Discovery of benzamides and triarylimidazoles active against Plasmodium falciparum via haemozoin inhibition : high throughput screening, synthesis and structure-activity relationships

Includes bibliographical referencesNew antimalarials are desperately needed to overcome growing P. falciparum resistance to the current drugs. Successful quinoline-based drugs target haemozoin formation causing a cytotoxic accumulation of free haem (Fe(III)PPIX) in the parasite, a target which remains promising for future treatments. Much research has been undertaken on the quinoline antimalarials, which has led to several hypotheses of haemozoin inhibition and drug accumulation mechanisms, however, relatively few studies have been carried out for haemozoin antimalarials with alternate chemotypes. High throughput screening (HTS) can be used to identify novel scaffolds that inhibit β-haematin (βH - synthetic haemozoin) formation and which have favourable P. falciparum activities. In this project, HTS has been carried out on 43,520 small, organic, drug-like compounds as part of a larger screen of 144,330 Vanderbilt University Institute of Chemical Biology (VU) chemical library compounds and 530 were found to be good inhibitors of βH relative to the chloroquine (CQ) and amodiaquine (AQ) controls. A further 171 compounds were found to inhibit parasite growth, showing improved hit rates from previous HTS efforts. Two scaffolds (A=benzamides and B=triarylimidazoles) were selected for further analysis, whereupon analogues were synthesised

Study of the radiative penguin B0s [to] [phi] [gamma] and B0s [to] [gamma] [gamma] decays and the resonant B+ [to] K+ [gamma] [gamma] decays at Belle

We present the study of the radiative penguin Bs0 → &#x03D5;γ and Bs0 → γγ decays and the resonant B+ → K+h → K+γγ decays. We use data samples recorded at the Υ(4S) and Υ(5S) resonances with the Belle detector at KEKB, an electron-positron collider located in Tsukuba, Japan. The Υ(4S) sample corresponds to an integrated luminosity of 492 fb-1 and contains 535 million BB pairs. At the Υ(5S) resonance, we use a sample of 23.6 fb-1 containing 2.8 million Bs0 mesons. Penguin decays are loop-induced diagrams involving the heaviest particles of the Standard Model, the model describing, successfully so far, all particles and interactions, except the gravitation. Penguin decays are sensitive to physics beyond the Standard Model: particles foreseen by theories extending the Standard Model, whatever their masses are, can enter the loop and modify physics observables away from their Standard Model expectations. We report the first observation of a radiative penguin decay of the Bs0 meson in the Bs0 → &#x03D5;γ mode with a significance of 5.5 standard deviations. We measure Β(Bs0 → &#x03D5;γ) = (57 -15+18 (stat)  -11+12 (syst)) × 10-6 in agreement with the expectation of the Standard Model. We do not observe any significant Bs0 → γγ signal and we compute an upper limit at the 90% confidence level on its branching fraction of Β(Bs0 → γγ) < 8.7 × 10-6. This limit is about six times more stringent than the previously published one. However, it is still about one order of magnitude larger than the expectation of the Standard Model and still above expectations of theories beyond the Standard Model. For the resonant B+ → K+h → K+γγ decays, we search for decays where the h particle can be a η, η', ηc, ηc(2S), χc0, χc2 or a J/ψ meson, or the X(3872) particle discovered in 2003 by the Belle collaboration. We observe the modes with h = η and η'. We obtain an evidence of the mode with h = ηc; this is the first time that a B+ → K+ηc signal is seen in the K+ γγ final state. We measure Β(B+ → K+η → K+γγ) = (0.87 -0.15+0.16 (stat)  -0.07+0.10 (syst)) × 10-6, Β(B+ → K+η' → K+γγ) = (1.40 -0.15+0.16 (stat)  -0.12+0.15 (syst)) × 10-6, Β(B+ → K+ηc → K+γγ) = (0.22 -0.07+0.09 (stat)  -0.02+0.04 (syst)) × 10-6, with significances of 7.3, 13.8 and 4.1, respectively. For the other modes, we obtain limits on their branching fractions. We also measure or set limits on the branching fractions of the h → γγ decays for the modes where Β(B+ → K+h) has been measured elsewhere. We set for the first time an upper limit at the 90% confidence level on the branching fraction of the decay of the X(3872) particle into two photons of Β(X(3872) → γγ) < 1.1%

Les organisations publiques dans la concurrence : Compte-rendu de la 6ème Journée de la Gouvernance des Entreprises Publiques, le 4 avril 2019

Alors que certains marchés étaient entre les mains exclusives de monopoles publics, une vague de libéralisation et d’ouverture des marchés a pris forme dans de nombreux pays dès le milieu des années 1990. En Suisse, divers marchés ont ainsi été ouverts largement à la concurrence, en particulier les marchés des télécommunications (1997) et des colis (2004), tandis que d’autres marchés ont été ouverts partiellement à l’instar du courrier postal (2006) et de l’électricité (2009). Dans un même temps, alors qu’elles se retrouvaient désormais concurrencées dans leur secteur historique de monopole, certaines entreprises publiques ont étendu leurs activités vers des secteurs traditionnellement concurrentiels. Cette porosité croissante entre des marchés et des statuts historiquement distincts n’est pas sans soulever d’importantes questions quant à leur régulation et leur gouvernance. La Suisse est-elle dotée d’un cadre légal approprié pour encadrer et réguler les entreprises publiques soumises aux pressions sans cesse croissantes du marché et à un environnement de plus en plus complexe ? Quelles réformes faut-il attendre dans la structure de gouvernance interne des entreprises publiques faisant face désormais à la pression concurrentielle ? Comment ces marchés vont-ils continuer à évoluer et quelles adaptations – du cadre de la régulation, comme de la gouvernance des entreprises publiques, voire du service universel – s’imposent pour le futur ? Autant de questions qui sont au cœur des réflexions menées par les différent.e.s intervenant.e.s de cette journée

Measurements of prompt charm production cross-sections in pp collisions at s=5 TeV

Production cross-sections of prompt charm mesons are measured using data from pp collisions at the LHC at a centre-of-mass energy of 5 TeV. The data sample corresponds to an integrated luminosity of 8.60 ± 0.33 pb−1 collected by the LHCb experiment. The production cross-sections of D0, D+, Ds+, and D∗+ mesons are measured in bins of charm meson transverse momentum, pT, and rapidity, y. They cover the rapidity range 2.0 < y < 4.5 and transverse momentum ranges 0 < pT< 10 GeV/c for D0 and D+ and 1 < pT< 10 GeV/c for Ds+ and D∗+ mesons. The inclusive cross-sections for the four mesons, including charge-conjugate states, within the range of 1 < pT< 8 GeV/c are determined to be σpp→D0X=1004±3±54μb,σpp→D+X=402±2±30μb,σpp→Ds+X=170±4±16μb,σpp→D∗+X=421±5±36μb, where the uncertainties are statistical and systematic, respectively

Measurement of the properties of the Ξb∗ 0 baryon

We perform a search for near-threshold Ξb0 resonances decaying to Ξb−π+ in a sample of proton-proton collision data corresponding to an integrated luminosity of 3 fb−1 collected by the LHCb experiment. We observe one resonant state, with the following properties: mΞb∗0−mΞb−−mπ+=15.727±0.068stat±0.023systMeV/c2ΓΞb∗0=0.90±0.16stat±0.08systMeV.This confirms the previous observation by the CMS collaboration. The state is consistent with the JP = 3/2+ Ξb∗ 0 resonance expected in the quark model. This is the most precise determination of the mass and the first measurement of the natural width of this state. We have also measured the ratio σpp→Ξb∗0XℬΞb∗0→Ξb−π+σpp→Ξb−X=0.28±0.03stat.±0.01syst.

Observation of Λb0 → ψ(2S)pK− and Λb0 → J/ψπ+π−pK− decays and a measurement of the Λb0 baryon mass

The decays Λb0 → ψ(2S)pK− and Λb0 → J/ψπ+π−pK− are observed in a data sample corresponding to an integrated luminosity of 3 fb−1, collected in proton-proton collisions at 7 and 8 TeV centre-of-mass energies by the LHCb detector. The ψ(2S) mesons are reconstructed through the decay modes ψ(2S) → μ+μ− and ψ(2S) → J/ψπ+π−.The branching fractions relative to that of Λb0 → J/ψpK− are measured to be ℬΛb0→ψ2SpK−ℬΛb0→J/ψpK−=20.70±0.76±0.46±0.37×10−2, where the first uncertainties are statistical, the second are systematic and the third is related to the knowledge of J/ψ and ψ(2S) branching fractions. The mass of the Λb0 baryon is measured to be MΛb0=5619.65±0.17±0.17MeV/c2, where the uncertainties are statistical and systematic

Measurement of the B± production cross-section in pp collisions at s=7 and 13 TeV

The production of B± mesons is studied in pp collisions at centre-of-mass energies of 7 and 13 TeV, using B± → J/ψ K± decays and data samples corresponding to 1.0 fb−1 and 0.3 fb−1, respectively. The production cross-sections summed over both charges and integrated over the transverse momentum range 0 < pT < 40 GeV/c and the rapidity range 2.0 < y < 4.5 are measured to be σpp→B±X,s=7TeV=43.0±0.2±2.5±1.7μb, σpp→B±X,s=13TeV=86.6±0.5±5.4±3.4μb, where the first uncertainties are statistical, the second are systematic, and the third are due to the limited knowledge of the B± → J/ψ K± branching fraction. The ratio of the cross-section at 13 TeV to that at 7 TeV is determined to be 2.02 ± 0.02 (stat) ± 0.12 (syst). Differential cross-sections are also reported as functions of pT and y. All results are in agreement with theoretical calculations based on the state-of-art fixed next-to-leading order quantum chromodynamics