An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.eber hereditary optic neuropathy (LHON), the first inherited mitochondrial (mt)DNA disease reported (1), is thought to be one of the most prevalent diseases caused by mtDNA missense mutations, having an estimated frequency of 15 in 100,000 (2). Most European LHON mutations occur in the mtDNA oxidative phosphorylation (OXPHOS) complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) genes, the three most common being the ND4 gene mutation at nucleotide G11778A causing an arginine 340 to histidine (R340H) substitution (1), the ND1 G3460A (A52T) mutation (3), and the ND6 T14484C (M64V) mutation (4). Milder LHON mutations are generally homoplasmic (pure mutant). In contrast, more severe mtDNA complex I ND gene mutations can cause basal ganglia degeneration presenting as dystonia or Leigh syndrome when homoplasmic but optic atrophy when heteroplasmic (mixed mutant and normal mtDNAs). Two examples of such mutations are ND6 G14459A (A72V) (5) and ND6 G14600A (P25L) (6).LHON generally presents in the second or third decade of life as acute or subacute onset of central vision loss, first in one eye and then in the other. The percentage of optic atrophy in patients varies markedly among pedigrees. Male patients are two to five times more likely to develop blindness than female patients (2), and maternal relatives who have not progressed to subacute optic atrophy can still show signs of visual impairment (7,8).In LHON, optic atrophy is associated with preferential loss of the central small-caliber optic nerve fibers of the papillomacular bundle, resulting in central scotoma but with sparing of the largercaliber peripheral fibers and retention of peripheral vision. The loss of the optic nerve fibers is attributed to the death of retinal ganglion cells (RGC) as a result of the high energy demand placed on the unmyelinated portion of the optic nerve fibers anterior to the lamina cribosa, an area associated with high mitochondrial density (2).Complex I is the largest and most intricate of the mitochondrial OXPHOS complexes. It is comprised of 45 subunits, 7 (ND1, -2, -3, -4, -4L, -5, and -6) of which are coded by the mtDNA (9). Complex I transfers electrons from NADH to ubiquinone, and the energy released from this redox reaction is coupled to pumping protons across the mitochondrial in...

The use of SVM (Support Vector Machine) as component classifier in AdaBoost may seem like going against the grain of the Boosting principle since SVM is not an easy classifier to train. Moreover, Wickramaratna et al. [2001. Performance degradation in boosting. In: Proceedings of the Second International Workshop on Multiple Classifier Systems, show that AdaBoost with strong component classifiers is not viable. In this paper, we shall show that AdaBoost incorporating properly designed RBFSVM (SVM with the RBF kernel) component classifiers, which we call AdaBoostSVM, can perform as well as SVM.Furthermore, the proposed AdaBoostSVM demonstrates better generalization performance than SVM on imbalanced classification problems. The key idea of AdaBoostSVM is that for the sequence of trained RBFSVM component classifiers, starting with large s values (implying weak learning), the s values are reduced progressively as the Boosting iteration proceeds. This effectively produces a set of RBFSVM component classifiers whose model parameters are adaptively different manifesting in better generalization as compared to AdaBoost approach with SVM component classifiers using a fixed (optimal) s value. From benchmark data sets, we show that our AdaBoostSVM approach outperforms other AdaBoost approaches using component classifiers such as Decision Trees and Neural Networks. AdaBoostSVM can be seen as a proof of concept of the idea proposed in Valentini and Dietterich [2004. Bias-variance analysis of support vector machines for the development of SVM-based ensemble methods. Journal of Machine Learning Research 5, that Adaboost with heterogeneous SVMs could work well. Moreover, we extend AdaBoostSVM to the Diverse AdaBoostSVM to address the reported accuracy/diversity dilemma of the original Adaboost. By designing parameter adjusting strategies, the distributions of accuracy and diversity over RBFSVM component classifiers are tuned to maintain a good balance between them and promising results have been obtained on benchmark data sets. r

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Antagonists at serotonin type 6 (5-HT 6 ) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT 6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic-(tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT 6 receptor antagonists.