SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA

Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially modified, in response to hormone binding, by phosphorylation, sumoylation, and acetylation; these modifications might thus contribute to DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is neuroprotective in many neurodegenerative disease models. Our studies reveal that SIRT1 also offers protection against polyQexpanded AR by deacetylating the AR at lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent studies revealed that the polyQ-expanded AR is hyperacetylated and that pharmacologic reduction of acetylation reduces mutantARaggregation. Moreover, genetic mutation to inhibit polyQ-expanded ARacetylation of lysines 630/632/633 substantially decreased its aggregation and completely abrogated its toxicity in cell lines and motor neurons. Our studies also reveal one means by which the AR acetylation state likely modifies polyQ-expanded AR metabolism and toxicity, through its effect on DHT-dependent AR stabilization. Overall, our findings reveal a neuroprotective function of SIRT1 that operates through its deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and AR acetylation as powerful therapeutic targets in SBMA. © 2011 the authors

Juegos serios para el tratamiento o la prevención de la depresión: una revisión sistemática

Serious games (computerised interventions which utilise gaming for serious purposes) have been shown to support improved outcomes in several health conditions. We aimed to review evidence regarding serious games for depression. We undertook electronic searches of PsycInfo, EMBASE and Medline, using terms relevant to computer games and depression. We included fulltext articles published in English in peer-reviewed literature since 2000, where the intervention was designed to treat or prevent depression and which included pre-and post-intervention measurement of depression. Nine studies relating to a total of six interventions met inclusion criteria. Most studies were small and were carried out by the developers of the programs. All were tested with young people (ages between 9 and 25 years). Most reported promising results with some positive impact on depression although one universal program had mixed results. Serious gaming interventions show promise for depression, however evidence is currently very limited.Se ha demostrado que los juegos serios (intervenciones computarizadas que utilizan juegos) mejoran los resultados en diferentes problemas de salud. Pretendemos examinar las evidencias de estos juegos para la depresión. Se realizaron búsquedas electrónicas en PsycINFO, EMBASE y Medline usando términos relacionados con juegos de ordenador y depresión. Se incluyeron artículos publicados desde el año 2000, donde se diseñó la intervención para tratar o prevenir la depresión incluyendo medidas pre- y post-intervención. Nueve estudios sobre un total de seis intervenciones cumplieron los criterios de inclusión. La mayoría de estos fueron pequeños y los llevaron a cabo los desarrolladores de los programas. Todos incluían población joven (9 - 25 años). La mayoría presentan resultados prometedores con un impacto positivo sobre la depresión aunque un programa universal tuvo resultados mixtos. Se concluye que las intervenciones basadas en juegos serios son prometedoras para la depresión, aunque la evidencia es todavía muy limitada

Doctors’ willingness to give honest answers about end of life practices : a cross-sectional survey.

OBJECTIVES: We aimed to (1) evaluate the extent to which doctors in New Zealand would be willing to answer honestly questions about their care of patients at the end of their lives and (2) identify the assurances that would encourage this. Results were compared with findings from a previous pilot study from the UK. DESIGN: Survey study involving a mailed questionnaire. SETTING: New Zealand hospital and community-based medical care settings. PARTICIPANTS: The questionnaire was mailed to a random sample of 800 doctors in New Zealand who were vocationally registered with the Medical Council of New Zealand in disciplines involving caring for patients at the end of their lives. PRIMARY AND SECONDARY OUTCOME MEASURES: Willingness to provide honest answers about various aspects of end-of-life care; assurances that might increase willingness to provide honest answers to questions about end-of-life practices. RESULTS: Completed questionnaires were returned by 436 doctors. The majority of respondents (59.9–91.5%) indicated willingness to provide honest answers to such questions. However, more than a third of doctors were unwilling to give honest answers to certain questions regarding euthanasia. These results are comparable with the UK data. Complete anonymity was the assurance most likely to encourage honest answering, with most of the respondents preferring the use of anonymous written replies. Respondents were less reassured by survey endorsements from regulatory bodies. Themes in free comments included the deterrent effect of medicolegal consequences, fear of censure from society, peers and the media and concerns about the motivations and potential uses of such research. CONCLUSIONS: Many New Zealand doctors were willing to give honest answers to questions about end-of-life practices, particularly if anonymity was guaranteed; others, however, expressed doubts or indicated that they would not be willing to provide honest answers to questions of this sort

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

SERIOUS GAMES FOR THE TREATMENT OR PREVENTION OF DEPRESSION: A SYSTEMATIC REVIEW

Abstract: Serious games (computerised interventions which utilise gaming for serious purposes) have been shown to support improved outcomes in several health conditions. We aimed to review evidence regarding serious games for depression. We undertook electronic searches of PsycInfo, EMBASE and Medline, using terms relevant to computer games and depression. We included fulltext articles published in English in peer-reviewed literature since 2000, where the intervention was designed to treat or prevent depression and which included pre-and post-intervention measurement of depression. Nine studies relating to a total of six interventions met inclusion criteria. Most studies were small and were carried out by the developers of the programs. All were tested with young people (ages between 9 and 25 years). Most reported promising results with some positive impact on depression although one universal program had mixed results. Serious gaming interventions show promise for depression, however evidence is currently very limited. Keywords: Depression; adolescents; computerised CBT; serious gaming; e-therapy. Juegos serios para el tratamiento o la prevención de la depresión: una revisión sistemática Resumen: Se ha demostrado que los juegos serios (intervenciones computarizadas que utilizan juegos) mejoran los resultados en diferentes problemas de salud. Pretendemos examinar las evidencias de estos juegos para la depresión. Se realizaron búsquedas electrónicas en PsycINFO, EMBA-SE y Medline usando términos relacionados con juegos de ordenador y depresión. Se incluyeron artículos publicados desde el año 2000, donde se diseñó la intervención para tratar o prevenir la depresión incluyendo medidas pre-y post-intervención. Nueve estudios sobre un total de seis intervenciones cumplieron los criterios de inclusión. La mayoría de estos fueron pequeños y los llevaron a cabo los desarrolladores de los programas. Todos incluían población joven (9 -25 años). La mayoría presentan resultados prometedores con un impacto positivo sobre la depresión aunque un programa universal tuvo resultados mixtos. Se concluye que las intervenciones basadas en juegos serios son prometedoras para la depresión, aunque la evidencia es todavía muy limitada

Rates of influenza vaccination in older adults and factors associated with vaccine use: A secondary analysis of the Canadian Study of Health and Aging

BACKGROUND: Influenza vaccination has been shown to reduce morbidity and mortality in the older adult population. In Canada, vaccination rates remain suboptimal. We identified factors predictive of influenza vaccination, in order to determine which segments of the older adult population might be targeted to increase coverage in influenza vaccination programs. METHODS: The Canadian Study of Health and Aging (CSHA) is a population-based national cohort study of 10263 older adults (≥ 65) conducted in 1991. We used data from the 5007 community-dwelling participants in the CSHA without dementia for whom self-reported influenza vaccination status is known. RESULTS: Of 5007 respondents, 2763 (55.2%) reported having received an influenza vaccination within the previous 2 years. The largest predictive factors for flu vaccination included: being married (57.4 vs. 52.6%, p = 0.0007), having attained a higher education (11.0 vs. 10.3 years, p < 0.0001), smoking (57.1% vs. 52.9%, p = 0.0032), more alcohol use (57.9% of those who drank more vs. 53.2% of those who drank less, p = 0.001), poorer self-rated health (54.1% of those with good self-rated health vs. 60.6% of those with poor self-rated health, p = 0.0006), regular exercise (56.8% vs. 52.0%, p = 0.001), and urban living (55.8% vs. 51.0%, p = 0.03). While many other differences were statistically significant, most were small (e.g. mean age 75.1 vs. 74.6 years for immunized vs. unimmunized older adults, p = 0.006, higher Modified Mini Mental Status Examination score (89.9 vs. 89.1, p < 0.0001), higher comorbidity (2.7 vs. 2.3 comorbidities, p < 0.0001). Residents of Ontario were more likely (64.6%) to report vaccination (p < 0.0001), while those living in Quebec were less likely to do so (48.2%, p < 0.0001). Factors retaining significance in a multivariate analysis included older age, higher education, married status, drinking alcohol, smoking, engaging in regular exercise, and having higher comorbidity. CONCLUSIONS: The vaccination rate in this sample, in whom influenza vaccination is indicated, was low (55.2%). Even in a publicly administered health care setting, influenza vaccination did not reach an important proportion of the elderly population. Whether these differences reflect patient preference or access remains to be determined

Increased SIRT3 Combined With PARP Inhibition Rescues Motor Function of SBMA Mice

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe