Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells

<p>Abstract</p> <p>Background</p> <p>Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs) and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.</p> <p>Methods</p> <p>Primary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin), lipophobic (pravastatin) and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.</p> <p>Results</p> <p>Treatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550) was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.</p> <p>Conclusions</p> <p>Lipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.</p

Enhanced production of multi-strange hadrons in high-multiplicity proton-proton collisions

At sufficiently high temperature and energy density, nuclear matter undergoes a transition to a phase in which quarks and gluons are not confined: the quark-gluon plasma (QGP)(1). Such an exotic state of strongly interacting quantum chromodynamics matter is produced in the laboratory in heavy nuclei high-energy collisions, where an enhanced production of strange hadrons is observed(2-6). Strangeness enhancement, originally proposed as a signature of QGP formation in nuclear collisions(7), is more pronounced for multi-strange baryons. Several effects typical of heavy-ion phenomenology have been observed in high-multiplicity proton-proton (pp) collisions(8,9), but the enhanced production of multi-strange particles has not been reported so far. Here we present the first observation of strangeness enhancement in high-multiplicity proton-proton collisions. We find that the integrated yields of strange and multi-strange particles, relative to pions, increases significantly with the event charged-particle multiplicity. The measurements are in remarkable agreement with the p-Pb collision results(10,11), indicating that the phenomenon is related to the final system created in the collision. In high-multiplicity events strangeness production reaches values similar to those observed in Pb-Pb collisions, where a QGP is formed.Peer reviewe

Precision Measurement of the Boron to Carbon Flux Ratio in Cosmic Rays from 1.9 GV to 2.6 TV with the Alpha Magnetic Spectrometer on the International Space Station

Knowledge of the rigidity dependence of the boron to carbon flux ratio (B/C) is important in understanding the propagation of cosmic rays. The precise measurement of the B/C ratio from 1.9 GV to 2.6 TV, based on 2.3 million boron and 8.3 million carbon nuclei collected by AMS during the first 5 years of operation, is presented. The detailed variation with rigidity of the B/C spectral index is reported for the first time. The B/C ratio does not show any significant structures in contrast to many cosmic ray models that require such structures at high rigidities. Remarkably, above 65 GV, the B/C ratio is well described by a single power law R[superscript Δ] with index Δ=-0.333±0.014(fit)±0.005(syst), in good agreement with the Kolmogorov theory of turbulence which predicts Δ=-1/3 asymptotically.National Science Foundation (U.S.) (Grants 1455202 and 1551980)Wyle Research (Firm) (Grant 2014/T72497)United States. National Aeronautics and Space Administration (NASA Earth and Space Science Fellowship Grant HELIO15F-0005

Electron and positron fluxes in primary cosmic rays measured with the alpha magnetic spectrometer on the international space station

Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at &sim;30GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons.</p

High statistics measurement of the positron fraction in primary cosmic rays of 0.5-500 GeV with the alpha magnetic spectrometer on the international space station

A precision measurement by AMS of the positron fraction in primary cosmic rays in the energy range from 0.5 to 500 GeV based on 10.9 million positron and electron events is presented. This measurement extends the energy range of our previous observation and increases its precision. The new results show, for the first time, that above &sim;200GeV the positron fraction no longer exhibits an increase with energy.</p

Properties of Iron Primary Cosmic Rays: Results from the Alpha Magnetic Spectrometer

We report the observation of new properties of primary iron (Fe) cosmic rays in the rigidity range 2.65 GV to 3.0 TV with 0.62 million iron nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. Above 80.5 GV the rigidity dependence of the cosmic ray Fe flux is identical to the rigidity dependence of the primary cosmic ray He, C, and O fluxes, with the Fe/O flux ratio being constant at 0.155±0.006. This shows that unexpectedly Fe and He, C, and O belong to the same class of primary cosmic rays which is different from the primary cosmic rays Ne, Mg, and Si class

Properties of Heavy Secondary Fluorine Cosmic Rays: Results from the Alpha Magnetic Spectrometer

Precise knowledge of the charge and rigidity dependence of the secondary cosmic ray fluxes and the secondary-to-primary flux ratios is essential in the understanding of cosmic ray propagation. We report the properties of heavy secondary cosmic ray fluorine F in the rigidity R range 2.15 GV to 2.9 TV based on 0.29 million events collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The fluorine spectrum deviates from a single power law above 200 GV. The heavier secondary-to-primary F/Si flux ratio rigidity dependence is distinctly different from the lighter B/O (or B/C) rigidity dependence. In particular, above 10 GV, the F/SiB/O ratio can be described by a power law Rδ with δ=0.052±0.007. This shows that the propagation properties of heavy cosmic rays, from F to Si, are different from those of light cosmic rays, from He to O, and that the secondary cosmic rays have two classes

Energy dependence and fluctuations of anisotropic flow in Pb-Pb collisions at √sNN=5.02 and 2.76 TeV

Measurements of anisotropic flow coefficients with two- and multi-particle cumulants for inclusive charged particles in Pb-Pb collisions at sqrt(s_NN) = 5.02 and 2.76TeV are reported in the pseudorapidity range |eta|< 0.8 and transverse momentum 0.2 < pT < 50 GeV/c. The full data sample collected by the ALICE detector in 2015 (2010), corresponding to an integrated luminosity of 12.7 (2.0) ub^-1 in the centrality range 0-80%, is analysed. Flow coefficients up to the sixth flow harmonic (v6) are reported and a detailed comparison among results at the two energies is carried out. The pT dependence of anisotropic flow coefficients and its evolution with respect to centrality and harmonic number n are investigated. An approximate power-law scaling of the form vn(pT) ~ pT^(n/3) is observed for all flow harmonics at low pT (0.2 < pT < 3 GeV/c). At the same time, the ratios vn/vm^(n/m) are observed to be essentially independent of pT for most centralities up to about pT = 10 GeV/c. Analysing the differences among higher-order cumulants of elliptic flow (v2), which have different sensitivities to flow fluctuations, a measurement of the standardised skewness of the event-by-event v2 distribution P(v2) is reported and constraints on its higher moments are provided. The Elliptic Power distribution is used to parametrise P(v2), extracting its parameters from fits to cumulants. The measurements are compared to different model predictions in order to discriminate among initial-state models and to constrain the temperature dependence of the shear viscosity to entropy-density ratio