Part I, Unified Pharmacophore Protein Models of the Benzodiazepine Receptor Subtypes ; Part II, Subtype

Part I. New models of unified pharmacophore/receptors have been constructed guided by the synthesis of subtype selective compounds in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with comparative models of the α1β2γ2, α2β2γ2, α3β2γ2 and α5β2γ2 GABA(A) receptors has led to an orientation of the pharmacophore model within the benzodiazepine binding site (Bz BS). These results not only are important for the rational design of new selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket. More importantly, the process summarized here may be used as a general template to help scientists develop novel ligands for receptors for which the three dimensional structure has not yet been confirmed by X-ray crystallography or cryo-electron microscopy. Presented here are new models of the α1β2γ2, α2β2γ2, α3β2γ2 and α5β2γ2 GABA(A) receptors which have incorporated homology models built based on the acetylcholine binding protein. These new models will further our ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists to the Bz BS of the GABA(A) receptor. This approach will also serve as a powerful model for structure based approaches carried out using ligand-protein docking methods. Part II. An effective strategy to alleviate memory deficits would be to enhance memory and cognitive processes by augmenting the impact of acetylcholine released from cholinergic neurons of the hippocampus. Using the included volume pharmacophore presented in Part I, a number of a5 selective compounds were synthesized, notably PWZ-029. PWZ-029 was examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests which are indicative of the effects on memory acquisition, locomotor activity, anxiety, and muscle tone. Improvement of task learning was shown at a dose of 5mg/kg in passive avoidance test without effect on anxiety or muscle tone. Moderate negative modulation at GABA(A) receptors containing the α5 subunit using a moderate inverse agonist such as PWZ-029, is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory. Using low temperature NMR and X-ray analysis, it was shown that enhanced selectivity and potent in vitro affinity of α5 selective benzodiazepine dimers was possible with aliphatic linkers of 3 to 5 carbons in length. Although originally proposed to enhance solubility, oxygen-containing linkers caused the dimer to fold back on itself leading to the inability of dimers to enter the binding pocket. In addition, studies of a series of PWZ-029 analogs found that the electrostatic potential near the ligands\u27 terminal substituent correlated with its binding selectivity toward the α5β2γ2 versus α1β2γ2 Bzr/GABA(A) ergic isoform. Investigations further found that compound PWZ-029, which exhibits reasonable binding selectivity toward GABA(A) receptors containing the a5 subunit and possesses a favorable electrophysiological profile, was able to attenuate scopolamine induced contextual memory impairment in mice. This compound appears to be useful (Harris, Delorey et al.) for the treatment of cognitive deficits in rodents as well as primates (Rowlett et al.) and may well be a compound for the treatment of patients with Alzheimers disease

Substituição do grão de milho pelo grão de milheto em dietas contendo silagem de milho ou silagem de capim-elefante na alimentação de bovinos de corte Replacement of corn grain by pearl millet grain in diets containing corn or elephant grass silage fed beef cattle

O objetivo neste trabalho foi avaliar os efeitos da substituição do grão de milho pelo grão de milheto em dietas contendo silagem de milho ou de capim-elefante sobre o consumo, a digestibilidade aparente dos nutrientes e os parâmetros ruminais de bovinos de corte. Seis novilhos da raça Nelore, providos de cânula ruminal, foram distribuídos em quadrado latino 6 x 6, em arranjo fatorial 2 x 3, com duas fontes de volumoso (silagem de milho ou silagem de capim-elefante) e três níveis de substituição do grão de milho pelo grão de milheto (0, 50 ou 100%). A substituição do grão de milho pelo grão de milheto e as fontes de volumoso não influenciaram o consumo de nutrientes. Entretanto, a utilização da silagem de capim-elefante aumentou o consumo de fibra em detergente ácido e reduziu o consumo de amido em comparação às dietas contendo silagem de milho. Não houve efeito da substituição do grão de milho pelo grão de milheto sobre a digestibilidade de matéria seca, matéria orgânica, proteína bruta, fibra em detergente neutro e fibra em detergente ácido. Contudo, houve aumento da digestibilidade do extrato etéreo, e os maiores valores foram observados para as dietas contendo 50 e 100% de grão de milheto em relação às dietas contendo 100% de grão de milho, independentemente da fonte de volumoso. A digestibilidade do amido também aumentou com a substituição do grão de milho pelo grão de milheto. A fonte de volumoso influenciou a digestibilidade da fibra em detergente neutro e da fibra em detergente ácido, que aumentou com a utilização da silagem de capim-elefante. A substituição do grão de milho pelo grão de milheto na dieta reduz a concentração ruminal de amônia sem alterar a concentração de acetato, propionato, ácidos graxos voláteis totais e o pH ruminal. A utilização de silagem de capim-elefante aumenta a concentração ruminal de acetato e a relação acetato:propionato.<br>The objective of this experiment was to evaluate the effects of replacing corn grain by pearl millet grain in diets containing corn silage or elephant grass silage on feed intake, apparent digestibility of nutrients and ruminal parameters of beef cattle. Six cannulated Nellore steers were distributed in a 6 x 6 Latin square, in a 2 x 3 factorial scheme, with two sources of roughages (corn silage or elephant grass silage) and three levels of replacement of corn grain by pearl millet grain (0, 50 or 100%). Replacement of corn grain by pearl millet grain and the roughage sources did not affect nutrient intake. However, the use of elephant grass silage increased acid detergent fiber and decreased starch intake when compared to diets containing corn silage. There was no effect of replacement of corn grain by pearl millet grain on digestibilities of dry matter, organic matter, crude protein, neutral detergent fiber and acid detergent fiber. However, there was an increase of digestibility of ether extract and the highest values were observed for diets containing 50 and 100% of pearl millet grain in relation to diets containg 100% corn grain, regardless to roughage source. Digestibility of starch was also increased by the replacement of corn grain by pearl millet grain. Roughage source also had an effect on neutral and acid detergent fiber digestibilities, which increased with the use of elephant grass silage. Replacement of corn grain by pearl millet grain in the diet decreases ruminal ammonia concentration without changing concentrations of ruminal acetate, propionate, total volatile fatty acids and ruminal pH. The use of elephant grass silage increases ruminal acetate concentration and acetate:propionate ratio

Search for a high-mass dimuon resonance produced in association with b quark jets at s\sqrt{s}=13 TeV

International audienceA search for high-mass dimuon resonance production in association with one or more b quark jets is presented. The study uses proton-proton collision data collected with the CMS detector at the LHC corresponding to an integrated luminosity of 138 fb$^{-1}$ at a center-of-mass energy of 13 TeV. Model-independent limits are derived on the number of signal events with exactly one or more than one b quark jet. Results are also interpreted in a lepton-flavor-universal model with Z$'$ boson couplings to a bb quark pair ($g_\mathrm{b}$), an sb quark pair ($g_\mathrm{b}\delta_\mathrm{bs}$), and any same-flavor charged lepton ($g_\ell$) or neutrino pair ($g_\nu$), with $\left|g_{\nu}\right|=\left|g_\ell\right|$. For a Z$'$ boson with a mass $m_{\mathrm{Z}'}$ = 350 GeV (2 TeV) and $\left|\delta_\mathrm{bs}\right| \lt$ 0.25, the majority of the parameter space with 0.0057 $\lt \left|g_\ell\right| \lt$ 0.35 (0.25 $\lt \left|g_\ell\right| \lt$ 0.43) and 0.0079 $\lt \left|g_\mathrm{b}\right| \lt$ 0.46 (0.34 $\lt \left|g_\mathrm{b}\right| \lt$ 0.57) is excluded at 95% confidence level. Finally, constraints are set on a Z$'$ model with parameters consistent with low-energy b $\to$ s$\ell\ell$ measurements. In this scenario, most of the allowed parameter space is excluded for a Z$'$ boson with 350 $\lt m_{\mathrm{Z}'}\lt$ 500 GeV, while the constraints are less stringent for higher $m_{\mathrm{Z}'}$ hypotheses. This is the first dedicated search at the LHC for a high-mass dimuon resonance produced in association with multiple b quark jets, and the constraints obtained on models with this signature are the most stringent to date

First measurement of the top quark pair production cross section in proton-proton collisions at s \sqrt{s} = 13.6 TeV

The first measurement of the top quark pair ($\textrm{t}\overline{\textrm{t}}$) production cross section in proton-proton collisions at $\sqrt{s}$ = 13.6 TeV is presented. Data recorded with the CMS detector at the CERN LHC in Summer 2022, corresponding to an integrated luminosity of 1.21 fb$^{−1}$, are analyzed. Events are selected with one or two charged leptons (electrons or muons) and additional jets. A maximum likelihood fit is performed in event categories defined by the number and flavors of the leptons, the number of jets, and the number of jets identified as originating from b quarks. An inclusive $\textrm{t}\overline{\textrm{t}}$ production cross section of 881 ± 23 (stat + syst) ± 20 (lumi) pb is measured, in agreement with the standard model prediction of ${924}_{-40}^{+32}$ pb.[graphic not available: see fulltext

Measurements of inclusive and differential cross sections for the Higgs boson production and decay to four-leptons in proton-proton collisions at s \sqrt{s} = 13 TeV

Measurements of the inclusive and differential fiducial cross sections for the Higgs boson production in the H → ZZ → 4ℓ (ℓ = e, μ) decay channel are presented. The results are obtained from the analysis of proton-proton collision data recorded by the CMS experiment at the CERN LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb$^{−1}$. The measured inclusive fiducial cross section is 2.73 ± 0.26 fb, in agreement with the standard model expectation of 2.86 ± 0.1 fb. Differential cross sections are measured as a function of several kinematic observables sensitive to the Higgs boson production and decay to four leptons. A set of double-differential measurements is also performed, yielding a comprehensive characterization of the four leptons final state. Constraints on the Higgs boson trilinear coupling and on the bottom and charm quark coupling modifiers are derived from its transverse momentum distribution. All results are consistent with theoretical predictions from the standard model

Search for new physics in multijet events with at least one photon and large missing transverse momentum in proton-proton collisions at 13 TeV

International audienceA search for new physics in final states consisting of at least one photon, multiple jets, and large missing transverse momentum is presented, using proton-proton collision events at a center-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 137 fb$^{-1}$, recorded by the CMS experiment at the CERN LHC from 2016 to 2018. The events are divided into mutually exclusive bins characterized by the missing transverse momentum, the number of jets, the number of b-tagged jets, and jets consistent with the presence of hadronically decaying W, Z, or Higgs bosons. The observed data are found to be consistent with the prediction from standard model processes. The results are interpreted in the context of simplified models of pair production of supersymmetric particles via strong and electroweak interactions. Depending on the details of the signal models, gluinos and squarks of masses up to 2.35 and 1.43 TeV, respectively, and electroweakinos of masses up to 1.23 TeV are excluded at 95% confidence level

Luminosity determination using Z boson production at the CMS experiment

International audienceThe measurement of Z boson production is presented as a method to determine the integrated luminosity of CMS data sets. The analysis uses proton-proton collision data, recorded by the CMS experiment at the CERN LHC in 2017 at a center-of-mass energy of 13 TeV. Events with Z bosons decaying into a pair of muons are selected. The total number of Z bosons produced in a fiducial volume is determined, together with the identification efficiencies and correlations from the same dataset, in small intervals of 2 pb$^{-1}$ of integrated luminosity, thus facilitating the efficiency and rate measurement as a function of time and instantaneous luminosity. Using the ratio of the efficiency-corrected numbers of Z bosons, the precisely measured integrated luminosity of one data set is used to determine the luminosity of another. For the first time, a full quantitative uncertainty analysis of the use of Z bosons for the integrated luminosity measurement is performed. The uncertainty in the extrapolation between two data sets, recorded in 2017 at low and high instantaneous luminosity, is less than 0.5%. We show that the Z boson rate measurement constitutes a precise method, complementary to traditional methods, with the potential to improve the measurement of the integrated luminosity

Measurement of the double-differential inclusive jet cross section in proton-proton collisions at s\sqrt{s} = 5.02 TeV

International audienceThe inclusive jet cross section is measured as a function of jet transverse momentum $p_\mathrm{T}$ and rapidity $y$. The measurement is performed using proton-proton collision data at $\sqrt{s}$ = 5.02 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 27.4 pb$^{-1}$. The jets are reconstructed with the anti-$k_\mathrm{T}$ algorithm using a distance parameter of $R$ = 0.4, within the rapidity interval $\lvert y\rvert$$\lt$ 2, and across the kinematic range 0.06 $\lt$$p_\mathrm{T}$$\lt$ 1 TeV. The jet cross section is unfolded from detector to particle level using the determined jet response and resolution. The results are compared to predictions of perturbative quantum chromodynamics, calculated at both next-to-leading order and next-to-next-to-leading order. The predictions are corrected for nonperturbative effects, and presented for a variety of parton distribution functions and choices of the renormalization/factorization scales and the strong coupling $\alpha_\mathrm{S}$