MAPK phosphorylation of connexin 43 promotes binding of cyclin E and smooth muscle cell proliferation

<p>Rationale: Dedifferentiation of vascular smooth muscle cells (VSMC) leading to a proliferative cell phenotype significantly contributes to the development of atherosclerosis. Mitogen-activated protein kinase (MAPK) phosphorylation of proteins including connexin 43 (Cx43) has been associated with VSMC proliferation in atherosclerosis.</p> <p>Objective: To investigate whether MAPK phosphorylation of Cx43 is directly involved in VSMC proliferation.</p> <p>Methods and Results: We show in vivo that MAPK-phosphorylated Cx43 forms complexes with the cell cycle control proteins cyclin E and cyclin-dependent kinase 2 (CDK2) in carotids of apolipoprotein-E receptor null (ApoE−/−) mice and in C57Bl/6 mice treated with platelet-derived growth factor–BB (PDGF). We tested the involvement of Cx43 MAPK phosphorylation in vitro using constructs for full-length Cx43 (Cx43) or the Cx43 C-terminus (Cx43CT) and produced null phosphorylation Ser>Ala (Cx43MK4A/Cx43CTMK4A) and phospho-mimetic Ser>Asp (Cx43MK4D/Cx43CTMK4D) mutations. Coimmunoprecipitation studies in primary VSMC isolated from Cx43 wild-type (Cx43+/+) and Cx43 null (Cx43−/−) mice and analytic size exclusion studies of purified proteins identify that interactions between cyclin E and Cx43 requires Cx43 MAPK phosphorylation. We further demonstrate that Cx43 MAPK phosphorylation is required for PDGF-mediated VSMC proliferation. Finally, using a novel knock-in mouse containing Cx43-MK4A mutation, we show in vivo that interactions between Cx43 and cyclin E are lost and VSMC proliferation does not occur after treatment of carotids with PDGF and that neointima formation is significantly reduced in carotids after injury.</p> <p>Conclusions: We identify MAPK-phosphorylated Cx43 as a novel interacting partner of cyclin E in VSMC and show that this interaction is critical for VSMC proliferation. This novel interaction may be important in the development of atherosclerotic lesions.</p&gt

Effect of novel porphyrazine photosensitizers on normal and tumor brain cells

Photodynamic therapy (PDT) is a clinically approved procedure for targeting tumor cells. Though several different photosensitizers have been developed, there is still much demand for novel photosensitizers with improved properties. In this study we aim to characterize the accumulation, localization and dark cytotoxicity of the novel photosensitizers developed in-house derivatives of porphyrazines (pz I-IV) in primary murine neuronal cells, as well as to identify the concentrations at which pz still effectively induces death in glioma cells yet is nontoxic to nontransformed cells. The study shows that incubation of primary neuronal and glioma cells with pz I-IV leads to their accumulation in both types of cells, but their rates of internalization, subcellular localization and dark toxicity differ significantly. Pz II was the most promising photosensitizer. It efficiently killed glioma cells while remaining nontoxic to primary neuronal cells. This opens up the possibility of evaluating pz II for experimental PDT for glioma

Transverse-momentum-dependent Multiplicities of Charged Hadrons in Muon-Deuteron Deep Inelastic Scattering

A semi-inclusive measurement of charged hadron multiplicities in deep inelastic muon scattering off an isoscalar target was performed using data collected by the COMPASS Collaboration at CERN. The following kinematic domain is covered by the data: photon virtuality $Q^{2}>1$ (GeV/$c$)$^2$, invariant mass of the hadronic system $W > 5$ GeV/$c^2$, Bjorken scaling variable in the range $0.003 < x < 0.4$, fraction of the virtual photon energy carried by the hadron in the range $0.2 < z < 0.8$, square of the hadron transverse momentum with respect to the virtual photon direction in the range 0.02 (GeV/$c)^2 < P_{\rm{hT}}^{2} < 3$ (GeV/$c$)$^2$. The multiplicities are presented as a function of $P_{\rm{hT}}^{2}$ in three-dimensional bins of $x$, $Q^2$, $z$ and compared to previous semi-inclusive measurements. We explore the small-$P_{\rm{hT}}^{2}$ region, i.e. $P_{\rm{hT}}^{2} < 1$ (GeV/$c$)$^2$, where hadron transverse momenta are expected to arise from non-perturbative effects, and also the domain of larger $P_{\rm{hT}}^{2}$, where contributions from higher-order perturbative QCD are expected to dominate. The multiplicities are fitted using a single-exponential function at small $P_{\rm{hT}}^{2}$ to study the dependence of the average transverse momentum $\langle P_{\rm{hT}}^{2}\rangle$ on $x$, $Q^2$ and $z$. The power-law behaviour of the multiplicities at large $P_{\rm{hT}}^{2}$ is investigated using various functional forms. The fits describe the data reasonably well over the full measured range.Comment: 28 pages, 20 figure

Light isovector resonances in π-p →π-π-π+p at 190 GeV/c

We have performed the most comprehensive resonance-model fit of π-π-π+ states using the results of our previously published partial-wave analysis (PWA) of a large data set of diffractive-dissociation events from the reaction π-+p→π-π-π++precoil with a 190 GeV/c pion beam. The PWA results, which were obtained in 100 bins of three-pion mass, 0.5<2.5 GeV/c2, and simultaneously in 11 bins of the reduced four-momentum transfer squared, 0.1<1.0 (GeV/c)2, are subjected to a resonance-model fit using Breit-Wigner amplitudes to simultaneously describe a subset of 14 selected waves using 11 isovector light-meson states with JPC=0-+, 1++, 2++, 2-+, 4++, and spin-exotic 1-+ quantum numbers. The model contains the well-known resonances π(1800), a1(1260), a2(1320), π2(1670), π2(1880), and a4(2040). In addition, it includes the disputed π1(1600), the excited states a1(1640), a2(1700), and π2(2005), as well as the resonancelike a1(1420). We measure the resonance parameters mass and width of these objects by combining the information from the PWA results obtained in the 11 t′ bins. We extract the relative branching fractions of the ρ(770)π and f2(1270)π decays of a2(1320) and a4(2040), where the former one is measured for the first time. In a novel approach, we extract the t′ dependence of the intensity of the resonances and of their phases. The t′ dependence of the intensities of most resonances differs distinctly from the t′ dependence of the nonresonant components. For the first time, we determine the t′ dependence of the phases of the production amplitudes and confirm that the production mechanism of the Pomeron exchange is common to all resonances. We have performed extensive systematic studies on the model dependence and correlations of the measured physical parameters

Double J/ψJ/\psi production in pion-nucleon scattering at COMPASS

We present the study of the production of double $J/\psi$ mesons using COMPASS data collected with a 190 GeV/$c$ $\pi^-$ beam scattering off NH$_{3}$, Al and W targets. Kinematic distributions of the collected double $J/\psi$ events are analysed, and the double $J/\psi$ production cross section is estimated for each of the COMPASS targets. The results are compared to predictions from single- and double-parton scattering models as well as the pion intrinsic charm and the tetraquark exotic resonance hypotheses. It is demonstrated that the single parton scattering production mechanism gives the dominant contribution that is sufficient to describe the data. An upper limit on the double intrinsic charm content of pion is evaluated. No significant signatures that could be associated with exotic tetraquarks are found in the double $J/\psi$ mass spectrum.Comment: 12 pages, 4 figure

Feasibility studies for the measurement of time-like proton electromagnetic form factors from p¯ p→ μ+μ- at P ¯ ANDA at FAIR

This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, | GE| and | GM| , using the p¯ p→ μ+μ- reaction at P ¯ ANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at P ¯ ANDA , using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is p¯ p→ π+π-, due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distributions of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented

Longitudinal double-spin asymmetry A1pand spin-dependent structure function g1pof the proton at small values of x and Q2

We present a precise measurement of the proton longitudinal double-spin asymmetry Ap1 and the proton spin-dependent structure function gp 1 at photon virtualities 0.006 (GeV/c)2 < Q 2 < 1 (GeV/c)2 in the Bjorken x range of 4 7 10 125 < x < 4 7 10 122. The results are based on data collected by the COMPASS Collaboration at CERN using muon beam energies of 160 GeV and 200 GeV. The statistical precision is more than tenfold better than that of the previous measurement in this region. In the whole range of x, the measured values of Ap1 and gp1 are found to be positive. It is for the first time that spin effects are found at such low values of

Precision resonance energy scans with the PANDA experiment at FAIR: Sensitivity study for width and line shape measurements of the X(3872)

This paper summarises a comprehensive Monte Carlo simulation study for precision resonance energy scan measurements. Apart from the proof of principle for natural width and line shape measurements of very narrow resonances with PANDA, the achievable sensitivities are quantified for the concrete example of the charmonium-like X(3872) state discussed to be exotic, and for a larger parameter space of various assumed signal cross-sections, input widths and luminosity combinations. PANDA is the only experiment that will be able to perform precision resonance energy scans of such narrow states with quantum numbers of spin and parities that differ from J P C = 1 - -