Hyperphosphatemia in chronic kidney disease exacerbates atherosclerosis via a mannosidases-mediated complex-type conversion of SCAP N-glycans

Blood phosphate levels are linked to atherosclerotic cardiovascular disease in patients with chronic kidney disease (CKD), but the molecular mechanisms remain unclear. Emerging studies indicate an involvement of hyperphosphatemia in CKD accelerated atherogenesis through disturbed cholesterol homeostasis. Here, we investigated a potential atherogenic role of high phosphate concentrations acting through aberrant activation of sterol regulatory element-binding protein (SREBP) and cleavage-activating protein (SCAP)-SREBP2 signaling in patients with CKD, hyperphosphatemic apolipoprotein E (ApoE) knockout mice, and cultured vascular smooth muscle cells. Hyperphosphatemia correlated positively with increased atherosclerotic cardiovascular disease risk in Chinese patients with CKD and severe atheromatous lesions in the aortas of ApoE knockout mice. Mice arteries had elevated SCAP levels with aberrantly activated SCAP-SREBP2 signaling. Excess phosphate in vitro raised the activity of α-mannosidase, resulting in delayed SCAP degradation through promoting complex-type conversion of SCAP N-glycans. The retention of SCAP enhanced transactivation of SREBP2 and expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, boosting intracellular cholesterol synthesis. Elevated α-mannosidase II activity was also observed in the aortas of ApoE knockout mice and the radial arteries of patients with uremia and hyperphosphatemia. High phosphate concentration in vitro elevated α-mannosidase II activity in the Golgi, enhanced complex-type conversion of SCAP N-glycans, thereby upregulating intracellular cholesterol synthesis. Thus, our studies explain how hyperphosphatemia independently accelerates atherosclerosis in CKD

Possible Way to Synthesize Superheavy Element Z=117

Within the framework of the dinuclear system model, the production of superheavy element Z=117 in possible projectile-target combinations is analyzed systematically. The calculated results show that the production cross sections are strongly dependent on the reaction systems. Optimal combinations, corresponding excitation energies and evaporation channels are proposed in this letter, such as the isotopes ^{248,249}Bk in ^{48}Ca induced reactions in 3n evaporation channels and the reactions ^{45}Sc+^{246,248}Cm in 3n and 4n channels, and the system ^{51}V+^{244}Pu in 3n channel.Comment: 10 pages, 4 figures, 1 tabl

A eukaryotic specific transmembrane segment is required for tetramerization in AMPA receptors

Most fast excitatory synaptic transmission in the nervous system is mediated by glutamate acting through ionotropic glutamate receptors (iGluRs). iGluRs (AMPA, kainate, and NMDA receptor subtypes) are tetrameric assemblies, formed as a dimer of dimers. Still, the mechanism underlying tetramerization-the necessary step for the formation of functional receptors that can be inserted into the plasma membrane-is unknown. All eukaryotic compared to prokaryotic iGluR subunits have an additional transmembrane segment, theM4segment, which positions the physiologically critical C-terminal domain on the cytoplasmic side of the membrane.AMPAreceptor (AMPAR) subunits lacking M4 do not express on the plasma membrane. Here, we show that these constructs are retained in the endoplasmic reticulum, the major cellular compartment mediating protein oligomerization. Using approaches to assay the native oligomeric state of AMPAR subunits, we find that subunits lacking M4 or containing single amino acid substitutions along an "interacting" face of the M4 helix that block surface expression no longer tetramerize in either homomeric or heteromeric assemblies. In contrast, subunit dimerization appears to be largely intact. These experiments define the M4 segment as a unique functional unit in AMPARs that is required for the critical dimer-to-tetramer transition. © 2013 the authors

Lattice Boltzmann study on Kelvin-Helmholtz instability: the roles of velocity and density gradients

A two-dimensional lattice Boltzmann model with 19 discrete velocities for compressible Euler equations is proposed (D2V19-LBM). The fifth-order Weighted Essentially Non-Oscillatory (5th-WENO) finite difference scheme is employed to calculate the convection term of the lattice Boltzmann equation. The validity of the model is verified by comparing simulation results of the Sod shock tube with its corresponding analytical solutions. The velocity and density gradient effects on the Kelvin-Helmholtz instability (KHI) are investigated using the proposed model. Sharp density contours are obtained in our simulations. It is found that, the linear growth rate $\gamma$ for the KHI decreases with increasing the width of velocity transition layer ${D_{v}}$ but increases with increasing the width of density transition layer ${D_{\rho}}$. After the initial transient period and before the vortex has been well formed, the linear growth rates, $\gamma_v$ and $\gamma_{\rho}$, vary with ${D_{v}}$ and ${D_{\rho}}$ approximately in the following way, $\ln\gamma_{v}=a-bD_{v}$ and $\gamma_{\rho}=c+e\ln D_{\rho} ({D_{\rho}}<{D_{\rho}^{E}})$, where $a$, $b$, $c$ and $e$ are fitting parameters and ${D_{\rho}^{E}}$ is the effective interaction width of density transition layer. When ${D_{\rho}}>{D_{\rho}^{E}}$ the linear growth rate $\gamma_{\rho}$ does not vary significantly any more. One can use the hybrid effects of velocity and density transition layers to stabilize the KHI. Our numerical simulation results are in general agreement with the analytical results [L. F. Wang, \emph{et al.}, Phys. Plasma \textbf{17}, 042103 (2010)].Comment: Accepted for publication in PR

Frequency variations of gravity waves interacting with a time-varying tide

Using a nonlinear, 2-D time-dependent numerical model, we simulate the propagation of gravity waves (GWs) in a time-varying tide. Our simulations show that when a GW packet propagates in a time-varying tidal-wind environment, not only its intrinsic frequency but also its ground-based frequency would change significantly. The tidal horizontal-wind acceleration dominates the GW frequency variation. Positive (negative) accelerations induce frequency increases (decreases) with time. More interestingly, tidal-wind acceleration near the critical layers always causes the GW frequency to increase, which may partially explain the observations that high-frequency GW components are more dominant in the middle and upper atmosphere than in the lower atmosphere. The combination of the increased ground-based frequency of propagating GWs in a time-varying tidal-wind field and the transient nature of the critical layer induced by a time-varying tidal zonal wind creates favorable conditions for GWs to penetrate their originally expected critical layers. Consequently, GWs have an impact on the background atmosphere at much higher altitudes than expected, which indicates that the dynamical effects of tidal–GW interactions are more complicated than usually taken into account by GW parameterizations in global models