Epigenetics and cell death: DNA hypermethylation in programmed retinal cell death.

BackgroundVertebrate genomes undergo epigenetic reprogramming during development and disease. Emerging evidence suggests that DNA methylation plays a key role in cell fate determination in the retina. Despite extensive studies of the programmed cell death that occurs during retinal development and degeneration, little is known about how DNA methylation might regulate neuronal cell death in the retina.MethodsThe developing chicken retina and the rd1 and rhodopsin-GFP mouse models of retinal degeneration were used to investigate programmed cell death during retinal development and degeneration. Changes in DNA methylation were determined by immunohistochemistry using antibodies against 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC).ResultsPunctate patterns of hypermethylation paralleled patterns of caspase3-dependent apoptotic cell death previously reported to occur during development in the chicken retina. Degenerating rd1 mouse retinas, at time points corresponding to the peak of rod cell death, showed elevated signals for 5mC and 5hmC in photoreceptors throughout the retina, with the most intense staining observed in the peripheral retina. Hypermethylation of photoreceptors in rd1 mice was associated with TUNEL and PAR staining and appeared to be cCaspase3-independent. After peak rod degeneration, during the period of cone death, occasional hypermethylation was observed in the outer nuclear layer.ConclusionThe finding that cell-specific increases of 5mC and 5hmC immunostaining are associated with the death of retinal neurons during both development and degeneration suggests that changes in DNA methylation may play a role in modulating gene expression during the process of retinal degeneration. During retinal development, hypermethylation of retinal neurons associates with classical caspase-dependent apoptosis as well as caspase-3 independent cell death, while hypermethylation in the rd1 mouse photoreceptors is primarily associated with caspase-3 independent programmed cell death. These findings suggest a previously unrecognized role for epigenetic mechanisms in the onset and/or progression of programed cell death in the retina

Gender and Personality in Media Rich Interfaces: Do Birds of a Feather Flock Together?

This research explores how user and interface characteristics can interact to influence decision performance. Specifically, this research examines the effects of gender, personality similarity, and increased levels of information cues on user involvement with a computer-based decision aid. In addition, this research explores the downstream effects of user involvement on decision time, effort, satisfaction, confidence, and quality. Findings indicate that gender has a significant influence on user involvement, and that involvement and the level of information cues provided by the decision aid have a direct influence on decision performance

Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors

The nuclear Dbf2-related protein kinases 1 and 2 (NDR1/2) are closely-related AGC family kinases that are strongly conserved through evolution. In mammals, they are activated inter alia by phosphorylation of an hydrophobic domain threonine-residue [NDR1(Thr-444)/NDR2(Thr-442)] by an extrinsic protein kinase followed by autophosphorylation of a catalytic domain serine-residue [NDR1(Ser-281)/NDR2(Ser-282)]. We examined NDR1/2 expression and regulation in primary cultures of neonatal rat cardiac myocytes and in perfused adult rat hearts. In myocytes, transcripts for NDR2, but not NDR1, were induced by the hypertrophic agonist, endothelin-1. NDR1(Thr-444) and NDR2(Thr-442) were rapidly phosphorylated (maximal in 15-30 min) in myocytes exposed to some phosphoprotein Ser-/Thr-phosphatase 1/2 inhibitors (calyculin A, okadaic acid) and, to a lesser extent, by hyperosmotic shock, low concentrations of H(2)O(2), or chelerythrine. In myocytes adenovirally-transduced to express FLAG-NDR2 (which exhibited a mainly-cytoplasmic localisation), the same agents increased FLAG-NDR2 activity as assessed by in vitro protein kinase assays, indicative of FLAG-NDR2(Ser-282/Thr-442) phosphorylation. Calyculin A-induced phosphorylation of NDR1(Thr-444)/NDR2(Thr-442) and activation of FLAG-NDR2 were inhibited by staurosporine, but not by other protein kinase inhibitors tested. In ex vivo rat hearts, NDR1(Thr-444)/NDR2(Thr-442) were phosphorylated in response to ischaemia-reperfusion or calyculin A. From a pathological viewpoint, we conclude that activities of NDR1 and NDR2 are responsive to cytotoxic stresses in heart preparations and this may represent a previously-unidentified response to myocardial ischaemia in vivo

Nuclear Physics Neutrino PreTown Meeting: Summary and Recommendations

In preparation for the nuclear physics Long Range Plan exercise, a group of 104 neutrino physicists met in Seattle September 21-23 to discuss both the present state of the field and the new opportunities of the next decade. This report summarizes the conclusions of that meeting and presents its recommendations. Further information is available at the workshop's web site. This report will be further reviewed at the upcoming Oakland Town Meeting.Comment: Latex, 31 pages. This version has been updated to include final Comments from the working group

Exploring the costs and outcomes of sexually transmitted infection (STI) screening interventions targeting men in football club settings: preliminary cost-consequence analysis of the SPORTSMART pilot randomised controlled trial

Background: The objective of this study was to compare the costs and outcomes of two sexually transmitted infection (STI) screening interventions targeted at men in football club settings in England, including screening promoted by team captains. Methods: A comparison of costs and outcomes was undertaken alongside a pilot cluster randomised control trial involving three trial arms: (1) captain-led and poster STI screening promotion; (2) sexual health advisor-led and poster STI screening promotion and (3) poster-only STI screening promotion (control/comparator). For all study arms, resource use and cost data were collected prospectively. Results: There was considerable variation in uptake rates between clubs, but results were broadly comparable across study arms with 50% of men accepting the screening offer in the captain-led arm, 67% in the sexual health advisor-led arm and 61% in the poster-only control arm. The overall costs associated with the intervention arms were similar. The average cost per player tested was comparable, with the average cost per player tested for the captain-led promotion estimated to be £88.99 compared with £88.33 for the sexual health advisor-led promotion and £81.87 for the poster-only (control) arm. Conclusions: Costs and outcomes were similar across intervention arms. The target sample size was not achieved, and we found a greater than anticipated variability between clubs in the acceptability of screening, which limited our ability to estimate acceptability for intervention arms. Further evidence is needed about the public health benefits associated with screening interventions in non-clinical settings so that their cost-effectiveness can be fully evaluated

Global Prospects for Dairy in Argentina and Chile: Evidence from Field Visits and Model Simulations

We assess the international competitiveness of the dairy industries in Argentina and Chile, combining recent market intelligence gathered from field visits with quantitative simulations of global policy reform scenarios. Both countries exhibit strong potential for export growth but face significant internal and external barriers to expanding their dairy industries. Global policy reforms would resolve some of the international obstacles to their expansion. Argentina has great potential, but it is handicapped by its current macroeconomic policies, trade policy distortions, and the uncertainty associated with policy implementation. Chile is more limited in terms of natural capacity for expansion, but it has a positive trade and investment environment

Examining the potential public health benefit of offering STI testing to men in amateur football clubs: evidence from cross-sectional surveys

Background: In Britain, young people continue to bear the burden of sexually transmitted infections (STIs) so efforts are required, especially among men, to encourage STI testing. The SPORTSMART study trialled an intervention that sought to achieve this by offering chlamydia and gonorrhoea test-kits to men attending amateur football clubs between October and December 2012. With football the highest participation team sport among men in England, this paper examines the potential public health benefit of offering STI testing to men in this setting by assessing their sociodemographic characteristics, sexual behaviours, and healthcare behaviour and comparing them to men in the general population. Methods: Data were collected from 192 (male) members of 6 football clubs in London, United Kingdom, aged 18–44 years via a 20-item pen-and-paper self-completion questionnaire administered 2 weeks after the intervention. These were compared to data collected from 409 men of a similar age who were resident in London when interviewed during 2010–2012 for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a national probability survey that used computer-assisted-personal-interviewing with computer-assisted-self-interview. Age standardisation and multivariable regression were used to account for sociodemographic differences between the surveys. Results: Relative to men in the general population, SPORTSMART men were younger (32.8 % vs. 21.7 % aged under 25 y), and more likely to report (all past year) at least 2 sexual partners (adjusted odds ratio, AOR: 3.25, 95 % CI: 2.15–4.92), concurrent partners (AOR: 2.05, 95 % CI: 1.39–3.02), and non-use of condoms (AOR: 2.17, 95 % CI: 1.39–3.41). No difference was observed in STI/HIV risk perception (AOR for reporting “not at all at risk” of STIs: 1.25, 95 % CI: 0.76–2.04; of HIV: AOR: 1.54, 95 % CI: 0.93–2.55), nor in reporting STI testing in the past year (AOR: 0.83, 95 % CI: 0.44–1.54), which was reported by only one in six men. Conclusions: Relative to young men in the general population, football club members who completed the SPORTSMART survey reported greater sexual risk behaviour but similar STI/HIV risk perception and STI testing history. Offering STI testing in amateur football clubs may therefore widen access to STI testing and health promotion messages for men at higher STI risk, which, given the minority currently testing and the popularity of football in England, should yield both individual and public health benefit

Using Group Model Building to Understand Factors That Influence Childhood Obesity in an Urban Environment

Background: Despite increased attention, conventional views of obesity are based upon individual behaviors, and children and parents living with obesity are assumed to be the primary problem solvers. Instead of focusing exclusively on individual reduction behaviors for childhood obesity, greater focus should be placed on better understanding existing community systems and their effects on obesity. The Milwaukee Childhood Obesity Prevention Project is a community-based coalition established to develop policy and environmental change strategies to impact childhood obesity in Milwaukee, Wisconsin. The coalition conducted a Group Model Building exercise to better understand root causes of childhood obesity in its community. Methods: Group Model Building is a process by which a group systematically engages in model construction to better understand the systems that are in place. It helps participants make their mental models explicit through a careful and consistent process to test assumptions. This process has 3 main components: (1) assembling a team of participants; (2) conducting a behavior-over-time graphs exercise; and (3) drawing the causal loop diagram exercise. Results: The behavior-over-time graph portion produced 61 graphs in 10 categories. The causal loop diagram yielded 5 major themes and 7 subthemes. Conclusions: Factors that influence childhood obesity are varied, and it is important to recognize that no single solution exists. The perspectives from this exercise provided a means to create a process for dialogue and commitment by stakeholders and partnerships to build capacity for change within the community

The Mare Reproductive Loss Syndrome and the Eastern Tent Caterpillar II: A Toxicokinetic/Clinical Evaluation and a Proposed Pathogenesis: Septic Penetrating Setae

Reviewing the mare reproductive loss syndrome (MRLS), it is proposed that the fundamental mechanism of this syndrome, which includes early fetal loss, late fetal loss, uveitis, pericarditis, and encephalitis, is tissue penetration by septic barbed setal fragments (septic penetrating setae) from Eastern tent caterpillars (Malacosoma americanum). Once ingested, these barbed setal fragments migrate through moving tissues, followed by rapid hematogenous spread of bacteria, bacterial emboli, and/or septic fragments of setae (septic penetrating setal emboli), collectively referred to as septic materials. Pathogenic bacteria, therefore, enter the horse as hitchhikers on or in the caterpillar setal fragments, and MRLS is caused by 1) the barbed setal fragments’ ability to penetrate moving tissues, including blood vessels, releasing septic materials, which rapidly distribute hematogenously; 2) the high sensitivity of the pregnant mare to bacteria from such septic materials introduced into the uterus, fetal membranes, or fetal fluids; 3) the unusually broad spectrum of bacterial pathogens carried on or in the setal fragments; and 4) the less effective antibacterial responses in certain susceptible extracellular fluids (e.g., fetal, ocular, pericardial, and cerebrospinal fluids). The driving force for MRLS pathology, including abortions, is septic material- induced bacterial proliferation, which provides a critical amplification step, enabling approximately 1-gram caterpillars to rapidly (32 hours) cause abortions in 680-kg (1,500- lb) mares. Calculations based on the unique eye data suggest that the actual number of distributing effective septic material quanta in field cases may be small—on the order of 10/horse/day—accounting for the lack of systemic clinical signs in affected horses. Therefore, it is proposed that MRLS starts with ingestion of Eastern tent caterpillars, followed by barbed setal fragments randomly penetrating intestinal tissues, including thinwalled venules and other blood vessels, with release of septic material that distributes hematogenously to all points in the body. Identification of abortigenic activity with the integument of the caterpillar and recent findings of large numbers of granulomatous lesions containing setal fragments in the intestines of pigs and rats directly supports the septic penetrating setal portion of the hypothesis. Analysis of the clinical syndromes and a toxicokinetic/ statistical analysis of MRLS suggest that setally-mediated introduction of septic material into blood vessels and other tissues may be key to understanding the very unusual toxicokinetics and pathogenesis of the unique group of syndromes that constitute MRLS. Like MRLS itself, this hypothesis is unique. The septic penetrating setal emboli portion is without precedent, is based on the unique clinical characteristics of MRLS, and appears well supported by ongoing experimental approaches