Structure and Dynamics of Amyloid-β Segmental Polymorphisms

Conceived and designed the experiments: WB UH. Performed the experiments: WB. Analyzed the data: WB UH. Contributed reagents/materials/analysis tools: WB UH. Wrote the paper: WB UH.It is believed that amyloid-beta (Aβ) aggregates play a role in the pathogenesis of Alzheimer’s disease. Aβ molecules form β-sheet structures with multiple interaction sites. This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity. We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture. Our results demonstrate the importance of inter-sheet side chain-side chain contacts, hydrophobic contacts among the strands (β1 and β2) and of salt bridges in stabilizing the aggregates. Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile. The inter-peptide salt bridges between Asp23 and Lys28 are strong compared to intra-chain salt bridge and there is an exchange of the inter-chain salt-bridge with intra-chain salt bridge. As our results suggest that Aβ exists under physiological conditions as an ensemble of distinct segmental polymorphs, it may be necessary to account in the development of therapeutics for Alzheimer’s disease the differences in structural stability and aggregation behavior of the various Aβ polymorphic forms.Yeshttp://www.plosone.org/static/editorial#pee

The influence of muscular action on bone strength via exercise

Mechanical stimuli influence bone strength, with internal muscular forces thought to be the greatest stressors of bone. Consequently, the effects of exercise in improving and maintaining bone strength have been explored in a number of interventional studies. These studies demonstrate a positive effect of high-impact activities (i.e. where large muscle forces are produced) on bone strength, with benefits being most pronounced in interventions in early pubertal children. However, current studies have not investigated the forces acting on bones and subsequent deformation, preventing the development of optimised and targeted exercise interventions. Similarly, the effects of number and frequency of exercise repetitions and training sessions on bone accrual are unexplored. There are conflicting results as to gender effects on bone response to exercise, and the effects of age and starting age on the osteogenic effects of exercise are not well known. It also appears that exercise interventions are most effective in physically inactive people or counteracting conditions of disuse such as bed rest. Bone strength is only one component of fracture risk, and it may be that exercise resulting in improvements in, e.g., muscle force/power and/or balance is more effective than those whose effects are solely osteogenic. In summary, exercise is likely to be an effective tool in maintaining bone strength but current interventions are far from optimal. © Springer Science+Business Media 2013