The N-terminal intrinsically disordered domain of mgm101p is localized to the mitochondrial nucleoid.

The mitochondrial genome maintenance gene, MGM101, is essential for yeasts that depend on mitochondrial DNA replication. Previously, in Saccharomyces cerevisiae, it has been found that the carboxy-terminal two-thirds of Mgm101p has a functional core. Furthermore, there is a high level of amino acid sequence conservation in this region from widely diverse species. By contrast, the amino-terminal region, that is also essential for function, does not have recognizable conservation. Using a bioinformatic approach we find that the functional core from yeast and a corresponding region of Mgm101p from the coral Acropora millepora have an ordered structure, while the N-terminal domains of sequences from yeast and coral are predicted to be disordered. To examine whether ordered and disordered domains of Mgm101p have specific or general functions we made chimeric proteins from yeast and coral by swapping the two regions. We find, by an in vivo assay in S.cerevisiae, that the ordered domain of A.millepora can functionally replace the yeast core region but the disordered domain of the coral protein cannot substitute for its yeast counterpart. Mgm101p is found in the mitochondrial nucleoid along with enzymes and proteins involved in mtDNA replication. By attaching green fluorescent protein to the N-terminal disordered domain of yeast Mgm101p we find that GFP is still directed to the mitochondrial nucleoid where full-length Mgm101p-GFP is targeted

Mood instability, mental illness and suicidal ideas : results from a household survey

Purpose: There is weak and inconsistent evidence that mood instability (MI) is associated with depression, post traumatic stress disorder (PTSD) and suicidality although the basis of this is unclear. Our objectives were first to test whether there is an association between depression and PTSD, and MI and secondly whether MI exerts an independent effect on suicidal thinking over and above that explained by common mental disorders. Methods: We used data from the Adult Psychiatric Morbidity Survey 2007 (N = 7,131). Chi-square tests were used to examine associations between depression and PTSD, and MI, followed by regression modelling to examine associations between MI and depression, and with PTSD. Multiple logistic regression analyses were used to assess the independent effect of MI on suicidal thinking, after adjustment for demographic factors and the effects of common mental disorder diagnoses. Results: There are high rates of MI in depression and PTSD and the presence of MI increases the odds of depression by 10.66 [95 % confidence interval (CI) 7.51–15.13] and PTSD by 8.69 (95 % CI 5.90–12.79), respectively, after adjusting for other factors. Mood instability independently explained suicidal thinking, multiplying the odds by nearly five (odds ratio 4.82; 95 % CI 3.39–6.85), and was individually by some way the most important single factor in explaining suicidal thoughts. Conclusions: MI is strongly associated with depression and PTSD. In people with common mental disorders MI is clinically significant as it acts as an additional factor exacerbating the risk of suicidal thinking. It is important to enquire about MI as part of clinical assessment and treatment studies are required

Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al

How acceptable are antiretrovirals for the prevention of sexually transmitted HIV? A review of research on the acceptability of oral pre-exposure prophylaxis and treatment as prevention

Recent research has demonstrated how antiretrovirals (ARVs) could be effective in the prevention of sexually transmitted HIV. We review research on the acceptability of oral pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) for HIV prevention amongst potential users. We consider with whom, where and in what context this research has been conducted, how acceptability has been approached, and what research gaps remain. Findings from 33 studies show a lack of TasP research, PrEP studies which have focused largely on men who have sex with men (MSM) in a US context, and varied measures of acceptability. In order to identify when, where and for whom PrEP and TasP would be most appropriate and effective, research is needed in five areas: acceptability of TasP to people living with HIV; motivation for PrEP use and adherence; current perceptions and management of risk; the impact of broader social and structural factors; and consistent definition and operationalisation of acceptability which moves beyond adherence

Incongruous consultation behaviour: results from a UK-wide population survey

<p>Abstract</p> <p>Background</p> <p>Symptom characteristics are strong drivers of care seeking. Despite this, incongruous consultation behaviour occurs and has implications for both individuals and health-care services. The aim of this study was to determine how frequently incongruous consultation behaviour occurs, to examine whether it is more common for certain types of symptoms and to identify the factors associated with being an incongruous consulter.</p> <p>Methods</p> <p>An age and sex stratified random sample of 8,000 adults was drawn from twenty UK general practices. A postal questionnaire was used to collect detailed information on the presence and characteristics of 25 physical and psychological symptoms, actions taken to manage the symptoms, general health, attitudes to symptom management and demographic/socio-economic details. Two types of incongruous consultation behaviour were examined: i) consultation with a GP for symptoms self-rated as low impact and ii) no consultation with a GP for symptoms self-rated as high impact.</p> <p>Results</p> <p>A fifth of all symptoms experienced resulted in consultation behaviour which was incongruous based on respondents' own rating of the symptoms' impact. Low impact consultations were not common, although symptoms indicative of a potentially serious condition resulted in a higher proportion of low impact consultations. High impact non-consultations were more common, although there was no clear pattern in the type of associated symptoms. Just under half of those experiencing symptoms in the previous two weeks were categorised as an incongruous consulter (low impact consulter: 8.3%, high impact non-consulter: 37.1%). Employment status, having a chronic condition, poor health, and feeling that reassurance or advice from a health professional is important were associated with being a low impact consulter. Younger age, employment status, being an ex-smoker, poor health and feeling that not wasting the GPs time is important were associated with being a high impact non-consulter.</p> <p>Conclusions</p> <p>This is one of the first studies to examine incongruous consultation behaviour for a range of symptoms. High impact non-consultations were common and may have important health implications, particularly for symptoms indicative of serious disease. More research is now needed to examine incongruous consultation behaviour and its impact on both the public's health and health service use.</p

Suicide among Arab-Americans

BACKGROUND: Arab-American (AA) populations in the US are exposed to discrimination and acculturative stress-two factors that have been associated with higher suicide risk. However, prior work suggests that socially oriented norms and behaviors, which characterize recent immigrant ethnic groups, may be protective against suicide risk. Here we explored suicide rates and their determinants among AAs in Michigan, the state with the largest proportion of AAs in the US. METHODOLOGY/PRINCIPAL FINDINGS: ICD-9/10 underlying cause of death codes were used to identify suicide deaths from among all deaths in Michigan between 1990 and 2007. Data from the 2000 U.S. Census were collected for population denominators. Age-adjusted suicide rates among AAs and non-ethnic whites were calculated by gender using the direct method of standardization. We also stratified by residence inside or outside of Wayne County (WC), the county with the largest AA population in the state. Suicide rates were 25.10 per 100,000 per year among men and 6.40 per 100,000 per year among women in Michigan from 1990 to 2007. AA men had a 51% lower suicide rate and AA women had a 33% lower rate than non-ethnic white men and women, respectively. The suicide rate among AA men in WC was 29% lower than in all other counties, while the rate among AA women in WC was 20% lower than in all other counties. Among non-ethnic whites, the suicide rate in WC was higher compared to all other counties among both men (12%) and women (16%). CONCLUSIONS/SIGNIFICANCE: Suicide rates were higher among non-ethnic white men and women compared to AA men and women in both contexts. Arab ethnicity may protect against suicide in both sexes, but more so among men. Additionally, ethnic density may protect against suicide among Arab-Americans

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Ethnic Inequalities in Mortality: The Case of Arab-Americans

BACKGROUND: Although nearly 112 million residents of the United States belong to a non-white ethnic group, the literature about differences in health indicators across ethnic groups is limited almost exclusively to Hispanics. Features of the social experience of many ethnic groups including immigration, discrimination, and acculturation may plausibly influence mortality risk. We explored life expectancy and age-adjusted mortality risk of Arab-Americans (AAs), relative to non-Arab and non-Hispanic Whites in Michigan, the state with the largest per capita population of AAs in the US. METHODOLOGY/PRINCIPAL FINDINGS: Data were collected about all deaths to AAs and non-Arab and non-Hispanic Whites in Michigan between 1990 and 2007, and year 2000 census data were collected for population denominators. We calculated life expectancy, age-adjusted all-cause, cause-specific, and age-specific mortality rates stratified by ethnicity and gender among AAs and non-Arab and non-Hispanic Whites. Among AAs, life expectancies among men and women were 2.0 and 1.4 years lower than among non-Arab and non-Hispanic White men and women, respectively. AA men had higher mortality than non-Arab and non-Hispanic White men due to infectious diseases, chronic diseases, and homicide. AA women had higher mortality than non-Arab and non-Hispanic White women due to chronic diseases. CONCLUSIONS/SIGNIFICANCE: Despite better education and higher income, AAs have higher age-adjusted mortality risk than non-Arab and non-Hispanic Whites, particularly due to chronic diseases. Features specific to AA culture may explain some of these findings