Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

DNA methylation [1], [2] is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimer's disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities

Delineation of an insula-BNST circuit engaged by struggling behavior that regulates avoidance in mice

Active responses to stressors involve motor planning, execution, and feedback. The authors identify a neuronal projection from the insular cortex to the bed nucleus of the stria terminalis that is activated during motor struggling in response to restraint stress as a potential active coping response

Integrated human pseudoislet system and microfluidic platform demonstrate differences in GPCR signaling in islet cells

Pancreatic islets secrete insulin from β cells and glucagon from α cells, and dysregulated secretion of these hormones is a central component of diabetes. Thus, an improved understanding of the pathways governing coordinated β and α cell hormone secretion will provide insight into islet dysfunction in diabetes. However, the 3D multicellular islet architecture, essential for coordinated islet function, presents experimental challenges for mechanistic studies of intracellular signaling pathways in primary islet cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. Further, we developed a microperifusion system that allowed synchronous acquisition of GCaMP6f biosensor signal and hormone secretory profiles. We demonstrate the utility of this experimental approach by studying the effects of G i and G q GPCR pathways on insulin and glucagon secretion by expressing the designer receptors exclusively activated by designer drugs (DREADDs) hM4Di or hM3Dq. Activation of G i signaling reduced insulin and glucagon secretion, while activation of G q signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion, which occur through changes in intracellular Ca 2+ . The experimental approach of combining pseudoislets with a microfluidic system allowed the coregistration of intracellular signaling dynamics and hormone secretion and demonstrated differences in GPCR signaling pathways between human β and α cells. Integration of a pseudoislet approach with a microfluidic perifusion system and live cell imaging provides an experimental platform to investigate human islet biology

Human pseudoislet system enables detection of differences in G-protein-coupled-receptor signaling pathways between α and β cells

SUMMARY G-protein-coupled-receptors (GPCRs) modulate insulin secretion from β cells and glucagon secretion from α cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. We studied the G i and G q GPCR pathways by expressing the designer receptors exclusively activated by designer drugs (DREADDs) hM4Di or hM3Dq. Activation of G i signaling reduced insulin and glucagon secretion, while activation of G q signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion. Further, we developed a microperifusion system that allowed synchronous acquisition of GCaMP6f biosensor signal and hormone secretory profiles and showed that the dual effects for G q signaling occur through changes in intracellular Ca 2+ . By combining pseudoislets with a microfluidic system, we co-registered intracellular signaling dynamics and hormone secretion and demonstrated differences in GPCR signaling pathways between human β and α cells

Macro and micro sleep architecture and cognitive performance in older adults

We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults

Evidence supporting nutritional interventions for persons in early stage Alzheimer's disease (AD)

The purpose of this paper is to grade research evidence supporting nutritional interventions for persons with early stage dementias and to report the recommendations of a consensus panel. Thirty four studies were reviewed in the areas of dietary restriction, antioxidants, and Mediterranean diet with strong support from epidemiological studies found in all three areas. The body of evidence to support nutritional interventions in the prevention and treatment of AD is growing and has potential as a treatment modality following translational studies. The Journal of Nutrition, Health & Agin