Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations

Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD

Challenges and Future Directions of Palliative Care

The unprecedented global development of palliative care over the past 50 years, originating in a counterculture and evolving through to an integral element of the health-care system, has enabled many more of the world’s population to have access to quality palliative care. More of the world’s population, particularly those living in high-income countries, such as Europe, North America, Australia, and parts of Asia, now die at an older age of, or with, noncommunicable diseases. The need for palliative care is also significant and largely unmet in low- and middle-income countries such as sub-Saharan Africa where communicable diseases such as HIV/AIDS, tuberculosis, and malaria continue to lead to expected deaths for many people.These new patterns of dying have implications for the configuration of international, national, and local palliative care policies, health-care service delivery models, palliative care delivery, engagement with primary and specialist clinical streams, workforce education, and the focus of future research.This chapter will describe the current and future challenges to palliative care development in low-, middle-, and high-income countries and the opportunities offered by adopting a public health approach, novel technologies, and remote monitoring and better engaging communities to increase palliative care access globally