The regulated expansion of membrane contact sites, which mediate the nonvesicular exchange of lipids between organelles, requires the recruitment of additional contact site proteins. Yeast Vps13 ...dynamically localizes to membrane contacts that connect the ER, mitochondria, endosomes, and vacuoles and is recruited to the prospore membrane in meiosis, but its targeting mechanism is unclear. In this study, we identify the sorting nexin Ypt35 as a novel adaptor that recruits Vps13 to endosomal and vacuolar membranes. We characterize an interaction motif in the Ypt35 N terminus and identify related motifs in the prospore membrane adaptor Spo71 and the mitochondrial membrane protein Mcp1. We find that Mcp1 is a mitochondrial adaptor for Vps13, and the Vps13-Mcp1 interaction, but not Ypt35, is required when ER-mitochondria contacts are lost. All three adaptors compete for binding to a conserved six-repeat region of Vps13 implicated in human disease. Our results support a competition-based model for regulating Vps13 localization at cellular membranes.
Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte ...progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9–12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.
The article Niacin‑mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. ...Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher’s internet.
Dietary modification would be the most translatable, cost-efficient, and, likely, the safest approach available that can reduce the reliance on pharmaceutical treatments for treating acute or chronic ...neurological disorders. A wide variety of evidence suggests that the ketogenic diet (KD) could have beneficial effects in acute traumatic events, such as spinal cord injury and traumatic brain injury. Review of existing human and animal studies revealed that KD can improve motor neuro-recovery, gray matter sparing, pain thresholds, and neuroinflammation and decrease depression. Although the exact mechanism by which the KD provides neuroprotection is not fully understood, its effects on cellular energetics, mitochondria function and inflammation are likely to have a role.
Abstract
Background
frailty syndrome is common amongst older people. Low physical activity is part of frailty, but long-term prospective studies investigating leisure-time physical activity (LTPA) ...during the life course as a predictor of frailty are still warranted. The aim of this study is to investigate whether earlier life LTPA predicts frailty in older age.
Methods
the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older adults (aged 60–77 years) from the general population who were at increased risk of cognitive decline. Frailty was assessed for 1,137 participants at a baseline visit using a modified version of Fried’s phenotype, including five criteria: weight loss, exhaustion, weakness, slowness and low physical activity. Self-reported data on earlier life LTPA were available from previous population-based studies (average follow-up time 13.6 years). A binomial logistic regression analysis was used to investigate the association between earlier life LTPA and pre-frailty/frailty in older age.
Results
the prevalence of frailty and pre-frailty was 0.8% and 27.3%, respectively. In the analyses, pre-frail and frail groups were combined. People who had been physically very active (OR 0.37, 95% CI 0.23–0.60) or moderately active (OR 0.45, 95% CI 0.32–0.65) earlier in life had lower odds of becoming pre-frail/frail than individuals who had been sedentary.
Conclusions
frailty was rare in this relatively healthy study population, but almost a third of the participants were pre-frail. Earlier life LTPA was associated with lower levels of pre-frailty/frailty. The results highlight the importance of physical activity when aiming to promote healthy old age.
•Sustainability challenges require both specialized and integrative approaches.•Domination of specialism and reductionism calls for emphasis on comprehensiveness.•The GHH framework can be used as a ...tool to add comprehensiveness in education.•The framework consists of three dimensions: generalism, holism, and holarchism.•The dialectical approach combines comprehensive and differentiative approaches.
Sustainability challenges such as climate change, biodiversity loss, poverty and rapid urbanization are complex and strongly interrelated. In order to successfully deal with these challenges, we need comprehensive approaches that integrate knowledge from multiple disciplines and perspectives and emphasize interconnections. In short, they aid in observing matters in a wider perspective without losing an understanding of the details. In order to teach and learn a comprehensive approach, we need to better understand what comprehensive thinking actually is. In this paper, we present a conceptual framework for a comprehensive approach, termed the GHH framework. The framework comprises three dimensions: generalism, holism, and holarchism. It contributes to the academic community’s understanding of comprehensive thinking and it can be used for integrating comprehensive thinking into education. Also, practical examples of the application of the framework in university teaching are presented. We argue that an ideal approach to sustainability challenges and complexity in general is a balanced, dialectical combination of comprehensive and differentiative approaches. The current dominance of specialization, or the differentiative approach, in university education calls for a stronger emphasis on comprehensive thinking skills. Comprehensiveness should not be considered as a flawed approach, but should instead be considered as important an aspect in education as specialized and differentiative skills.
As part of a study of the costs of rural health services in Papua New Guinea, an examination was made of the distribution and performance of rural health staff. The cost study and the use of a ...staffing model which related the staffing of health facilities to their workload both yielded valuable new data about the cost, distribution and productivity of rural health staff. Key findings of the workforce study included an inequitable distribution of staff among facilities, concentration on curative activities, better performance of staff of church run facilities and consequential variations between different categories of health worker in the allocation of work time to priority programmes. These findings are already being used to guide Papua New Guinea's health policy. They have also opened up several new important questions, such as the impact of different categories and mixes of staff on quality of health centre performance.
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