Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila

Beta-amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the beta-site APP-cleaving enzyme BACE, and the presenilins led to the generation of beta-amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates Abeta-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways

What should governments be doing to prevent diabetes throughout the life course?

Health systems and governments are increasingly required to implement measures that target at-risk populations to prevent noncommunicable diseases. In this review we lay out what governments should be doing to prevent diabetes throughout the life course. The following four target groups were used to structure the specific recommendations: (1) pregnant women and young families, (2) children and adolescents, (3) working age population, and (4) the elderly. The evidence to date supports the effectiveness of some known government policy measures, such as sugar taxes and regulatory measures in the (pre-)school setting for children and adolescents. Many of these appear to be more effective if they are part of a bundle of strategies and if they are supplemented by communication strategies. Although there is a current focus on strategies that target the individual, governments can make use of evidence-based population-level prevention strategies. More research and continuous evaluation of the overall and subgroup-specific effectiveness of policy strategies using high-quality longitudinal studies are needed

Family involvement in medical decision making in Europe and the United States: A replication and extension in five countries

Background In 2018, Alden et al. showed that the desired degree of family involvement in medical decisions is an individual preference that is largely independent from East-West cultural stereotypes. At the same time, individual-level interdependence influenced whether patients preferred more individual or more family involvement in their decision making together with their medical care provider. The present study provides empirical evidence and adds evidence for Europe for which no such data previously existed. Methods The present study is a direct replication and extension of the original Alden et al. (2018) study (N = 2031; Australia, China, Malaysia, India, South Korea, Thailand, United States [U.S.]), however, using survey data from four European countries (Austria, Belgium, Germany, Netherlands) and the United States (U.S.) with a total sample size of N = 2750. Results Random effects within-between models replicated the original primary finding that those with higher self-involvement in medical decision making preferred less family involvement. Furthermore, patients with lower self-independence, higher relational interdependence, and stronger beliefs in social hierarchy are more likely to want their families involved in medical decisions besides their health care provider. Conclusions These observed relationships are largely consistent both within and across the four European countries and the U.S. In conclusion, the results point to the importance of avoiding cultural stereotypes and instead, recognizing that patient desires for family involvement in medical decision making vary dramatically within cultures depending on multiple individual differences. Furthermore, a growing body of evidence suggests that these antecedents of family involvement as well as the construct itself may be measurable in diverse cultures with high levels of confidence in their reliability and validity

Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis.

The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective)

Early-life education may help bolster declarative memory in old age, especially for women

Although declarative memory declines with age, sex and education might moderate these weaknesses. We investigated effects of sex and education on nonverbal declarative (recognition) memory in 704 older adults (aged 58–98, 0–17 years of education). Items were drawings of real and made-up objects. Age negatively impacted declarative memory, though this age effect was moderated by sex and object-type: it was steeper for males than females, but only for real objects. Education was positively associated with memory, but also interacted with sex and object-type: education benefited women more than men (countering the age effects, especially for women), and remembering real more than made-up objects. The findings suggest that nonverbal memory in older adults is associated negatively with age but positively with education; both effects are modulated by sex, and by whether learning relates to preexisting or new information. The study suggests downstream benefits from education, especially for girls