Zebrafish toxicological screening could aid Leishmaniosis drug discovery

Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested through an optimization program, leading to a promising 2-aminobenzimidazoles derived compound (2amnbzl-d) that was progressed to in vivo mice studies. However, the not expected toxic effects prevented its progression to more advanced preclinical and clinical phases of drug development. Due to limitations of cell models in detecting whole organism complex interactions, 90% of the compounds submitted to pre-clinical tests are reproved. The use of Zebrafish embryo models could improve this rate, saving mammals, time and costs in the development of new drugs. To test this hypothesis, we compared 2amnbzl-d with two compounds with already established safety profile: carbamazepine and benznidazole, using an embryo Zebrafish platform based on acute toxicity, hepatotoxicity, neurotoxicity and cardiotoxicity assays (Pltf-AcHpNrCd). Results Tests were performed blindly, and the results demonstrated the presence of lethal and teratogenic effects (CL50%: 14.8 µM; EC50%: 8.6 µM), hepatotoxic in concentrations above 7.5 µM and neurotoxic in embryos exposed to 15 µM of 2amnbzl-d. Nevertheless, benznidazole exposition showed no toxicity and only the 100 µM of carbamazepine induced a bradycardia. Conclusions Results using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation

Potenciais usos do modelo animal Zebrafish Danio rerio em pesquisas na Medicina Veterinária

Zebrafish (Danio rerio) é um proeminente organismo utilizado como modelo para a avaliação da segurança e eficácia de novos compostos na saúde animal de maneira rápida e econômica. Considerando que, anualmente, mais de mil novas substâncias são introduzidas no mercado para o desenvolvimento de produtos como vacinas, medicamentos, aditivos alimentares e agroquímicos, o objetivo deste artigo é apresentar uma revisão do emprego do Zebrafish como modelo animal destinado a avaliação da eficácia e da biotoxidade de compostos em pesquisas em medicina veterinária. Diversos estudos confirmam que os perfis entre Zebrafish e mamíferos são surpreendentemente semelhantes, sendo que sua transparência, fertilização externa, pequeno porte e curto ciclo de vida permitem a avaliação direta in vivo e em tempo real dos (i) efeitos de compostos químicos no desenvolvimento animal, (II) eficácia de novas drogas no tratamento de doenças específicas, (iii) eficácia e segurança no desenvolvimento de vacinas contra doenças infecciosas, (iv) direcionamento de tratamento do câncer animal de forma direcionada e específica. Desta forma, a praticidade e eficiência deste modelo animal nas pesquisas pode acelerar o processo de desenvolvimento de novos compostos veterinários quando comparado com pesquisas realizadas em outros modelos animais, e com maior valor preditivo e informativo que pesquisas conduzidas com ensaios in vitro

Do type D personality and job demands-resources predict emotional exhaustion and work engagement? A 3-wave prospective study.

Objective Cross-sectional studies suggest that Type D personality is a risk factor for work-related exhaustion and engagement, but longitudinal evidence is lacking. The present 3-wave study examined its longitudinal effects, taking into account existing job demands and resources, exhaustion, engagement, and neuroticism. Methods Data were extracted from the LISS-panel, based on a random sample of the Dutch population. Hierarchical multiple regression analyses were conducted among respondents (N=2273) who were employed during the 7-month study. Respondents worked in sectors varying from healthcare to industry. Results In the longitudinal analyses Type D personality was not a significant predictor for exhaustion/engagement over and above existing exhaustion/engagement, neuroticism, job demands and resources, in contrast to cross-sectional analyses. Job demands and resources explained a trivial proportion of variance of exhaustion and engagement in longitudinal analyses. Using the two elements of Type D personality (negative affectivity and social inhibition) did not change main findings. Existing exhaustion and engagement were significant and dominant predictors. Conclusion We found no evidence to prove that Type D personality is relevant in the development of emotional exhaustion and engagement. Findings stress the necessity of longitudinal studies controlling for corresponding variables assessed earlier to prevent overestimations of effects

Measurement of the tt¯ charge asymmetry in events with highly Lorentz-boosted top quarks in pp collisions at s=13 TeV

The measurement of the charge asymmetry in top quark pair events with highly Lorentz-boosted top quarks decaying to a single lepton and jets is presented. The analysis is performed using proton-proton collisions at s=13TeV with the CMS detector at the LHC and corresponding to an integrated luminosity of 138 fb−1. The selection is optimized for top quarks produced with large Lorentz boosts, resulting in nonisolated leptons and overlapping jets. The top quark charge asymmetry is measured for events with a tt¯ invariant mass larger than 750 GeV and corrected for detector and acceptance effects using a binned maximum likelihood fit. The measured top quark charge asymmetry of (0.42−0.69+0.64)% is in good agreement with the standard model prediction at next-to-next-to-leading order in quantum chromodynamic perturbation theory with next-to-leading-order electroweak corrections. The result is also presented for two invariant mass ranges, 750–900 and >900GeV

Search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state in proton-proton collisions at s=13TeV

A search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state is presented. The analysis is based on proton-proton collision data recorded by the CMS detector in 2016–2018 at a centre-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 138fb−1. The search is sensitive to resonances with masses between 1.3 and 6TeV, decaying to bosons that are highly Lorentz-boosted such that each of the bosons forms a single large-radius jet. Machine learning techniques are employed to identify such jets. No significant excess over the estimated standard model background is observed. A maximum local significance of 3.6 standard deviations, corresponding to a global significance of 2.3 standard deviations, is observed at masses of 2.1 and 2.9 TeV. In a heavy vector triplet model, spin-1 Z′ and W′ resonances with masses below 4.8TeV are excluded at the 95% confidence level (CL). These limits are the most stringent to date. In a bulk graviton model, spin-2 gravitons and spin-0 radions with masses below 1.4 and 2.7TeV, respectively, are excluded at 95% CL. Production of heavy resonances through vector boson fusion is constrained with upper cross section limits at 95% CL as low as 0.1fb

Evidence for four-top quark production in proton-proton collisions at s=13TeV

The production of four top quarks (tt¯tt¯) is studied with LHC proton-proton collision data samples collected by the CMS experiment at a center-of-mass energy of 13 TeV, and corresponding to integrated luminosities of up to 138fb−1. Events that have no leptons (all-hadronic), one lepton, or two opposite-sign leptons (where lepton refers only to prompt electrons or prompt muons) are considered. This is the first tt¯tt¯ measurement that includes the all-hadronic final state. The observed significance of the tt¯tt¯ signal in these final states of 3.9 standard deviations (1.5 expected) provides evidence for tt¯tt¯ production, with a measured cross section of 36−11+12fb. Combined with earlier CMS results in other final states, the signal significance is 4.0 standard deviations (3.2 expected). The combination returns an observed cross section of 17±4(stat)±3(syst)fb, which is consistent with the standard model prediction

Measurement of the top quark mass using a profile likelihood approach with the lepton + jets final states in proton–proton collisions at s=13 TeV\sqrt{s}=13\,\text {Te}\hspace{-.08em}\text {V}

International audienceThe mass of the top quark is measured in 36.3$\,\text {fb}^{-1}$ of LHC proton–proton collision data collected with the CMS detector at $\sqrt{s}=13\,\text {Te}\hspace{-.08em}\text {V}$. The measurement uses a sample of top quark pair candidate events containing one isolated electron or muon and at least four jets in the final state. For each event, the mass is reconstructed from a kinematic fit of the decay products to a top quark pair hypothesis. A profile likelihood method is applied using up to four observables per event to extract the top quark mass. The top quark mass is measured to be $171.77\pm 0.37\,\text {Ge}\hspace{-.08em}\text {V}$. This approach significantly improves the precision over previous measurements