Relationship between adiposity and admixture in African-American and Hispanic-American women.

ObjectiveThe objective of this study was to investigate whether differences in admixture in African-American (AFA) and Hispanic-American (HA) adult women are associated with adiposity and adipose distribution.DesignThe proportion of European, sub-Saharan African and Amerindian admixture was estimated for AFA and HA women in the Women's Heath Initiative using 92 ancestry informative markers. Analyses assessed the relationship between admixture and adiposity indices.SubjectsThe subjects included 11 712 AFA and 5088 HA self-identified post-menopausal women.ResultsThere was a significant positive association between body mass index (BMI) and African admixture when BMI was considered as a continuous variable, and age, education, physical activity, parity, family income and smoking were included covariates (P<10(-4)). A dichotomous model (upper and lower BMI quartiles) showed that African admixture was associated with a high odds ratio (OR=3.27 (for 100% admixture compared with 0% admixture), 95% confidence interval 2.08-5.15). For HA, there was no association between BMI and admixture. In contrast, when waist-to-hip ratio (WHR) was used as a measure of adipose distribution, there was no significant association between WHR and admixture in AFA but there was a strong association in HA (P<10(-4); OR Amerindian admixture=5.93, confidence interval=3.52-9.97).ConclusionThese studies show that: (1) African admixture is associated with BMI in AFA women; (2) Amerindian admixture is associated with WHR but not BMI in HA women; and (3) it may be important to consider different measurements of adiposity and adipose distribution in different ethnic population groups

Unique domain appended to vertebrate tRNA synthetase is essential for vascular development

New domains were progressively added to cytoplasmic aminoacyl transfer RNA (tRNA) synthetases during evolution. One example is the UNE-S domain, appended to seryl-tRNA synthetase (SerRS) in species that developed closed circulatory systems. Here we show using solution and crystal structure analyses and in vitro and in vivo functional studies that UNE-S harbours a robust nuclear localization signal (NLS) directing SerRS to the nucleus where it attenuates vascular endothelial growth factor A expression. We also show that SerRS mutants previously linked to vasculature abnormalities either deleted the NLS or have the NLS sequestered in an alternative conformation. A structure-based second-site mutation, designed to release the sequestered NLS, restored normal vasculature. Thus, the essential function of SerRS in vascular development depends on UNE-S. These results are the first to show an essential role for a tRNA synthetase-associated appended domain at the organism level, and suggest that acquisition of UNE-S has a role in the establishment of the closed circulatory systems of vertebrates

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.

Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta

Delegation in hard times:the financial management of arm's length bodies in the UK

This paper explores the effectiveness of financial management tools in regulating the use of resources by arm’s length bodies (ALBs) in a period of fiscal stress. The paper presents research undertaken into the implementation of a new financial management tool for ALBs in the UK since the 2008 financial crisis. Drawing on conflict ambiguity theory, the paper shows how the effectiveness of such tools is affected by deep-rooted tensions implicit within arm’s length governance. This gives rise to micro-level conflict over the means of achieving fiscal regulation, underpinned by macro-level ambiguity over the logic of governance pursued by the government

Is dignity therapy feasible to enhance the end of life experience for people with motor neurone disease and their family carers?

Background: Development of interventions that address psychosocial and existential distress in people with motor neurone disease (MND) or that alleviate caregiver burden in MND family carers have often been suggested in the research literature. Dignity therapy, which was developed to reduce psychosocial and existential distress at the end of life, has been shown to benefit people dying of cancer and their families. These results may not be transferable to people with MND. The objectives of this study are to assess the feasibility, acceptability and potential effectiveness of dignity therapy to enhance the end of life experience for people with motor neurone disease and their family carers. Methods/design: This is a cross-sectional study utilizing a single treatment group and a pre/post test design. The study population will comprise fifty people diagnosed with MND and their nominated family carers. Primarily quantitative outcomes will be gathered through measures assessed at baseline and at approximately one week after the intervention. Outcomes for participants include hopefulness, spirituality and dignity. Outcomes for family carers include perceived caregiver burden, hopefulness and anxiety/depression. Feedback and satisfaction with the intervention will be gathered through a questionnaire. Discussion: This detailed research will explore if dignity therapy has the potential to enhance the end of life experience for people with MND and their family carers, and fill a gap for professionals who are called on to address the spiritual, existential and psychosocial needs of their MND patients and families

Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity

Dendritic cell (DC) immunotherapy has shown a promising ability to promote anti-tumor immunity in vitro and in vivo. Many trials have tested single epitopes and single antigens to activate single T cell specificities, and often CD8+ T cells only. We previously found that determinant spreading and breadth of antitumor immunity correlates with improved clinical response. Therefore, to promote activation and expansion of polyclonal, multiple antigen-specific CD8+ T cells, as well as provide cognate help from antigen-specific CD4+ T cells, we have created an adenovirus encoding three full length melanoma tumor antigens (tyrosinase, MART-1 and MAGE-A6, “AdVTMM”). We previously showed that adenovirus (AdV)-mediated antigen engineering of human DC is superior to peptide pulsing for T cell activation, and has positive biological effects on the DC, allowing for efficient activation of not only antigen-specific CD8+ and CD4+ T cells, but also NK cells. Here we describe the cloning and testing of “AdVTMM2,” an E1/E3-deleted AdV encoding the three melanoma antigens. This novel three-antigen virus expresses mRNA and protein for all antigens, and AdVTMM-transduced DC activate both CD8+ and CD4+ T cells which recognize melanoma tumor cells more efficiently than single antigen AdV. Addition of physiological levels of interferon-α (IFNα) further amplifies melanoma antigen-specific T cell activation. NK cells are also activated, and show cytotoxic activity. Vaccination with multi-antigen engineered DC may provide for superior adaptive and innate immunity and ultimately, improved antitumor responses

Effect of training and sudden detraining on the patellar tendon and its enthesis in rats

<p>Abstract</p> <p>Background</p> <p>Different conditions may alter tendon characteristics. Clinical evidence suggests that tendon injuries are more frequent in athletes that change type, intensity and duration of training. Aim of the study was the assessment of training and especially detraining on the patellar tendon (PT) and its enthesis.</p> <p>Methods</p> <p>27 male adult Sprague-Dawley rats were divided into 3 groups: 20 rats were trained on a treadmill for 10 weeks. Of these, 10 rats were euthanized immediately after training (trained group), and 10 were caged without exercise for 4 weeks before being euthanized (de-trained group). The remaining 7 rats were used as controls (untrained rats). PT insertion, structure (collagen fiber organization and proteoglycan, PG, content), PT thickness, enthesis area, and subchondral bone volume at the enthesis were measured by histomorphometry and microtomography.</p> <p>Results</p> <p>Both PG content and collagen fiber organization were significantly lower in untrained and detrained animals than in trained ones (<it>p </it>< 0.05 and <it>p </it>< 0.0001). In the detrained group, fiber organization and PG content were worse than that of the untrained groups and the untrained group showed a significantly higher score than the detrained group (<it>p </it>< 0.05). In the trained group, the PT was significantly thicker than in untrained group (<it>p </it>< 0.05). No significant differences in the enthesis area and subchondral bone volume among the three groups were seen.</p> <p>Conclusions</p> <p>Moderate exercise exerts a protective effect on the PT structure while sudden discontinuation of physical activity has a negative effect on tendons. The present results suggest that after a period of sudden de-training (such as after an injury) physical activity should be restarted with caution and with appropriate rehabilitation programs.</p

“Science capital”: a conceptual, methodological, and empirical argument for extending bourdieusian notions of capital beyond the arts

This paper sets out an argument and approach for moving beyond a primarily arts-based conceptualization of cultural capital, as has been the tendency within Bourdieusian approaches to date. We advance the notion that, in contemporary society, scientific forms of cultural and social capital can command a high symbolic and exchange value. Our previous research [Archer et al. (2014) Journal of Research in Science Teaching 51, 1–30] proposed the concept of “science capital” (science-related forms of cultural and social capital) as a theoretical lens for explaining differential patterns of aspiration and educational participation among young people. Here, we attempt to theoretically, methodologically, and empirically advance a discussion of how we might conceptualize science capital and how this might be translated into a survey tool for use with students. We report on findings from a survey conducted with 3658 secondary school students, aged 11–15 years, in England. Analysis found that science capital was unevenly spread across the student population, with 5% being classified as having “high” science capital and 27% “low” science capital. Analysis shows that levels of science capital (high, medium, or low) are clearly patterned by cultural capital, gender, ethnicity, and set (track) in science. Students with high, medium, or low levels of science capital also seem to have very different post-16 plans (regarding studying or working in science) and different levels of self-efficacy in science. They also vary dramatically in terms of whether they feel others see them as a “science person.” The paper concludes with a discussion of conceptual and methodological issues and implications for practice