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

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed

Crystallization of a classical two-dimensional electron system: Positional and orientational orders

Crystallization of a classical two-dimensional one-component plasma (electrons interacting with the Coulomb repulsion in a uniform neutralizing positive background) is investigated with a molecular dynamics simulation. The positional and the orientational correlation functions are calculated for the first time. We have found an indication that the solid phase has a quasi-long-range (power-law) positional order along with a long-range orientational order. This indicates that, although the long-range Coulomb interaction is outside the scope of Mermin's theorem, the absence of ordinary crystalline order at finite temperatures applies to the electron system as well. The `hexatic' phase, which is predicted between the liquid and the solid phases by the Kosterlitz-Thouless-Halperin-Nelson-Young theory, is also discussed.Comment: 3 pages, 4 figures; Corrected typos; Double columne

Combined CI+MBPT calculations of energy levels and transition amplitudes in Be, Mg, Ca, and Sr

Configuration interaction (CI) calculations in atoms with two valence electrons, carried out in the V(N-2) Hartree-Fock potential of the core, are corrected for core-valence interactions using many-body perturbation theory (MBPT). Two variants of the mixed CI+MBPT theory are described and applied to obtain energy levels and transition amplitudes for Be, Mg, Ca, and Sr

Isospin-Violating Meson-Nucleon Vertices as an Alternate Mechanism of Charge-Symmetry Breaking

We compute isospin-violating meson-nucleon coupling constants and their consequent charge-symmetry-breaking nucleon-nucleon potentials. The couplings result from evaluating matrix elements of quark currents between nucleon states in a nonrelativistic constituent quark model; the isospin violations arise from the difference in the up and down constituent quark masses. We find, in particular, that isospin violation in the omega-meson--nucleon vertex dominates the class IV CSB potential obtained from these considerations. We evaluate the resulting spin-singlet--triplet mixing angles, the quantities germane to the difference of neutron and proton analyzing powers measured in elastic $\vec{n}-\vec{p}$ scattering, and find them commensurate to those computed originally using the on-shell value of the $\rho$-$\omega$ mixing amplitude. The use of the on-shell $\rho$-$\omega$ mixing amplitude at $q^2=0$ has been called into question; rather, the amplitude is zero in a wide class of models. Our model possesses no contribution from $\rho$-$\omega$ mixing at $q^2=0$, and we find that omega-meson exchange suffices to explain the measured $n-p$ analyzing power difference~at~183 MeV.Comment: 20 pages, revtex, 3 uuencoded PostScript figure

Knowledge-based energy functions for computational studies of proteins

This chapter discusses theoretical framework and methods for developing knowledge-based potential functions essential for protein structure prediction, protein-protein interaction, and protein sequence design. We discuss in some details about the Miyazawa-Jernigan contact statistical potential, distance-dependent statistical potentials, as well as geometric statistical potentials. We also describe a geometric model for developing both linear and non-linear potential functions by optimization. Applications of knowledge-based potential functions in protein-decoy discrimination, in protein-protein interactions, and in protein design are then described. Several issues of knowledge-based potential functions are finally discussed.Comment: 57 pages, 6 figures. To be published in a book by Springe

Heavy Quarks and Heavy Quarkonia as Tests of Thermalization

We present here a brief summary of new results on heavy quarks and heavy quarkonia from the PHENIX experiment as presented at the "Quark Gluon Plasma Thermalization" Workshop in Vienna, Austria in August 2005, directly following the International Quark Matter Conference in Hungary.Comment: 8 pages, 5 figures, Quark Gluon Plasma Thermalization Workshop (Vienna August 2005) Proceeding

Proximity effect at superconducting Sn-Bi2Se3 interface

We have investigated the conductance spectra of Sn-Bi2Se3 interface junctions down to 250 mK and in different magnetic fields. A number of conductance anomalies were observed below the superconducting transition temperature of Sn, including a small gap different from that of Sn, and a zero-bias conductance peak growing up at lower temperatures. We discussed the possible origins of the smaller gap and the zero-bias conductance peak. These phenomena support that a proximity-effect-induced chiral superconducting phase is formed at the interface between the superconducting Sn and the strong spin-orbit coupling material Bi2Se3.Comment: 7 pages, 8 figure

Demonstration of the temporal matter-wave Talbot effect for trapped matter waves

We demonstrate the temporal Talbot effect for trapped matter waves using ultracold atoms in an optical lattice. We investigate the phase evolution of an array of essentially non-interacting matter waves and observe matter-wave collapse and revival in the form of a Talbot interference pattern. By using long expansion times, we image momentum space with sub-recoil resolution, allowing us to observe fractional Talbot fringes up to 10th order.Comment: 17 pages, 7 figure