Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression.

Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA Pol(II) is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts

Annular electroconvection with shear

We report experiments on convection driven by a radial electrical force in suspended annular smectic A liquid crystal films. In the absence of an externally imposed azimuthal shear, a stationary one-dimensional (1D) pattern consisting of symmetric vortex pairs is formed via a supercritical transition at the onset of convection. Shearing reduces the symmetries of the base state and produces a traveling 1D pattern whose basic periodic unit is a pair of asymmetric vortices. For a sufficiently large shear, the primary bifurcation changes from supercritical to subcritical. We describe measurements of the resulting hysteresis as a function of the shear at radius ratio $\eta \sim 0.8$. This simple pattern forming system has an unusual combination of symmetries and control parameters and should be amenable to quantitative theoretical analysis.Comment: 12 preprint pages, 3 figures in 2 parts each. For more info, see http://mobydick.physics.utoronto.c

Evaluating a team-based approach to research capacity building using a matched-pairs study design

Background: There is a continuing need for research capacity building initiatives for primary health care professionals. Historically strategies have focused on interventions aimed at individuals but more recently theoretical frameworks have proposed team-based approaches. Few studies have evaluated these new approaches. This study aims to evaluate a team-based approach to research capacity building (RCB) in primary health using a validated quantitative measure of research capacity in individual, team and organisation domains

Birth weight, cardiometabolic risk factors and effect modification of physical activity in children and adolescents : pooled data from 12 international studies

Objectives: Low and high birth weight is associated with higher levels of cardiometabolic risk factors and adiposity in children and adolescents, and increases the risk of cardiovascular diseases, obesity, and early mortality later in life. Moderate-to-vigorous physical activity (MVPA) is associated with lower cardiometabolic risk factors and may mitigate the detrimental consequences of high or low birth weight. Thus, we examined whether MVPA modified the associations between birth weight and cardiometabolic risk factors in children and adolescents. Methods: We used pooled individual data from 12 cohort- or cross-sectional studies including 9,100 children and adolescents. Birth weight was measured at birth or maternally reported retrospectively. Device-measured physical activity (PA) and cardiometabolic risk factors were measured in childhood or adolescence. We tested for associations between birth weight, MVPA, and cardiometabolic risk factors using multilevel linear regression, including study as a random factor. We tested for interaction between birth weight and MVPA by introducing the interaction term in the models (birth weight x MVPA). Results: Most of the associations between birth weight (kg) and cardiometabolic risk factors were not modified by MVPA (min/day), except between birth weight and waist circumference (cm) in children (p = 0.005) and HDL-cholesterol (mmol/l) in adolescents (p = 0.040). Sensitivity analyses suggested that some of the associations were modified by VPA, i.e., the associations between birth weight and diastolic blood pressure (mmHg) in children (p = 0.009) and LDL- cholesterol (mmol/l) (p = 0.009) and triglycerides (mmol/l) in adolescents (p = 0.028). Conclusion: MVPA appears not to consistently modify the associations between low birth weight and cardiometabolic risk. In contrast, MVPA may mitigate the association between higher birth weight and higher waist circumference in children. MVPA is consistently associated with a lower cardiometabolic risk across the birth weight spectrum. Optimal prenatal growth and subsequent PA are both important in relation to cardiometabolic health in children and adolescents.publishedVersio

Substituting prolonged sedentary time and cardiovascular risk in children and youth: a meta-analysis within the International Children's Accelerometry database (ICAD).

BACKGROUND: Evidence on the association between sitting for extended periods (i.e. prolonged sedentary time (PST)) and cardio-metabolic health is inconsistent in children. We aimed to estimate the differences in cardio-metabolic health associated with substituting PST with non-prolonged sedentary time (non-PST), light (LIPA) or moderate-to-vigorous physical activity (MVPA) in children. METHODS: Cross-sectional data from 14 studies (7 countries) in the International Children's Accelerometry Database (ICAD, 1998-2009) was included. Accelerometry in 19,502 participants aged 3-18 years, together with covariate and outcome data, was pooled and harmonized. Iso-temporal substitution in linear regression models provided beta coefficients (95%CI) for substitution of 1 h/day PST (sedentary time accumulated in bouts > 15 min) with non-PST, LIPA or MVPA, for each study, which were meta-analysed. RESULTS: Modelling substitution of 1 h/day of PST with non-PST suggested reductions in standardized BMI, but estimates were > 7-fold greater for substitution with MVPA (- 0.44 (- 0.62; - 0.26) SD units). Only reallocation by MVPA was beneficial for waist circumference (- 3.07 (- 4.47; - 1.68) cm), systolic blood pressure (- 1.53 (- 2.42; - 0.65) mmHg) and clustered cardio-metabolic risk (- 0.18 (- 0.3; - 0.1) SD units). For HDL-cholesterol and diastolic blood pressure, substitution with LIPA was beneficial; however, substitution with MVPA showed 5-fold stronger effect estimates (HDL-cholesterol: 0.05 (0.01; 0.10) mmol/l); diastolic blood pressure: - 0.81 (- 1.38; - 0.24) mmHg). CONCLUSIONS: Replacement of PST with MVPA may be the preferred scenario for behaviour change, given beneficial associations with a wide range of cardio-metabolic risk factors (including adiposity, HDL-cholesterol, blood pressure and clustered cardio-metabolic risk). Effect estimates are clinically relevant (e.g. an estimated reduction in waist circumference of ≈1.5 cm for 30 min/day replacement). Replacement with LIPA could be beneficial for some of these risk factors, however with substantially lower effect estimates.This work was supported by the National Prevention Research Initiative [grant number: G0701877] (http://www.mrc.ac.uk/research/initiatives/national-prevention-research-initiative-npri/). The funding partners relevant to this award are: British Heart Foundation; Cancer Research UK; Department of Health; Diabetes UK; Economic and Social Research Council; Medical Research Council; Research and Development Office for the Northern Ireland Health and Social Services; Chief Scientist Office; Scottish Executive Health Department; The Stroke Association; Welsh Assembly Government and World Cancer Research Fund. This work was additionally supported by the Medical Research Council [grant numbers MC_UU_12015/3, MC_UU_12015/7], The Research Council of Norway [grant number 249932/F20], Bristol University, Loughborough University and Norwegian School of Sport Sciences. We also gratefully acknowledge the contribution of Prof Chris Riddoch, Prof Ken Judge, Prof Ashley Cooper and Dr Pippa Griew to the development of ICAD. This work was further supported by a British Heart Foundation Intermediate Basic Science Research Fellowship [grant number FS/12/58/29709]

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the <i>LPA</i> and 1 SNP in the <i>APOE</i> gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the <i>LPA</i> , 1 in the <i>APOE</i> gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, <i>P</i> = 3.35 × 10 <sup>-30</sup> ). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the <i>APOE2</i> -determining allele of rs7412 to be significantly associated with Lp(a) concentrations ( <i>P</i> = 3.47 × 10 <sup>-10</sup> ). Each <i>APOE2</i> allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the <i>TLR2</i> gene with Lp(a) ( <i>P</i> = 3.4 × 10 <sup>-4</sup> ). In summary, we identified a large number of independent SNPs in the <i>LPA</i> gene region, as well as the <i>APOE2</i> allele, to be significantly associated with Lp(a) concentrations

Characterisation of breast fine-needle aspiration biopsies by centrosome aberrations and genomic instability

Recent studies have suggested that aneuploidy in malignant tumours could be a consequence of centrosome aberrations. Using immunofluorescence analysis with an antibody against γ-tubulin and DNA image cytometry, we measured centrosome aberrations and DNA ploidy patterns in fine-needle aspiration biopsies (FNABs) of 58 breast lesions. Benign lesions did not show any centrosome aberrations. DNA diploid carcinomas showed a mean percentage of cells with centrosomal defects of 2.1%. The aneuploid invasive carcinomas could be divided into two subgroups by their significantly (P=0.0003) different percentage of cells with centrosome aberrations (2.0 and 10.3%, respectively) and their significantly (P=0.0003) different percentage of cells with nonmodal DNA content values determined by the Stemline Scatter Index (SSI), a measure of genomic instability. The percentage of cells with centrosome aberrations demonstrated a positive, linear correlation with the corresponding SSI (r=0.82, P<0.0001) and loss of tissue differentiation (r=0.78, P<0.0001). Our results indicate the percentage of cells with centrosome aberrations as being sufficient to divide the investigated tumours into three significantly different groups: benign lesions with no centrosomal aberrations, and two malignant tumour types with mean values of 2.1 and 9.6% of centrosomal defects, respectively. Together, these results demonstrate that centrosome aberrations correlate with genomic instability and loss of tissue differentiation. Furthermore, this study shows the feasibility of centrosomal analysis in FNAB of the breast and suggests centrosomal aberrations as possessing diagnostic and prognostic value