-treated at 700 °C show the formation of a tetragonal tungsten bronze (TTB) structure. The activity for the catalytic abatement of trichloroethylene strongly depends on the heat-treatment temperature and the catalyst composition. Thus, samples with W/(Mo + W) atomic ratios of 0.25-0.75 and heat-treated at 500 °C are the most active ones. The enhanced activity has been related to the remarkable higher surface area of the catalyst and to the catalyst composition which influences the acid characteristics as well as the reducibility and reoxidation of the catalysts. The importance of the oxygen dissociation on the catalyst surface and the diffusion of oxygen species through the catalyst are also discussed.The authors wish to thank DGICYT in Spain (Project CTQ2009-14495 and CSD2009-00050-CONSOLIDER/INGENIO 2010) and Universitat Politecnica de Valencia for the financial support. N.B.R. acknowledges Catedra Cemex Sostenibilidad (UPV) for a fellowship. M.D.S. acknowledges Universitat Politecnica de Valencia for a fellowship.Blanch Raga, N.; Soriano Rodríguez, MD.; Palomares Gimeno, AE.; Concepción Heydorn, P.; Martínez Triguero, LJ.; López Nieto, JM. (2013). Catalytic abatement of trichloroethylene over Mo and/or W-based bronzes. Applied Catalysis B: Environmental. 130-131:36-43. https://doi.org/10.1016/j.apcatb.2012.10.016S3643130-13