Skeletal muscle disuse atrophy : implications on intracellular signaling pathways and mitochondrial permeability transition pore function

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Demenciák megelőzésének gyógyszeres és egyéb lehetőségei: irodalmi összefoglaló

BACKGROUND: At present 34 million people live with Alzheimer's disease around the world. This figure is expected to triple in the next 40 years. The major cause of this increase is the well-known aging of the society in Europe and in the US as well. AIMS AND METHODS: In this paper we review the results of the last 10 years, and discuss those pharmaceutical and other methods, which can be effective in the prevention of dementias. RESULTS: The most important pharmaceutical agents are beta secretase inhibitors, and active and passive immunizations. Several drugs in these groups are in phase III at the moment. The results from studies with intranasal insulin are also encouraging. As a non-drug option Mediterranean diet can be effective. However at present cognitive trainings seem to be the most effective in the prevention of dementias. These remediation therapies are based on the lifelong plasticity of the human brain. CONCLUSIONS: In summary we can conclude that there are promising drug developments in progess for the prevention of dementias, but the breakthrough has not been achieved yet. At present the best option is decreasing risk factors, that is treatment of hypertension, prevention of obesity and diabetes, and cognitive trainings are recommended for prevention

Relating the shape of protein binding sites to binding affinity profiles: is there an association?

<p>Abstract</p> <p>Background</p> <p>Various pattern-based methods exist that use <it>in vitro </it>or <it>in silico </it>affinity profiles for classification and functional examination of proteins. Nevertheless, the connection between the protein affinity profiles and the structural characteristics of the binding sites is still unclear. Our aim was to investigate the association between virtual drug screening results (calculated binding free energy values) and the geometry of protein binding sites. Molecular Affinity Fingerprints (MAFs) were determined for 154 proteins based on their molecular docking energy results for 1,255 FDA-approved drugs. Protein binding site geometries were characterized by 420 PocketPicker descriptors. The basic underlying component structure of MAFs and binding site geometries, respectively, were examined by principal component analysis; association between principal components extracted from these two sets of variables was then investigated by canonical correlation and redundancy analyses.</p> <p>Results</p> <p>PCA analysis of the MAF variables provided 30 factors which explained 71.4% of the total variance of the energy values while 13 factors were obtained from the PocketPicker descriptors which cumulatively explained 94.1% of the total variance. Canonical correlation analysis resulted in 3 statistically significant canonical factor pairs with correlation values of 0.87, 0.84 and 0.77, respectively. Redundancy analysis indicated that PocketPicker descriptor factors explain 6.9% of the variance of the MAF factor set while MAF factors explain 15.9% of the total variance of PocketPicker descriptor factors. Based on the salient structures of the factor pairs, we identified a clear-cut association between the shape and bulkiness of the drug molecules and the protein binding site descriptors.</p> <p>Conclusions</p> <p>This is the first study to investigate complex multivariate associations between affinity profiles and the geometric properties of protein binding sites. We found that, except for few specific cases, the shapes of the binding pockets have relatively low weights in the determination of the affinity profiles of proteins. Since the MAF profile is closely related to the target specificity of ligand binding sites we can conclude that the shape of the binding site is not a pivotal factor in selecting drug targets. Nonetheless, based on strong specific associations between certain MAF profiles and specific geometric descriptors we identified, the shapes of the binding sites do have a crucial role in virtual drug design for certain drug categories, including morphine derivatives, benzodiazepines, barbiturates and antihistamines.</p

EEG and ERP biomarkers of Alzheimer's disease: a critical review

Here we critically review studies that used electroencephalography (EEG) or event-related potential (ERP) indices as a biomarker of Alzheimer's disease. In the first part we overview studies that relied on visual inspection of EEG traces and spectral characteristics of EEG. Second, we survey analysis methods motivated by dynamical systems theory (DST) as well as more recent network connectivity approaches. In the third part we review studies of sleep. Next, we compare the utility of early and late ERP components in dementia research. In the section on mismatch negativity (MMN) studies we summarize their results and limitations and outline the emerging field of computational neurology. In the following we overview the use of EEG in the differential diagnosis of the most common neurocognitive disorders. Finally, we provide a summary of the state of the field and conclude that several promising EEG/ERP indices of synaptic neurotransmission are worth considering as potential biomarkers. Furthermore, we highlight some practical issues and discuss future challenges as well