Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric oxide synthase (nNOS) and inhibits its catalytic activity. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we also found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3 deficiency.
AbstTuct We propose linear programming formulatiens of support vector machines (SVM). Unlike standard SVMs which use quadratic programs, eur approach explores a fairly small dimensional subspace of a feature space to construct the nonlinear discrirninator. This allows us to obtain the discriminator by solving a smaller sized linear program. We demonstrate that an orthonormal basis of the subspace can be implicitly t・reated by eigenvectors of the Gram matrix defined by the asseciated kernel function. When the number of given data points is very large, we construct a subspace by randonn sampling of data points. Numerical experiments indicate that the subspace generated by less than 2% of the entire training data points achieves reasonable performance for a fairly large instance with 60000 data points.
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