Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...
Textured crystalline NiO thin films were grown on Si(100) substrates by off-axis RF magnetron sputtering without substrate heating using a NiO target. (100)-textured NiO films were obtained using pure Ar gas. On the other hand, (111)-textured NiO films were obtained using pure O2 gas. Also, the surface morphology and roughness of the NiO thin films were closely related to the type of sputtering gas and RF power.
We improve the method proposed by Yao et al (2003) to resolve the X-ray dust scattering halos of point sources. Using this method we re-analyze the Cygnus X-1 data observed with Chandra (ObsID 1511) and derive the halo radial profile in different energy bands and the fractional halo intensity (FHI) askeV . We also apply the method to the Cygnus X-3 data (Chandra ObsID 425) and derive the halo radial profile from the first order data with the Chandra ACIS+HETG. It is found that the halo radial profile could be fit by the halo model MRN (Mathis, Rumpl & Nordsieck, 1977) and WD01 (Weingartner & Draine, 2001); the dust clouds should be located at between 1/2 to 1 of the distance to Cygnus X-1 and between 1/6 to 3/4 (from MRN model) or 1/6 to 2/3 (from WD01 model) of the distance to Cygnus X-3, respectively.
Microroughness at the surface and interface of SiO2 thermally grown on an atomically flat Si terrace was investigated by atomic force microscopy. Although surface protuberances on SiO2 increased in height during oxidation, their relative locations were preserved. Their positions were mostly determined in the initial stage of oxidation and their heights increased during the subsequent oxidation. It was also found that, at many positions, protuberances on the SiO2 surface correspond to dimples at the interface and the dimples on the SiO2 surface correspond to the protuberances on the Si/SiO2 interface. With decreasing thickness, the thickness of the SiO2 layer becomes two-dimensionally less uniform. The Weibull slope of the time-dependent dielectric breakdown lifetime decreased when the thermal SiO2 films were grown on rougher Si substrates, which was attributed to film thickness nonuniformity. The SiO2 film formed on well-defined Si wafers showed a higher microscopic thickness uniformity and higher long-term reliability.
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