CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels

Inhibition of the mitochondrial Na+/Ca2+ exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca2+ homeostasis. However, the Ca2+ signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca2+ levels are modulated by CGP37157 (10 mu M) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca2+ homeostasis using cameleon-based mitochondrial Ca2+ and cytosolic Ca2+ ([Ca2+](i)) live imaging. We observed that NCLX-driven mitochondrial Ca2+ exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca-2](i) concomitant with a Ca2+ accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca2+ efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca2+](i) increase by blocking voltage-gated Ca2+ channels (VGCCs), whereas it did not induce depletion of ER Ca2+ stores. Moreover, mitochondrial Ca2+ overload was reduced as a consequence of diminished Ca2+ entry through VGCCs. The decrease in cytosolic and mitochondrial Ca2+ overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca2+ dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs.

Reynolds number influence on turbulent blocking effects of a rigid plane boundary (2nd report, direct numerical simulation using townsend's eddy forcing)

The Reynolds number influence on turbulent blocking effects by a rigid plane boundary is studied using direct numerical simulation (DNS). A new forcing method using 'simple model eddies' (Townsend 1976) for DNS of stationary homogeneous isotropic turbulence is proposed. A force field is obtained in real space by sprinkling many space-filling 'simple model eddies' whose centers are randomly but uniformly distributed in space and whose axes of rotation are random. The method is applied to a shear-free turbulent boundary layer over a rigid plane boundary and the blocking effects are investigated. The results show that stationary homogeneous isotropic turbulence is generated in real space using the present method. By using different model eddies with different sizes and rotation speeds, we could change the turbulence properties such as the integral and micro scales, the turbulent Reynolds number and the isotropy of turbulence. Turbulence intensities near the wall showed good agreements with the previous measurement and the linear analysis based on a rapid distortion theory (RDT). The splat effect (i.e., turbulence intensities of the components parallel to the boundary are amplified) occurs near the boundary and the viscous effect prohibits the splat effect at the quasi steady state at low Reynolds number.

Secondary flow near an undulatory surface induced by wall blocking effect

Prandtl's secondary mean motions of the second kind near an undulating surface were explained in terms of turbulent blocking effect and kinematic boundary conditions at the surface, and its order of magnitude was estimated. Isotropic turbulence is distorted by the undulating surface of wavelength λ and amplitude h with a low slope, so that h « λ. The prime mechanism for generating the mean flow is that the far-field Isotropic turbulence is distorted by the non-local blocking effect of the surface to become anisotropic axisymmetric turbulence near the surface with principal axis that is not aligned with the local curvature of the undulation. Then the local analysis can be applied and the mechanism is similar to the mean flow generation mechanism for homogeneous axisymmetric turbulence over a planer surface, i.e. gradients of the Reynolds stress caused by the turbulent blocking effect generate the mean motions. The results from this simple analysis are consistent with previous exact analysis in which the effects of curvature are strictly taken into account. The results also qualitatively agree with flow visualization over an undulating surface in a mixing-box.

Reynolds number influence on turbulent blocking effects of a rigid plane boundary (3rd report, direct numerical simulation on wall blocking effects for anisotropic turbulence)

The Reynolds number influence on turbulent blocking effects by a rigid plane boundary is studied using direct numerical simulation (DNS). A new forcing method proposed in the second report using Townsend's "simple model eddies" for DNS was extended to generate axisymmetric anisotropic turbulence. A force field is obtained in real space by sprinkling many space-filling "simple model eddies" whose centers are randomly but uniformly distributed in space. The axes of rotation are controlled in this study to generate axisymmetric anisotropic turbulence. The method is applied to a shear-free turbulent boundary layer over a rigid plane boundary and the blocking effects for anisotropic turbulence are investigated. The results show that stationary axisymmetric anisotropic turbulence is generated using the present method. Turbulence intensities near the wall showed good agreements with the rapid distortion theory (RDT) for small t (t ≪ TL), where TL. is the eddy turnover time. The splat effect (i. e. turbulence intensities of the components parallel to the surface are amplified) occurs near the boundary and the viscous effect attenuates the splat effect at the quasi steady state at low Reynolds number as for Isotropic turbulence. Prandtl's secondary flow of the second kind does not occur for low Reynolds number flows, which qualitatively agrees with previous observetion in a mixing-box.

Physical Blocking Neural Tube Closure Affects Radial Intercalation and Neural Crest Midline-directed Migration in Xenopus Dorsal Explants

神经管闭合缺陷(NTDs)是一种严重的先天畸形疾病,在新生儿中有千分之一的发病率.神经管融合前后,多种组织参与形态发生运动.神经管一经融合,神经嵴细胞就会向背侧中线方向产生单极突出并向此方向迁移形成神经管的顶部.与此同时,神经管从腹侧开始发生辐射状切入以实现单层化.在此,我们在非洲爪蟾的移植体中机械阻断神经管的闭合以检测其细胞运动及随后的图式形成.结果显示神经管闭合缺陷的移植体不能形成单层化的神经管,并且神经嵴细胞滞留在侧面区域不能向背侧中线迁移,而对神经前体标记基因的检测显示神经管的背腹图式形成并未受到影响.以上结果表明神经管的融合对于辐射状切入和神经嵴细胞向背侧中线方向的迁移过程是必需的,而对于神经管的沿背腹轴方向的图式形成是非必需的.

Robust variable horizon MPC with move blocking

This paper introduces a new formulation of variable horizon model predictive control (VH-MPC) that utilises move blocking for reducing computational complexity. Various results pertaining to move blocking are derived, following which, a generalised blocked VH-MPC controller is formulated for linear discrete-time systems. Robustness to bounded disturbances is ensured through the use of tightened constraints. The resulting time-varying control scheme is shown to guarantee robust recursive feasibility and finite-time completion. An example is then presented for a particular choice of blocking regime, as would be applicable to vehicle manœuvring problems. Simulations demonstrate the efficacy of the formulation. © 2012 Elsevier B.V. All rights reserved.