Molecular Dynamics Simulation of HIV Fusion Inhibitor T-1249: Insights on Peptide-Lipid Interaction

T-1249 is a peptide that inhibits the fusion of HIV envelope with the target cell membrane. Recent results indicate that T-1249, as in the case of related inhibitor peptide T-20 (enfuvirtide), interacts with membranes, more extensively in the bilayer liquid disordered phase than in the liquid ordered state, which could be linked to its effectiveness. Extensive molecular dynamics simulations (100 ns) were carried out to investigate the interaction between T-1249 and bilayers of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and POPC/cholesterol (1 : 1). It was observed that T-1249 interacts to different extents with both membrane systems and that peptide interaction with the bilayer surface has a local effect on membrane structure. Formation of hydrogen bonding between certain peptide residues and several acceptor and donor groups in the bilayer molecules was observed. T-1249 showed higher extent of interaction with bilayers when compared to T-20. This is most notable in POPC/Chol membranes, owing to more peptide residues acting as H bond donors and acceptors between the peptide and the bilayer lipids, including H-bonds formed with cholesterol. This behavior is at variance with that of T-20, which forms no H bonds with cholesterol. This higher ability to interact with membranes is probably correlated with its higher inhibitory efficiency

Avaliação de propriedades estruturais de membranas lipídicas após substituição do colesterol por análogos fluorescentes

A espectroscopia e a microscopia de fluorescência têm sido usadas em biofísica de membranas há décadas. Como a unidade estrutural básica das membranas biológicas é a bicamada de lípidos e estes não fluorescem, o uso de sondas extrínsecas de membrana é uma necessidade. Contudo, duas questões preocupantes se levantam quanto ao uso de sondas extrínsecas de fluorescência em estudos de membranas. Em primeiro lugar, o comportamento das moléculas de sonda na bicamada (que região da bicamada elas reportam, as suas dinâmicas translacional e rotacional) é frequentemente mal conhecido. Em segundo lugar, na interpretação de resultados de experiências de fluorescência, pode ser difícil distinguir entre propriedades legítimas da membrana e efeitos de perturbação resultantes da incorporação da sonda. Para este efeito, as simulações por dinâmica molecular (MD), ao providenciarem informação detalhada à escala atómica, representam um meio valioso para caracterizar a localização e dinâmica de sondas na bicamada, assim como a magnitude de perturbação que elas induzem na estrutura lipídica [1]. Neste contexto, optimizaram-se, com recurso ao programa Firefly, as estruturas do colesterol e de dois análogos fluorescentes (desidroergoesterol e colestatrienol) ao nível de teoria DFT/R-B3LYP/6-31G(d) e submeteram-se em seguida ao servidor de topologias ATB, inscrevendo simultaneamente as cargas parciais calculadas na topologia molecular. Estas topologias foram utilizadas na construção de modelos de membranas lipídicas constituídas por POPC, colesterol e uma das sondas fluorescentes acima identificadas. Os modelos assim obtidos foram hidratados e sujeitos a simulações de MD, donde se calculou a área por lípido, a espessura e densidade da bicamada, os coeficientes de difusão lateral para as espécies presentes e os parâmetros de ordem das cadeias acilo. As simulações foram efectuadas em ensemble NPT através do pacote de software GROMACS. Análises preliminares permitiram a comparação dos comportamentos na bicamada dos esteróis fluorescentes com o do colesterol, informação vital para validar o uso dos primeiros como análogos fluorescentes do segundo. REFERÊNCIAS [1] Loura, L.M.S.; Prates Ramalho, J.P. Biophys. Rev. 1 (2009), 141

Search for Supersymmetry with Gauge-Mediated Breaking in Diphoton Events with Missing Transverse Energy at CDF II

accepted to Phys. Rev. LettWe present the results of a search for supersymmetry with gauge-mediated breaking and \NONE\to\gamma\Gravitino in the $\gamma\gamma$+missing transverse energy final state. In 2.6$\pm$0.2 \invfb of $p{\bar p}$ collisions at $\sqrt{s}$$=$1.96 TeV recorded by the CDF II detector we observe no candidate events, consistent with a standard model background expectation of 1.4$\pm$0.4 events. We set limits on the cross section at the 95% C.L. and place the world's best limit of 149\gevc on the \none mass at $\tau_{\tilde{\chi}_1^0}$$We present the results of a search for supersymmetry with gauge-mediated breaking and χ˜10→γG˜ in the γγ+missing transverse energy final state. In 2.6±0.2  fb-1 of pp̅ collisions at √s=1.96  TeV recorded by the CDF II detector we observe no candidate events, consistent with a standard model background expectation of 1.4±0.4 events. We set limits on the cross section at the 95% C.L. and place the world’s best limit of 149  GeV/c2 on the χ˜10 mass at τχ˜10≪1  ns. We also exclude regions in the χ˜10 mass-lifetime plane for τχ˜10≲2  ns.Peer reviewe

Measurements of branching fraction ratios and CP asymmetries in B+/- ->D_CP K+/- decays in hadron collisions

We reconstruct B+/- -> D K+/- decays in a data sample collected by the CDF II detector at the Tevatron collider corresponding to 1 fb-1 of integrated luminosity. We select decay modes where the D meson decays to either K- pi+ (flavor eigenstate) or K- K+, pi- pi+ (CP-even eigenstates), and measure the direct CP asymmetry A_CP+ = 0.39 +/- 0.17(stat) +/- 0.04(syst), and the double ratio of CP-even to flavor eigenstate branching fractions R_CP+ = 1.30 +/- 0.24(stat) +/- 0.12(syst). These measurements will improve the determination of the CKM angle gamma. They are performed here for the first time using data from hadron collisions.We reconstruct B±→DK± decays in a data sample collected by the CDF II detector at the Tevatron collider corresponding to 1  fb-1 of integrated luminosity. We select decay modes where the D meson decays to either K-π+ (flavor eigenstate) or K-K+, π-π+ (CP-even eigenstates), and measure the direct CP asymmetry ACP+=0.39±0.17(stat)±0.04(syst), and the double ratio of CP-even to flavor eigenstate branching fractions RCP+=1.30±0.24(stat)±0.12(syst). These measurements will improve the determination of the Cabibbo-Kobayashi-Maskawa angle γ. They are performed here for the first time using data from hadron collisions.Peer reviewe

Inclusive Search for Standard Model Higgs Boson Production in the WW Decay Channel using the CDF II Detector

We present a search for standard model (SM) Higgs boson production using ppbar collision data at sqrt(s) = 1.96 TeV, collected with the CDF II detector and corresponding to an integrated luminosity of 4.8 fb-1. We search for Higgs bosons produced in all processes with a significant production rate and decaying to two W bosons. We find no evidence for SM Higgs boson production and place upper limits at the 95% confidence level on the SM production cross section (sigma(H)) for values of the Higgs boson mass (m_H) in the range from 110 to 200 GeV. These limits are the most stringent for m_H > 130 GeV and are 1.29 above the predicted value of sigma(H) for mH = 165 GeV.We present a search for standard model (SM) Higgs boson production using pp̅ collision data at √s=1.96  TeV, collected with the CDF II detector and corresponding to an integrated luminosity of 4.8  fb-1. We search for Higgs bosons produced in all processes with a significant production rate and decaying to two W bosons. We find no evidence for SM Higgs boson production and place upper limits at the 95% confidence level on the SM production cross section (σH) for values of the Higgs boson mass (mH) in the range from 110 to 200 GeV. These limits are the most stringent for mH>130  GeV and are 1.29 above the predicted value of σH for mH=165  GeV.Peer reviewe

Measurement of the Lambda_b Lifetime in Lambda_b -> Lambda_c+ pi- Decays in p-pbar Collisions at sqrt(s) = 1.96 TeV

Submitted to Phys. Rev. LettWe report a measurement of the lifetime of the Lambda_b baryon in decays to the Lambda_C+ pi- final state in a sample corresponding to 1.1 fb^-1 collected in p-pbar collisions at sqrt(s) = 1.96 TeV by the CDF II detector at the Tevatron collider. Using a sample of about 3000 fully reconstructed Lambda_b events we measure tau(Lambda_b) = 1.401 +- 0.046 (stat) +- 0.035 (syst) ps (corresponding to c.tau(Lambda_b) = 420.1 +- 13.7 (stat) +- 10.6 (syst) um, where c is the speed of light). The ratio of this result and the world average B^0 lifetime yields tau(Lambda_b)/tau(B^0) = 0.918 +- 0.038 (stat and syst), in good agreement with recent theoretical predictions.We report a measurement of the lifetime of the Λb0 baryon in decays to the Λc+π- final state in a sample corresponding to 1.1  fb-1 collected in pp̅ collisions at √s=1.96  TeV by the CDF II detector at the Tevatron collider. Using a sample of about 3000 fully reconstructed Λb0 events we measure τ(Λb0)=1.401±0.046(stat)±0.035(syst)  ps (corresponding to cτ(Λb0)=420.1±13.7(stat)±10.6(syst)  μm, where c is the speed of light). The ratio of this result and the world average B0 lifetime yields τ(Λb0)/τ(B0)=0.918±0.038 (stat) and (syst), in good agreement with recent theoretical predictions.Peer reviewe

Measurement of the Top Quark Mass and ppbar -> ttbar Cross Section in the All-Hadronic Mode with the CDFII Detector

Submitted to Phys. Rev. DWe present a measurement of the top quark mass and of the top-antitop pair production cross section using p-pbar data collected with the CDFII detector at the Tevatron Collider at the Fermi National Accelerator Laboratory and corresponding to an integrated luminosity of 2.9 fb-1. We select events with six or more jets satisfying a number of kinematical requirements imposed by means of a neural network algorithm. At least one of these jets must originate from a b quark, as identified by the reconstruction of a secondary vertex inside the jet. The mass measurement is based on a likelihood fit incorporating reconstructed mass distributions representative of signal and background, where the absolute jet energy scale (JES) is measured simultaneously with the top quark mass. The measurement yields a value of 174.8 +- 2.4(stat+JES) ^{+1.2}_{-1.0}(syst) GeV/c^2, where the uncertainty from the absolute jet energy scale is evaluated together with the statistical uncertainty. The procedure measures also the amount of signal from which we derive a cross section, sigma_{ttbar} = 7.2 +- 0.5(stat) +- 1.0 (syst) +- 0.4 (lum) pb, for the measured values of top quark mass and JES.We present a measurement of the top quark mass and of the top-antitop (tt̅ ) pair production cross section using pp̅ data collected with the CDF II detector at the Tevatron Collider at the Fermi National Accelerator Laboratory and corresponding to an integrated luminosity of 2.9  fb-1. We select events with six or more jets satisfying a number of kinematical requirements imposed by means of a neural-network algorithm. At least one of these jets must originate from a b quark, as identified by the reconstruction of a secondary vertex inside the jet. The mass measurement is based on a likelihood fit incorporating reconstructed mass distributions representative of signal and background, where the absolute jet energy scale (JES) is measured simultaneously with the top quark mass. The measurement yields a value of 174.8±2.4(stat+JES)-1.0+1.2(syst)  GeV/c2, where the uncertainty from the absolute jet energy scale is evaluated together with the statistical uncertainty. The procedure also measures the amount of signal from which we derive a cross section, σtt̅ =7.2±0.5(stat)±1.0(syst)±0.4(lum)  pb, for the measured values of top quark mass and JES.Peer reviewe

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Measurement of ϒ production in pp collisions at √s = 2.76 TeV

The production of ϒ(1S), ϒ(2S) and ϒ(3S) mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 pb−1 collected in proton–proton collisions at a centre-of-mass energy of √s = 2.76 TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the ϒ transverse momentum and rapidity, over the ranges pT < 15 GeV/c and 2.0 < y < 4.5. The total cross-sections in this kinematic region, assuming unpolarised production, are measured to be σ (pp → ϒ(1S)X) × B ϒ(1S)→μ+μ− = 1.111 ± 0.043 ± 0.044 nb, σ (pp → ϒ(2S)X) × B ϒ(2S)→μ+μ− = 0.264 ± 0.023 ± 0.011 nb, σ (pp → ϒ(3S)X) × B ϒ(3S)→μ+μ− = 0.159 ± 0.020 ± 0.007 nb, where the first uncertainty is statistical and the second systematic

T-20 and T-1249 HIV fusion inhibitors' structure and conformation in solution: a molecular dynamics study

Fusion of the HIV envelope with the target cell membrane is a critical step of the HIV entry into the target cell. Several peptides based on the C-region of HIV gp41 have been used in clinical trials as possible HIV fusion inhibitors. Among these are T-1249 and T-20 (also known as enfurvitide). Despite recent works, a detailed molecular picture of the inhibitory mechanism of these molecules is still lacking. These peptides are usually depicted as α-helices by analogy with the structure of the sequence of the gp41 protein with which they are homologous. However, structures like these would be highly unstable in solution and thus would not explain, by themselves, the ability that the two fusion inhibitors have to become solvated by water and also interact effectively with cell membranes. To this effect, extensive molecular dynamics simulations were carried out to investigate the structure and conformational behavior of T-1249 and T-20 in water, as well as shorter homologous peptides CTP and 3f5, which show no inhibitory action. We found that the studied inhibitors have no stable structure in solution in the time scale studied. Additionally, the solvent accessible area varies significantly during the simulation. Our findings suggest that these peptides may assume not only one, but several possible sets of structures in solution, some of which more adequate to interact with the solvent, whereas others might be better suited to interact with cell membranes. Interestingly, and in accordance with published experimental studies, we verified that T-1249 displays considerably larger α-helical structure than T-20. Taking into account a recent study with design peptides with increased helicity, it is possible that this feature may be related to the increased inhibiting efficiency of T-1249 relative to that of T-20