The Na(+)–H(+ )exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells

INTRODUCTION: An increasing body of evidence shows that the tumour microenvironment is essential in driving neoplastic progression. The low serum component of this microenvironment stimulates motility/invasion in human breast cancer cells via activation of the Na(+)–H(+ )exchanger (NHE) isoform 1, but the signal transduction systems that underlie this process are still poorly understood. We undertook the present study to elucidate the role and pattern of regulation by the Rho GTPases of this serum deprivation-dependent activation of both NHE1 and subsequent invasive characteristics, such as pseudopodia and invadiopodia protrusion, directed cell motility and penetration of normal tissues. METHODS: The present study was performed in a well characterized human mammary epithelial cell line representing late stage metastatic progression, MDA-MB-435. The activity of RhoA and Rac1 was modified using their dominant negative and constitutively active mutants and the activity of NHE1, cell motility/invasion, F-actin content and cell shape were measured. RESULTS: We show for the first time that serum deprivation induces NHE1-dependent morphological and cytoskeletal changes in metastatic cells via a reciprocal interaction of RhoA and Rac1, resulting in increased chemotaxis and invasion. Deprivation changed cell shape by reducing the amount of F-actin and inducing the formation of leading edge pseudopodia. Serum deprivation inhibited RhoA activity and stimulated Rac1 activity. Rac1 and RhoA were antagonistic regulators of both basal and stimulated tumour cell NHE1 activity. The regulation of NHE1 activity by RhoA and Rac1 in both conditions was mediated by an alteration in intracellular proton affinity of the exchanger. Interestingly, the role of each of these G-proteins was reversed during serum deprivation; basal NHE1 activity was regulated positively by RhoA and negatively by Rac1, whereas RhoA negatively and Rac1 positively directed the stimulation of NHE1 during serum deprivation. Importantly, the same pattern of RhoA and Rac1 regulation found for NHE1 activity was observed in both basal and serum deprivation dependent increases in motility, invasion and actin cytoskeletal organization. CONCLUSION: Our findings suggest that the reported antagonistic roles of RhoA and Rac1 in cell motility/invasion and cytoskeletal organization may be due, in part, to their concerted action on NHE1 activity as a convergence point

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

Linear and non-linear flow mode in Pb-Pb collisions at root sNN=2.76 TeV

The second and the third order anisotropic flow, V-2 and V-3, are mostly determined by the corresponding initial spatial anisotropy coefficients, epsilon(2) and epsilon(3), in the initial density distribution. In addition to their dependence on the same order initial anisotropy coefficient, higher order anisotropic flow, Vn(n > 3), can also have a significant contribution from lower order initial anisotropy coefficients, which leads to mode-coupling effects. In this Letter we investigate the linear and non-linear modes in higher order anisotropic flow V-n for n = 4, 5, 6 with the ALICE detector at the Large Hadron Collider. The measurements are done for particles in the pseudorapidity range |eta| <0.8 and the transverse momentum range 0.2 <p(T)<5.0 GeV/c as a function of collision centrality. The results are compared with theoretical calculations and provide important constraints on the initial conditions, including initial spatial geometry and its fluctuations, as well as the ratio of the shear viscosity to entropy density of the produced system. (C) 2017 The Author(s). Published by Elsevier B.V.Peer reviewe

D-Meson Azimuthal Anisotropy in Midcentral Pb-Pb Collisions root S-NN=5.02 TeV

The azimuthal anisotropy coefficient v(2) of prompt D-0, D+, D*+, and D-s(+) mesons was measured in midcentral (30%-50% centrality class) Pb-Pb collisions at a center-of-mass energy per nucleon pair root s(NN)=5.02 TeV, with the ALICE detector at the LHC. The D mesons were reconstructed via their hadronic decays at midrapidity, |y| < 0.8, in the transverse momentum interval 1 < p(T) < 24 GeV/c. The measured D-meson v(2) has similar values as that of charged pions. The D-s(+) v(2), measured for the first time, is found to be compatible with that of nonstrange D mesons. The measurements are compared with theoretical calculations of charm-quark transport in a hydrodynamically expanding medium and have the potential to constrain medium parameters.Peer reviewe

Production of deuterons, tritons, He-3 nuclei, and their antinuclei in pp collisions at root s=0.9, 2.76, and 7 TeV

Invariant differential yields of deuterons and antideuterons in pp collisions at root s = 0.9, 2.76 and 7 TeV and the yields of tritons, He-3 nuclei, and their antinuclei at root s = 7 TeV have been measured with the ALICE detector at the CERN Large Hadron Collider. The measurements cover a wide transverse momentum (p(T)) range in the rapidity interval vertical bar y vertical bar <0.5, extending both the energy and the pT reach of previous measurements up to 3 GeV/c for A = 2 and 6 GeV/c for A = 3. The coalescence parameters of (anti) deuterons and 3 He nuclei exhibit an increasing trend with pT and are found to be compatible with measurements in pA collisions at low p(T) and lower energies. The integrated yields decrease by a factor of about 1000 for each increase of the mass number with one (anti) nucleon. Furthermore, the deuteron-to-proton ratio is reported as a function of the average charged particle multiplicity at different center-of-mass energies.Peer reviewe

Production of muons from heavy-flavour hadron decays in p-Pb collisions at root s(NN)=5.02 TeV

The production of muons from heavy-flavour hadron decays in p-Pb collisions at root s(NN) = 5.02 TeV was studied for 2 <p(T) <16 GeV/c with the ALICE detector at the CERN LHC. The measurement was performed at forward (p-going direction) and backward (Pb-going direction) rapidity, in the ranges of rapidity in the centre-of-mass system (cms) 2.03 <y(cms) <3.53 and -4.46 <y(cms) <-2.96, respectively. The production cross sections and nuclear modification factors are presented as a function of transverse momentum (P-T). At forward rapidity, the nuclear modification factor is compatible with unity while at backward rapidity, in the interval 2.5 <p(T) <3.5 GeV/c, it is above unity by more than 2 sigma. The ratio of the forward -to -backward production cross sections is also measured in the overlapping interval 2.96 <|y(cms)| <3.53 and is smaller than unity by 3.7 sigma in 2.5 <p(T) <3.5 GeV/c. The data are described by model calculations including cold nuclear matter effects. (C) 2017 The Author(s). Published by Elsevier B.V.Peer reviewe

Measurement of electrons from beauty-hadron decays in p-Pb collisions at root(NN)-N-S=5.02 TeV and Pb-Pb collisions at. root(NN)-N-S=2.76 TeV

The production of beauty hadrons was measured via semi-leptonic decays at mid-rapidity with the ALICE detector at the LHC in the transverse momentum interval 1<pT< 8 GeV/c in minimum-bias p-Pb collisions at sNN=5.02 TeV and in 1.3 < pT< 8 GeV/c in the 20% most central Pb-Pb collisions at sNN=2.76 TeV. The pp reference spectra at sNN=5.02 TeV and s=2.76 TeV, needed for the calculation of the nuclear modification factors RpPb and RPbPb, were obtained by a pQCD-driven scaling of the cross section of electrons from beauty-hadron decays measured at s=7 TeV. In the pT interval 3 < pT< 8 GeV/c, a suppression of the yield of electrons from beauty-hadron decays is observed in Pb-Pb compared to pp collisions. Towards lower pT, the RPbPb values increase with large systematic uncertainties. The RpPb is consistent with unity within systematic uncertainties and is well described by theoretical calculations that include cold nuclear matter effects in p-Pb collisions. The measured RpPb and these calculations indicate that cold nuclear matter effects are small at high transverse momentum also in Pb-Pb collisions. Therefore., the observed reduction of RPbPb below unity at high pT may be ascribed to an effect of the hot and dense medium formed in Pb-Pb collisions.[Figure not available: see fulltext.

Evolution of the longitudinal and azimuthal structure of the near-side jet peak in Pb-Pb collisions at sNN =2.76 TeV

In two-particle angular correlation measurements, jets give rise to a near-side peak, formed by particles associated to a higher-pT trigger particle. Measurements of these correlations as a function of pseudorapidity (Δη) and azimuthal (Δφ) differences are used to extract the centrality and pT dependence of the shape of the near-side peak in the pT range 1<pT<8 GeV/c in Pb-Pb and pp collisions at sNN = 2.76 TeV. A combined fit of the near-side peak and long-range correlations is applied to the data and the peak shape is quantified by the variance of the distributions. While the width of the peak in the Δφ direction is almost independent of centrality, a significant broadening in the Δη direction is found from peripheral to central collisions. This feature is prominent for the low-pT region and vanishes above 4 GeV/c. The widths measured in peripheral collisions are equal to those in pp collisions in the Δφ direction and above 3 GeV/c in the Δη direction. Furthermore, for the 10% most central collisions and 1<pT,assoc< 2 GeV/c, 1<pT,trig< 3 GeV/c, a departure from a Gaussian shape is found: a depletion develops around the center of the peak. The results are compared to A Multi-Phase Transport (AMPT) model simulation as well as other theoretical calculations indicating that the broadening and the development of the depletion are connected to the strength of radial and longitudinal flow

Measurement of the production of high-p(T) electrons from heavy-flavour hadron decays in Pb-Pb collisions at root s(NN)=2.76 TeV

Electrons from heavy-flavour hadron decays (charm and beauty) were measured with the ALICE detector in Pb–Pb collisions at a centre-of-mass of energy sNN=2.76 TeV. The transverse momentum (pT) differential production yields at mid-rapidity were used to calculate the nuclear modification factor RAA in the interval 3&lt;pT&lt;18 GeV/c. The RAA shows a strong suppression compared to binary scaling of pp collisions at the same energy (up to a factor of 4) in the 10% most central Pb–Pb collisions. There is a centrality trend of suppression, and a weaker suppression (down to a factor of 2) in semi-peripheral (50–80%) collisions is observed. The suppression of electrons in this broad pT interval indicates that both charm and beauty quarks lose energy when they traverse the hot medium formed in Pb–Pb collisions at LHC

Measurement of the production of high-p(T) electrons from heavy-flavour hadron decays in Pb-Pb collisions at root s(NN)=2.76 TeV

Electrons from heavy-flavour hadron decays (charm and beauty) were measured with the ALICE detector in Pb–Pb collisions at a centre-of-mass of energy sNN=2.76 TeV. The transverse momentum (pT) differential production yields at mid-rapidity were used to calculate the nuclear modification factor RAA in the interval 3<pT<18 GeV/c. The RAA shows a strong suppression compared to binary scaling of pp collisions at the same energy (up to a factor of 4) in the 10% most central Pb–Pb collisions. There is a centrality trend of suppression, and a weaker suppression (down to a factor of 2) in semi-peripheral (50–80%) collisions is observed. The suppression of electrons in this broad pT interval indicates that both charm and beauty quarks lose energy when they traverse the hot medium formed in Pb–Pb collisions at LHC