Loss of Dictyostelium HSPC300 causes a scar-like phenotype and loss of SCAR protein

<p>Abstract</p> <p>Background</p> <p>SCAR/WAVE proteins couple signalling to actin polymerization, and are thus fundamental to the formation of pseudopods and lamellipods. They are controlled as part of a five-membered complex that includes the tiny HSPC300 protein. It is not known why SCAR/WAVE is found in such a large assembly, but in <it>Dictyostelium </it>the four larger subunits have different, clearly delineated functions.</p> <p>Results</p> <p>We have generated <it>Dictyostelium </it>mutants in which the HSPC300 gene is disrupted. As has been seen in other regulatory complex mutants, SCAR is lost in these cells, apparently by a post-translational mechanism, though PIR121 levels do not change. HSPC300 knockouts resemble <it>scar </it>mutants in slow migration, roundness, and lack of large pseudopods. However <it>hspc300</it>-colonies on bacteria are larger and more similar to wild type, suggesting that some SCAR function can survive without HSPC300. We find no evidence for functions of HSPC300 outside the SCAR complex.</p> <p>Conclusion</p> <p>HSPC300 is essential for most SCAR complex functions. The phenotype of HSPC300 knockouts is most similar to mutants in <it>scar</it>, not the other members of the SCAR complex, suggesting that HSPC300 acts most directly on SCAR itself.</p

Behavioural and Cognitive Associations of Short Stature at 5 Years

Objectives To determine the extent to which childhood short stature is associated with cognitive, behavioural and chronic health problems, and whether these problems could be attributed to recognized adverse biological, psychosocial or psychological factors. Methodology At their first antenatal session, 8556 women were enrolled in a prospective study of pregnancy. When their children were 4 and 6 years of age, mothers completed a detailed questionnaire concerning their child's health and behaviour. A Peabody Picture Vocabulary Test-Revised (PPVT-R) was completed by the child at 5 years of age. Z scores were used to categorize height measurements in 3986 children. The relationship of these height categories with the child's health, and behavioural and cognitive problems was then examined. Results No association was found between height and symptoms of chronic disease or behaviour problems in boys or girls. On the unadjusted analysis, mean PPVT-R scores were significantly lower in boys with heights < 3 percentile and 3-10 percentile compared with study children between 10 to 90 percentile (P < 0.01). Scores were similarly significantly lower in girls with heights < 3 percentile and 3-10 percentile (P = 0.01). Even after adjusting for psychosocial and biological confounders, short stature remained a significant predictor for lower PPVT-R scores in both boys and girls, although height only accounted for 1.1% of the variance in scores in boys and 0.5% of the variance in PPVT-R scores in girls. Psychosocial factors had a greater role than height in determining PPVT-R scores at 5 years of age. Conclusions These findings suggest a significant, though small, association between height and PPVT-R scores at 5 years of age, independent of psychosocial disadvantage and known biological risk factors

High-Resolution X-Ray Structure of the Trimeric Scar/WAVE-Complex Precursor Brk1

The Scar/WAVE-complex links upstream Rho-GTPase signaling to the activation of the conserved Arp2/3-complex. Scar/WAVE-induced and Arp2/3-complex-mediated actin nucleation is crucial for actin assembly in protruding lamellipodia to drive cell migration. The heteropentameric Scar/WAVE-complex is composed of Scar/WAVE, Abi, Nap, Pir and a small polypeptide Brk1/HSPC300, and recent work suggested that free Brk1 serves as a homooligomeric precursor in the assembly of this complex. Here we characterized the Brk1 trimer from Dictyostelium by analytical ultracentrifugation and gelfiltration. We show for the first time its dissociation at concentrations in the nanomolar range as well as an exchange of subunits within different DdBrk1 containing complexes. Moreover, we determined the three-dimensional structure of DdBrk1 at 1.5 Å resolution by X-ray crystallography. Three chains of DdBrk1 are associated with each other forming a parallel triple coiled-coil bundle. Notably, this structure is highly similar to the heterotrimeric α-helical bundle of HSPC300/WAVE1/Abi2 within the human Scar/WAVE-complex. This finding, together with the fact that Brk1 is collectively sandwiched by the remaining subunits and also constitutes the main subunit connecting the triple-coil domain of the HSPC300/WAVE1/Abi2/ heterotrimer to Sra1(Pir1), implies a critical function of this subunit in the assembly process of the entire Scar/WAVE-complex

Do changes in traditional coronary heart disease risk factors over time explain the association between socio-economic status and coronary heart disease?

<p>Abstract</p> <p>Background</p> <p>Socioeconomic status (SES) predicts coronary heart disease independently of the traditional risk factors included in the Framingham risk score. However, it is unknown whether <it>changes </it>in Framingham risk score variables over time explain the association between SES and coronary heart disease. We examined this question given its relevance to risk assessment in clinical decision making.</p> <p>Methods</p> <p>The Atherosclerosis Risk in Communities study data (initiated in 1987 with 10-years follow-up of 15,495 adults aged 45-64 years in four Southern and Mid-Western communities) were used. SES was assessed at baseline, dichotomized as low SES (defined as low education and/or low income) or not. The time dependent variables - smoking, total and high density lipoprotein cholesterol, systolic blood pressure and use of blood pressure lowering medication - were assessed every three years. Ten-year incidence of coronary heart disease was based on EKG and cardiac enzyme criteria, or adjudicated death certificate data. Cox survival analyses examined the contribution of SES to heart disease risk independent of baseline Framingham risk score, without and with further adjustment for the time dependent variables.</p> <p>Results</p> <p>Adjusting for baseline Framingham risk score, low SES was associated with an increased coronary heart disease risk (hazard ratio [HR] = 1.53; 95% Confidence Interval [CI], 1.27 to1.85). After further adjustment for the time dependent variables, the SES effect remained significant (HR = 1.44; 95% CI, 1.19 to1.74).</p> <p>Conclusion</p> <p>Using Framingham Risk Score alone under estimated the coronary heart disease risk in low SES persons. This bias was not eliminated by subsequent changes in Framingham risk score variables.</p

Rapid appraisal of barriers to the diagnosis and management of patients with dementia in primary care: a systematic review

<p>Abstract</p> <p>Background</p> <p>The diagnosis of dementia in primary care is perceived as a problem across countries and systems, resulting in delayed recognition and adverse outcomes for patients and their carers. Improving its early detection is an area identified for development in the English National Dementia Strategy 2009; there are thought to be multiple benefits to the patient, family, and resources by doing this. The aim of this review was to carry out a rapid appraisal in order to inform the implementation of this policy.</p> <p>Method</p> <p>Publications in English up to August 2009 relating to barriers to the recognition of dementia, were identified by a broad search strategy, using electronic databases MEDLINE, EMBASE, and psycINFO. Exclusion criteria included non-English language, studies about pharmacological interventions or screening instruments, and settings without primary care.</p> <p>Results</p> <p>Eleven empirical studies were found: 3 quantitative, 6 qualitative, and 2 with mixed methodologies. The main themes from the qualitative studies were found to be lack of support, time constraints, financial constraints, stigma, diagnostic uncertainty, and disclosing the diagnosis. Quantitative studies yielded diverse results about knowledge, service support, time constraints, and confidence. The factors identified in qualitative and quantitative studies were grouped into 3 categories: patient factors, GP factors and system characteristics.</p> <p>Conclusion</p> <p>Much can still be done in the way of service development and provision, GP training and education, and the eradication of stigma attached to dementia, to improve the early detection and management of dementia. Implementation of dementia strategies should include attention to all three categories of barriers. Further research should focus on their interaction, using different methods from studies to date.</p

Not saying, not doing: Convergences, contingencies and causal mechanisms of state reform and decentralisation in Hollande’s France

Are States in contemporary Europe subject to new forms of convergence under the impact of economic crisis, enhanced European steering and international monitoring? Or is the evolution of governance (national and sub-national) driven fundamentally by diverging, mainly domestic pressures? Drawing on extensive new data, the article combines analysis of the State Modernisation and Decentralisation reform programmes of the Hollande–Ayrault administration, drawing comparisons where appropriate with the previous Sarkozy regime. The limits of President Hollande’s anti-Sarkozy method were demonstrated in the first 2 years; framing state reform and decentralisation in negative terms prevented the emergence of a coherent legitimising discourse. The empirical data is interpreted with reference to a comparative ‘States of Convergence’ framework, which is conceptualised as a heuristic device for analysing variation between places, countries and policy fields. The article concludes that the forces of hard convergence are gaining ground, as economic, epistemic and European pressures continually challenge the forces of institutional inertia

Influence of socio-economic status on habitual physical activity and sedentary behavior in 8- to 11-year old children

<p>Abstract</p> <p>Background</p> <p>While socio-economic status has been shown to be an important determinant of health and physical activity in adults, results for children and adolescents are less consistent. The purpose of this study, therefore, is to examine whether physical activity and sedentary behavior differs in children by socio-economic status (SES) independent of body mass index.</p> <p>Methods</p> <p>Data were from two cohorts including 271 children (117 males; 154 females) in study 1 and 131 children in study 2 (63 males; 68 females). The average age was 9.6 and 8.8 years respectively. Height and body mass were assessed according to standard procedures and body mass index (BMI, kg/m²) was calculated. Parent-reported household income was used to determine SES. Habitual, free-living physical activity (PA) was assessed by a pedometer (steps/day) in study 1 and accelerometer (time spent in moderate-to-vigorous PA) in study 2. Self-reported time spent watching TV and on the computer was used as measure of sedentary behavior. Differences in PA and sedentary behavior by SES were initially tested using ANOVA. Further analyses used ANCOVA controlling for BMI, as well as leg length in the pedometer cohort.</p> <p>Results</p> <p>In study 1, mean daily steps differed significantly among SES groups with lower SES groups approximating 10,500 steps/day compared to about 12,000 steps/day in the higher SES groups. These differences remained significant (p < 0.05) when controlling for leg length. Lower SES children, however, had higher body mass and BMI compared to higher SES groups (p < 0.05) and PA no longer remained significant when further controlling for BMI. In study 2 results depended on the methodology used to determine time spent in moderate-to-vigorous physical activity (MVPA). Only one equation resulted in significant group differences (p = 0.015), and these differences remained after controlling for BMI. Significant differences between SES groups were shown for sedentary behavior in both cohorts (P < 0.05) with higher SES groups spending less time watching TV than low SES groups.</p> <p>Conclusions</p> <p>Children from a low SES show a trend of lower PA levels and spend more time in sedentary behavior than high SES children; however, differences in PA were influenced by BMI. The higher BMI in these children might be another factor contributing to increased health risks among low SES children compared to children from with a higher SES.</p

Lifecourse socioeconomic circumstances and multimorbidity among older adults

<p>Abstract</p> <p>Background</p> <p>Many older adults manage multiple chronic conditions (i.e. multimorbidity); and many of these chronic conditions share common risk factors such as low socioeconomic status (SES) in adulthood and low SES across the lifecourse. To better capture socioeconomic condition in childhood, recent research in lifecourse epidemiology has broadened the notion of SES to include the experience of specific hardships. In this study we investigate the association among childhood financial hardship, lifetime earnings, and multimorbidity.</p> <p>Methods</p> <p>Cross-sectional analysis of 7,305 participants age 50 and older from the 2004 Health and Retirement Study (HRS) who also gave permission for their HRS records to be linked to their Social Security Records in the United States. Zero-inflated Poisson regression models were used to simultaneously model the likelihood of the absence of morbidity and the expected number of chronic conditions.</p> <p>Results</p> <p>Childhood financial hardship and lifetime earnings were not associated with the absence of morbidity. However, childhood financial hardship was associated with an 8% higher number of chronic conditions; and, an increase in lifetime earnings, operationalized as average annual earnings during young and middle adulthood, was associated with a 5% lower number of chronic conditions reported. We also found a significant interaction between childhood financial hardship and lifetime earnings on multimorbidity.</p> <p>Conclusions</p> <p>This study shows that childhood financial hardship and lifetime earnings are associated with multimorbidity, but not associated with the absence of morbidity. Lifetime earnings modified the association between childhood financial hardship and multimorbidity suggesting that this association is differentially influential depending on earnings across young and middle adulthood. Further research is needed to elucidate lifecourse socioeconomic pathways associated with the absence of morbidity and the presence of multimorbidity among older adults.</p