Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2.

BACKGROUND: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer's disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release. METHODOLOGY/FINDINGS: We first showed that application of 50 nM Aβ42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, Aβ42 can be detected at the presynaptic terminals where it interacts with Synaptophysin. Furthermore, data from dissociated hippocampal neurons as well as biochemical data provide evidence that Aβ42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that Aβ42 affects baseline transmission. CONCLUSIONS/SIGNIFICANCE: Our observations provide a necessary and timely insight into cellular mechanisms that underlie the initial pathological events that lead to synaptic dysfunction in Alzheimer's disease. Our results demonstrate a new mechanism by which Aβ42 affects synaptic activity

Modelling the impact of calorie‐reduction interventions on population prevalence and inequalities in childhood obesity in the Southampton Women’s Survey

Background: In the United Kingdom, rates of childhood obesity are high and inequalities in obesity have widened in recent years. Children with obesity face heightened risks of living with obesity as adults and suffering from associated morbidities. Addressing population prevalence and inequalities in childhood obesity is a key priority for public health policymakers in the United Kingdom and elsewhere. Where randomized controlled trials are not possible, potential policy actions can be simulated using causal modeling techniques. Objectives: Using data from the Southampton Women's Survey (SWS), a cohort with high quality dietary and lifestyle data, the potential impact of policy-relevant calorie-reduction interventions on population prevalence and inequalities of childhood obesity was investigated. Methods: Predicted probabilities of obesity (using UK90 cut-offs) at age 6–7 years were estimated from logistic marginal structural models adjusting for observed calorie consumption at age 3 years (using food diaries) and confounding. A series of policy-relevant intervention scenarios were modeled to simulate reductions in energy intake (differing in effectiveness, the targeting mechanisms, and level of uptake). Results: At age 6–7 years, 8.3% of children were living with obesity, after accounting for observed energy intake and confounding. A universal intervention to lower median energy intake to the estimated average requirement (a 13% decrease), with an uptake of 75%, reduced obesity prevalence by 1% but relative and absolute inequalities remained broadly unchanged. Conclusions: Simulated interventions substantially reduced population prevalence of obesity, which may be useful in informing policymakers

The effect of screen advertising on children's dietary intake: A systematic review and meta-analysis

Evidence indicates that screen advertising for unhealthy food results in significant increases in dietary intake among children. This review was undertaken with the main aim of estimating the quantitative effect of screen advertising in experimental and nonexperimental conditions on children's dietary intake. Systematic searches were undertaken of interdisciplinary databases. Studies from 1980 to April 2018, all geography and languages, were included; participants were children and adolescents aged between 2 and 18 years; the intervention was screen advertising; and the outcome was dietary intake. Meta-analyses were conducted for measured and nonmeasured outcomes. Food advertising was found to increase dietary intake among children (age range 2-14, mean 8.8 years) in experimental conditions for television (TV) advertising and advergames. Meta-analysis revealed that children exposed to food advertising on TV (11 studies) and advergames (five studies) respectively consumed an average 60.0 kcal (95% confidence interval [CI], 3.1-116.9) and 53.2 kcal (95% CI, 31.5-74.9) more than children exposed to nonfood advertising. There was also an effect by body mass index (BMI). Findings from nonexperimental studies revealed that exposure to TV food advertising was positively associated with and predictive of dietary intake in children. Short-term exposure to unhealthy food advertising on TV and advergames increases immediate calorie consumption in children

Cluster J Mycobacteriophages: Intron Splicing in Capsid and Tail Genes

Bacteriophages isolated on Mycobacterium smegmatis mc2155 represent many distinct genomes sharing little or no DNA sequence similarity. The genomes are architecturally mosaic and are replete with genes of unknown function. A new group of genomes sharing substantial nucleotide sequences constitute Cluster J. The six mycobacteriophages forming Cluster J are morphologically members of the Siphoviridae, but have unusually long genomes ranging from 106.3 to 117 kbp. Reconstruction of the capsid by cryo-electron microscopy of mycobacteriophage BAKA reveals an icosahedral structure with a triangulation number of 13. All six phages are temperate and homoimmune, and prophage establishment involves integration into a tRNA-Leu gene not previously identified as a mycobacterial attB site for phage integration. The Cluster J genomes provide two examples of intron splicing within the virion structural genes, one in a major capsid subunit gene, and one in a tail gene. These genomes also contain numerous free-standing HNH homing endonuclease, and comparative analysis reveals how these could contribute to genome mosaicism. The unusual Cluster J genomes provide new insights into phage genome architecture, gene function, capsid structure, gene mobility, intron splicing, and evolution. © 2013 Pope et al

The mixed problem for the Laplacian in Lipschitz domains

We consider the mixed boundary value problem or Zaremba's problem for the Laplacian in a bounded Lipschitz domain in R^n. We specify Dirichlet data on part of the boundary and Neumann data on the remainder of the boundary. We assume that the boundary between the sets where we specify Dirichlet and Neumann data is a Lipschitz surface. We require that the Neumann data is in L^p and the Dirichlet data is in the Sobolev space of functions having one derivative in L^p for some p near 1. Under these conditions, there is a unique solution to the mixed problem with the non-tangential maximal function of the gradient of the solution in L^p of the boundary. We also obtain results with data from Hardy spaces when p=1.Comment: Version 5 includes a correction to one step of the main proof. Since the paper appeared long ago, this submission includes the complete paper, followed by a short section that gives the correction to one step in the proo

Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphe neurones and cranial motoneurones

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol(-/-) embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol(-/-) mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphe nucleus and the trochlear motor nucleus are absent in mol(-/-) embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins

Student evaluation of an OSCE in paediatrics at the University of the West Indies, Jamaica

BACKGROUND: The Faculty of Medical Sciences, University of the West Indies first implemented the Objective Structured Clinical Examination (OSCE) in the final MB Examination in Medicine and Therapeutics during the 2000–2001 academic year. Simultaneously, the Child Health Department initiated faculty and student training, and instituted the OSCE as an assessment instrument during the Child Health (Paediatric) clerkship in year 5. The study set out to explore student acceptance of the OSCE as part of an evaluation of the Child Health clerkship. METHODS: A self-administered questionnaire was completed by successive groups of students immediately after the OSCE at the end of each clerkship rotation. Main outcome measures were student perception of examination attributes, which included the quality of instructions and organisation, the quality of performance, authenticity and transparency of the process, and usefulness of the OSCE as an assessment instrument compared to other formats. RESULTS: There was overwhelming acceptance of the OSCE in Child Health with respect to the comprehensiveness (90%), transparency (87%), fairness (70%) and authenticity of the required tasks (58–78%). However, students felt that it was a strong anxiety-producing experience. And concerns were expressed regarding the ambiguity of some questions and inadequacy of time for expected tasks. CONCLUSION: Student feedback was invaluable in influencing faculty teaching, curriculum direction and appreciation of student opinion. Further psychometric evaluation will strengthen the development of the OSCE

Selling Health Promotion to Corporate America: Uses and Abuses of the Economic Argument

Economic considerations constitute a significant factor in businesses' interest in adopting health promotion (HP) programs and in the wellness community's attempts to sell such programming to business. Substantial elements of both the business and wellness communities believe that HP programs are financially profitable, in addition to, and as a result of, improving employees' health. Examination of the foundation of this belief, however, leads to the conclusion that underlying analyses have been techni cally flawed and have ignored important costs of HP programs. This article discusses the limitations of these analyses and outlines the framework of a model that could provide a sound assessment of the economics of workplace HP programs. In general, it is expected that resultant analyses would find less direct profit potential in work place HP programs but would emphasize the cost-effectiveness of many such efforts. The latter would force recognition that health, and not profit, is the principal benefit of health promotion programming. The distinction between the cost-effectiveness and cost-saving potential of health promotion is one that all interested parties should master.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66785/2/10.1177_109019818701400106.pd