A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-11-14T13:03:57Z No. of bitstreams: 1 Palma, L. C. A docking....pdf: 2316481 bytes, checksum: 4b22ab5fe091a63eb03467552d28b571 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-11-14T13:31:09Z (GMT) No. of bitstreams: 1 Palma, L. C. A docking....pdf: 2316481 bytes, checksum: 4b22ab5fe091a63eb03467552d28b571 (MD5)Made available in DSpace on 2019-11-14T13:31:09Z (GMT). No. of bitstreams: 1 Palma, L. C. A docking....pdf: 2316481 bytes, checksum: 4b22ab5fe091a63eb03467552d28b571 (MD5) Previous issue date: 2019-01-14Conselho Nacional de Pesquisa e Desenvolvimento Científico (P.S.T.V. – Universal 422867/2016-0 http://www.cnpq.br) and Fundação de Amparo a Ciência e Tecnologia do Estado de Pernambuco (LFGRF – BFP-0063-4.03/17). P.S.T.V. holds a grant from CNPq for productivity in research (307832/2015-5).Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Parasita Interação e Epidemiologia do Hospedeiro. Salvador, BA, Brasil.Federal University of Pernambuco. Department of Pharmaceutical Sciences. Recife, PE, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Parasita Interação e Epidemiologia do Hospedeiro. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Parasita Interação e Epidemiologia do Hospedeiro. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Parasita Interação e Epidemiologia do Hospedeiro. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Engenharia de Tecidos e Imunofarmacologia. Salvador, BA, Brasil.Federal University of Pernambuco. Department of Pharmaceutical Sciences. Recife, PE, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Parasita Interação e Epidemiologia do Hospedeiro. Salvador, BA, Brasil.Leishmaniasis is a neglected disease that affects millions of individuals around the world. Regardless of clinical form, treatment is based primarily on the use of pentavalent antimonials. However, such treatments are prolonged and present intense side effects, which lead to patient abandonment in many cases. The search for chemotherapeutic alternatives has become a priority. Heat Shock Protein 90 (Hsp90) inhibitors have recently come under investigation due to antiparasitic activity in Plasmodium sp., Trypanosoma sp. and Leishmania sp. Some of these inhibitors, such as geldanamycin and its analogs, 17-AAG and 17-DMAG, bind directly to Hsp90, thereby inhibiting its activity. Previous studies have demonstrated that different parasite species are more susceptible to some of these inhibitors than host cells. We hypothesized that this increased susceptibility may be due to differences in binding of Hsp90 inhibitors to Leishmania protein compared to host protein. Based on the results of the in silico approach used in the present study, we propose that geldanamycin, 17-AAG and 17-DMAG present an increased tendency to bind to the N-terminal domain of Leishmania amazonensis Hsp83 in comparison to human Hsp90. This could be partially explained by differences in intermolecular interactions between each of these inhibitors and Hsp83 or Hsp90. The present findings demonstrate potential for the use of these inhibitors in the context of anti-Leishmania therapy

Monitoring the Establishment of VOC Gamma in Minas Gerais, Brazil: A Retrospective Epidemiological and Genomic Surveillance Study

Since its first identification in Brazil, the variant of concern (VOC) Gamma has been associated with increased infection and transmission rates, hospitalizations, and deaths. Minas Gerais (MG), the second-largest populated Brazilian state with more than 20 million inhabitants, observed a peak of cases and deaths in March–April 2021. We conducted a surveillance study in 1240 COVID-19-positive samples from 305 municipalities distributed across MG’s 28 Regional Health Units (RHU) between 1 March to 27 April 2021. The most common variant was the VOC Gamma (71.2%), followed by the variant of interest (VOI) zeta (12.4%) and VOC alpha (9.6%). Although the predominance of Gamma was found in most of the RHUs, clusters of Zeta and Alpha variants were observed. One Alpha-clustered RHU has a history of high human mobility from countries with Alpha predominance. Other less frequent lineages, such as P.4, P.5, and P.7, were also identified. With our genomic characterization approach, we estimated the introduction of Gamma on 7 January 2021, at RHU Belo Horizonte. Differences in mortality between the Zeta, Gamma and Alpha variants were not observed. We reinforce the importance of vaccination programs to prevent severe cases and deaths during transmission peaks

Elliptic anisotropy measurement of the f0_0(980) hadron in proton-lead collisions and evidence for its quark-antiquark composition

International audienceDespite the f$_0$(980) hadron having been discovered half a century ago, the question about its quark content has not been settled: it might be an ordinary quark-antiquark ($\mathrm{q\bar{q}}$) meson, a tetraquark ($\mathrm{q\bar{q}q\bar{q}}$) exotic state, a kaon-antikaon ($\mathrm{K\bar{K}}$) molecule, or a quark-antiquark-gluon ($\mathrm{q\bar{q}g}$) hybrid. This paper reports strong evidence that the f$_0$(980) state is an ordinary $\mathrm{q\bar{q}}$ meson, inferred from the scaling of elliptic anisotropies ($v_2$) with the number of constituent quarks ($n_\mathrm{q}$), as empirically established using conventional hadrons in relativistic heavy ion collisions. The f$_0$(980) state is reconstructed via its dominant decay channel f$_0$(980) $\to$$\pi^+\pi^-$, in proton-lead collisions recorded by the CMS experiment at the LHC, and its $v_2$ is measured as a function of transverse momentum ($p_\mathrm{T}$). It is found that the $n_q$ = 2 ($\mathrm{q\bar{q}}$ state) hypothesis is favored over $n_q$ = 4 ($\mathrm{q\bar{q}q\bar{q}}$ or $\mathrm{K\bar{K}}$ states) by 7.7, 6.3, or 3.1 standard deviations in the $p_\mathrm{T}$$\lt$ 10, 8, or 6 GeV/$c$ ranges, respectively, and over $n_\mathrm{q}$ = 3 ($\mathrm{q\bar{q}g}$ hybrid state) by 3.5 standard deviations in the $p_\mathrm{T}$$\lt$ 8 GeV/$c$ range. This result represents the first determination of the quark content of the f$_0$(980) state, made possible by using a novel approach, and paves the way for similar studies of other exotic hadron candidates

Extracting the speed of sound in the strongly interacting matter created in ultrarelativistic lead-lead collisions at the LHC

International audienceUltrarelativistic nuclear collisions create a strongly interacting state of hot and dense quark-gluon matter that exhibits a remarkable collective flow behavior with minimal viscous dissipation. To gain deeper insights into its intrinsic nature and fundamental degrees of freedom, we extracted the speed of sound in this medium created using lead-lead (PbPb) collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data were recorded by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 0.607 nb$^{-1}$. The measurement is performed by studying the multiplicity dependence of the average transverse momentum of charged particles emitted in head-on PbPb collisions. Our findings reveal that the speed of sound in this matter is nearly half the speed of light, with a squared value of 0.241 $\pm$ 0.002 (stat) $\pm$ 0.016 (syst) in natural units. The effective medium temperature, estimated using the mean transverse momentum, is 219 $\pm$ 8 (syst) MeV. The measured squared speed of sound at this temperature aligns precisely with predictions from lattice quantum chromodynamic (QCD) calculations. This result provides a stringent constraint on the equation of state of the created medium and direct evidence for a deconfined QCD phase being attained in relativistic nuclear collisions

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Measurement of multijet azimuthal correlations and determination of the strong coupling in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA measurement is presented of a ratio observable that provides a measure of the azimuthal correlations among jets with large transverse momentum $p_\mathrm{T}$. This observable is measured in multijet events over the range of $p_\mathrm{T}$ = 360-3170 GeV based on data collected by the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 134 fb$^{-1}$. The results are compared with predictions from Monte Carlo parton-shower event generator simulations, as well as with fixed-order perturbative quantum chromodynamics (pQCD) predictions at next-to-leading-order (NLO) accuracy obtained with different parton distribution functions (PDFs) and corrected for nonperturbative and electroweak effects. Data and theory agree within uncertainties. From the comparison of the measured observable with the pQCD prediction obtained with the NNPDF3.1 NLO PDFs, the strong coupling at the Z boson mass scale is $\alpha_\mathrm{S}(m_\mathrm{Z})$ = 0.1177 $\pm$ 0.0013 (exp) $_{-0.0073}^{+0.0116}$ (theo) = 0.1177$_{-0.0074}^{+0.0117}$, where the total uncertainty is dominated by the scale dependence of the fixed-order predictions. A test of the running of $\alpha_\mathrm{S}(m_\mathrm{Z})$ in the TeV region shows no deviation from the expected NLO pQCD behaviour

Performance of CMS muon reconstruction from proton-proton to heavy ion collisions

International audienceThe performance of muon tracking, identification, triggering, momentum resolution, and momentum scale has been studied with the CMS detector at the LHC using data collected at $\sqrt{s_\mathrm{NN}}$ = 5.02 TeV in proton-proton (pp) and lead-lead (PbPb) collisions in 2017 and 2018, respectively, and at $\sqrt{s_\mathrm{NN}}$ = 8.16 TeV in proton-lead (pPb) collisions in 2016. Muon efficiencies, momentum resolutions, and momentum scales are compared by focusing on how the muon reconstruction performance varies from relatively small occupancy pp collisions to the larger occupancies of pPb collisions and, finally, to the highest track multiplicity PbPb collisions. We find the efficiencies of muon tracking, identification, and triggering to be above 90% throughout most of the track multiplicity range. The momentum resolution and scale are unaffected by the detector occupancy. The excellent muon reconstruction of the CMS detector enables precision studies across all available collision systems

Test of lepton flavor universality in B± ⁣→ ⁣K±μ+μ− {\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-} and B± ⁣→ ⁣K±e+e− {\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^- decays in proton-proton collisions at s= \sqrt{s} = 13 TeV

A test of lepton flavor universality in ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}$ and ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^-$ decays, as well as a measurement of differential and integrated branching fractions of a nonresonant ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}$ decay are presented. The analysis is made possible by a dedicated data set of proton-proton collisions at $\sqrt{s} =$ 13 TeV recorded in 2018, by the CMS experiment at the LHC, using a special high-rate data stream designed for collecting about 10 billion unbiased b hadron decays. The ratio of the branching fractions $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-})$ to $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^-)$ is determined from the measured double ratio $R(\mathrm{K})$ of these decays to the respective branching fractions of the ${\mathrm{B}^{\pm}} \!\to\! {\mathrm{J}/\psi} \mathrm{K^{\pm}}$ with ${\mathrm{J}/\psi} \!\to\!\mu^{+}\mu^{-}$ and $\mathrm{e}^+\mathrm{e}^-$ decays, which allow for significant cancellation of systematic uncertainties. The ratio $R(\mathrm{K})$ is measured in the range 1.1 $< q^2 <$ 6.0 GeV$^2$, where $q$ is the invariant mass of the lepton pair, and is found to be $R(\mathrm{K})=$ 0.78 $^{+0.47}_{-0.23}$, in agreement with the standard model expectation $R(\mathrm{K}) \approx$ 1. This measurement is limited by the statistical precision of the electron channel. The integrated branching fraction in the same $q^2$ range, $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}) =$ (12.42 $\pm$ 0.68) $\times$ 10$^{-8}$, is consistent with the present world-average value and has a comparable precision.A test of lepton flavor universality in B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$ and B$^{\pm}$$\to$ K$^{\pm}$e$^+$e$^-$ decays, as well as a measurement of differential and integrated branching fractions of a nonresonant B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$ decay are presented. The analysis is made possible by a dedicated data set of proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded in 2018, by the CMS experiment at the LHC, using a special high-rate data stream designed for collecting about 10 billion unbiased b hadron decays. The ratio of the branching fractions $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$) to $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}$e$^+$e$^-$) is determined from the measured double ratio $R$(K) of these decays to the respective branching fractions of the B$^\pm$$\to$ J/$\psi$K$^\pm$ with J/$\psi$$\to$$\mu^+\mu^-$ and e$^+$e$^-$ decays, which allow for significant cancellation of systematic uncertainties. The ratio $R$(K) is measured in the range 1.1 $\lt q^2 \lt$ 6.0 GeV$^2$, where $q$ is the invariant mass of the lepton pair, and is found to be $R$(K) = 0.78$^{+0.47}_{-0.23}$, in agreement with the standard model expectation $R$(K) $\approx$ 1. This measurement is limited by the statistical precision of the electron channel. The integrated branching fraction in the same $q^2$ range, $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$) = (12.42 $\pm$ 0.68) $\times$ 10$^{-8}$, is consistent with the present world-average value and has a comparable precision

The CMS Statistical Analysis and Combination Tool: COMBINE

International audienceThis paper describes the COMBINE software package used for statistical analyses by the CMS Collaboration. The package, originally designed to perform searches for a Higgs boson and the combined analysis of those searches, has evolved to become the statistical analysis tool presently used in the majority of measurements and searches performed by the CMS Collaboration. It is not specific to the CMS experiment, and this paper is intended to serve as a reference for users outside of the CMS Collaboration, providing an outline of the most salient features and capabilities. Readers are provided with the possibility to run COMBINE and reproduce examples provided in this paper using a publicly available container image. Since the package is constantly evolving to meet the demands of ever-increasing data sets and analysis sophistication, this paper cannot cover all details of COMBINE. However, the online documentation referenced within this paper provides an up-to-date and complete user guide