We explored the involvement of the muscle-specific intermediate filament protein desmin in the model of tumor necrosis factor α (TNF-α)–induced cardiomyopathy. We demonstrate that in mice overexpressing TNF-α in the heart (α–myosin heavy chain promoter-driven secretable TNF-α [MHCsTNF]), desmin is modified, loses its intercalated disk (ID) localization, and forms aggregates that colocalize with heat shock protein 25 and ubiquitin. Additionally, other ID proteins such as desmoplakin and β-catenin show similar localization changes in a desmin-dependent fashion. To address underlying mechanisms, we examined whether desmin is a substrate for caspase-6 in vivo as well as the implications of desmin cleavage in MHCsTNF mice. We generated transgenic mice with cardiac-restricted expression of a desmin mutant (D263E) and proved that it is resistant to caspase cleavage in the MHCsTNF myocardium. The aggregates are diminished in these mice, and D263E desmin, desmoplakin, and β-catenin largely retain their proper ID localization. Importantly, D263E desmin expression attenuated cardiomyocyte apoptosis, prevented left ventricular wall thinning, and improved the function of MHCsTNF hearts.
In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dosedependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF 165 ). OTR4120 showed high affinity binding to VEGF 165 (K d ؍ 2.2 nM), as compared with heparin (K d ؍ 15 nM), and potentiated the affinity of VEGF 165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF 165 -induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel TM plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF 165 -induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel TM sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF 165 -induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.
In large-scale or evolving networks, such as the Internet, there is no authority possible to enforce a centralized traffic management. In such situations, game theory, and especially the concepts of Nash equilibria and congestion games [Rosenthal 1973] are a suitable framework for analyzing the equilibrium effects of selfish routes selection to network delays. We focus here on single-commodity networks where selfish users select paths to route their loads (represented by arbitrary integer weights). We assume that individual link delays are equal to the total load of the link. We then focus on the algorithm suggested in Fotakis et al. [2005], i.e., a potential-based method for finding pure Nash equilibria in such networks. A superficial analysis of this algorithm gives an upper bound on its time, which is polynomial in n (the number of users) and the sum of their weights W . This bound can be exponential in n when some weights are exponential. We provide strong experimental evidence that this algorithm actually converges to a pure Nash equilibrium in polynomial time. More specifically, our experimental findings suggest that the running time is a polynomial function of n and log W . In addition, we propose an initial allocation of users to paths that dramatically accelerates this algorithm, compared to an arbitrary initial allocation. A by-product of our research is the discovery of a weighted potential function when link delays are exponential to their loads. This asserts the existence of pure Nash equilibria for these delay functions and extends the result of Fotakis et al. [2005].
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