1,244 research outputs found

    Recognition of DNA Termini by the C-Terminal Region of the Ku80 and the DNA-Dependent Protein Kinase Catalytic Subunit

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    DNA double strand breaks (DSBs) can be generated by endogenous cellular processes or exogenous agents in mammalian cells. These breaks are highly variable with respect to DNA sequence and structure and all are recognized in some context by the DNA-dependent protein kinase (DNA-PK). DNA-PK is a critical component necessary for the recognition and repair of DSBs via non-homologous end joining (NHEJ). Previously studies have shown that DNA-PK responds differentially to variations in DSB structure, but how DNA-PK senses differences in DNA substrate sequence and structure is unknown. Here we explore the enzymatic mechanisms by which DNA-PK is activated by various DNA substrates and provide evidence that the DNA-PK is differentially activated by DNA structural variations as a function of the C-terminal region of Ku80. Discrimination based on terminal DNA sequence variations, on the other hand, is independent of the Ku80 C-terminal interactions and likely results exclusively from DNA-dependent protein kinase catalytic subunit interactions with the DNA. We also show that sequence differences in DNA termini can drastically influence DNA repair through altered DNA-PK activation. These results indicate that even subtle differences in DNA substrates influence DNA-PK activation and ultimately the efficiency of DSB repair

    Active commuting to school: How far is too far?

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    Walking and cycling to school provide a convenient opportunity to incorporate physical activity into an adolescent's daily routine. School proximity to residential homes has been identified as an important determinant of active commuting among children. The purpose of this study is to identify if distance is a barrier to active commuting among adolescents, and if there is a criterion distance above which adolescents choose not to walk or cycle. Data was collected in 2003-05 from a cross-sectional cohort of 15-17 yr old adolescents in 61 post primary schools in Ireland. Participants self-reported distance, mode of transport to school and barriers to active commuting. Trained researchers took physical measurements of height and weight. The relation between mode of transport, gender and population density was examined. Distance was entered into a bivariate logistic regression model to predict mode choice, controlling for gender, population density socio-economic status and school clusters. Of the 4013 adolescents who participated (48.1% female, mean age 16.02 ± 0.661), one third walked or cycled to school. A higher proportion of males than females commuted actively (41.0 vs. 33.8%, χ2 (1) = 22.21, p < 0.001, r = -0.074). Adolescents living in more densely populated areas had greater odds of active commuting than those in the most sparsely populated areas (χ2 (df = 3) = 839.64, p < 0.001). In each density category, active commuters travelled shorter distances to school. After controlling for gender and population density, a 1-mile increase in distance decreased the odds of active commuting by 71% (χ2 (df = 1) = 2591.86, p < 0.001). The majority of walkers lived within 1.5 miles and cyclists within 2.5 miles. Over 90% of adolescents who perceived distance as a barrier to active commuting lived further than 2.5 miles from school. Distance is an important perceived barrier to active commuting and a predictor of mode choice among adolescents. Distances within 2.5 miles are achievable for adolescent walkers and cyclists. Alternative strategies for increasing physical activity are required for individuals living outside of this criterion

    Hydrogen evolution from water using heteroatom substituted fluorene conjugated co-polymers

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    The photocatalytic performance of fluorene-type polymer photocatalysts for hydrogen production from water in the presence of a sacrificial hole scavenger is significantly improved by the incorporation of heteroatoms into the...</p

    Fertilization influences the nutrient acquisition strategy of a nomadic vine in a lowland tropical forest understory

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    © 2018, Springer Nature Switzerland AG. Aims: Tropical tree and lianas in the understory are limited by soil nutrients despite growing in extremely low light. It is not known if nomadic vines are also limited by nutrients in low light conditions. Methods: We measured differences in root architecture and mycorrhizal colonization, and leaf nutrients of a nomadic vine, Philodendron fragrantissimum (Araceae), in nitrogen (N) and phosphorus (P) fertilization plots in a lowland tropical moist forest in central Panama to measure potential nutrient limitation. Results: Relative to plants in control plots, leaf P concentration was 54% higher and leaf N concentration was 10% higher for plants in the P- and N-addition treatments, respectively. The N:P of leaves suggested P-limitation in the N-addition treatment and the control but not in the P-addition treatment. Root branching was highest in the P-addition treatment, and P-addition reduced mycorrhizal colonization. Conclusions: The large effect of P fertilization suggests that, like many tropical plants, P. fragrantissimum has the potential to be P-limited. Although further study is needed, we suggest that nomadic vines be added to the growth forms that respond to nutrient addition in the forest understory and conclude that nutrient-limitation seems like the rule rather than the exception in the light-limited understory

    Antibiotic prescribing in UK out-of-hours primary care services: a realist-informed scoping review of training and guidelines for healthcare professionals

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    Background: Antibiotic overuse has contributed to antimicrobial resistance, which is a global public health problem. In the UK, despite the fall in rates of antibiotic prescription since 2013, prescribing levels remain high in comparison with other European countries. Prescribing in out-of-hours (OOH) care provides unique challenges for prudent prescribing, for which professionals may not be prepared. Aim: To explore the guidance available to professionals on prescribing antibiotics for common infections in OOH primary care within the UK, with a focus on training resources, guidelines, and clinical recommendations. Design &amp; setting: A realist-informed scoping review of peer-reviewed articles and grey literature. Method: The review focused on antibiotic prescribing OOH (for example, clinical guidelines and training videos). General prescribing guidance was searched whenever OOH-focused resources were unavailable. Electronic databases and websites of national agencies and professional societies were searched following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Findings were organised according to realist review components, that is, mechanisms, contexts, and outcomes. Results: In total, 46 clinical guidelines and eight training resources were identified. Clinical guidelines targeted adults and children, and included recommendations on prescription strategy, spectrum of the antibiotic prescribed, communication with patients, treatment duration, and decision-making processes. No clinical guidelines or training resources focusing specifically on OOH were found. Conclusion: The results highlight a lack of knowledge about whether existing resources address the challenges faced by OOH antibiotic prescribers. Further research is needed to explore the training needs of OOH health professionals, and whether further OOH-focused resources need to be developed given the rates of antibiotic prescribing in this setting

    What is the 'problem' that outreach work seeks to address and how might it be tackled? Seeking theory in a primary health prevention programme

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    &lt;b&gt;Background&lt;/b&gt; Preventive approaches to health are disproportionately accessed by the more affluent and recent health improvement policy advocates the use of targeted preventive primary care to reduce risk factors in poorer individuals and communities. Outreach has become part of the health service response. Outreach has a long history of engaging those who do not otherwise access services. It has, however, been described as eclectic in its purpose, clientele and mode of practice; its effectiveness is unproven. Using a primary prevention programme in the UK as a case, this paper addresses two research questions: what are the perceived problems of non-engagement that outreach aims to address; and, what specific mechanisms of outreach are hypothesised to tackle these.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Drawing on a wider programme evaluation, the study undertook qualitative interviews with strategically selected health-care professionals. The analysis was thematically guided by the concept of 'candidacy' which theorises the dynamic process through which services and individuals negotiate appropriate service use.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The study identified seven types of engagement 'problem' and corresponding solutions. These 'problems' lie on a continuum of complexity in terms of the challenges they present to primary care. Reasons for non-engagement are congruent with the concept of 'candidacy' but point to ways in which it can be expanded.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; The paper draws conclusions about the role of outreach in contributing to the implementation of inequalities focused primary prevention and identifies further research needed in the theoretical development of both outreach as an approach and candidacy as a conceptual framework

    Validity and reliability of three self-report instruments for assessing attainment of physical activity guidelines in university students

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    The purpose of this study was to compare the validity and reliability of three short physical activity self-report instruments to determine their potential for use with university student populations. The participants (N = 155; 44.5% male; 22.9 ± 5.13 years) wore an accelerometer for 9 consecutive days and completed a single-item measure, the a brief two item measure and the International Physical Activity Questionnaire—Short Form questionnaires on day 1 and 9. Correlations between self-reported and accelerometer derived moderate-to-vigorous physical activity levels were moderate for the International Physical Activity Questionnaire—Short Form, while poor for the single-item measure and the a brief two item measure. The agreement level was high with the International Physical Activity Questionnaire—Short Form (77.4%) and moderate for both the single-item measure (45.2 %) and a brief two item measure (44.5 %). The intraclass correlations between the two administrations were moderate to strong across all measures (0.52–0.70) in 133 participants. The International Physical Activity Questionnaire—Short Form is the most suitable of these three self-report instruments for use with this population due to higher correlations and levels of agreement with accelerometry

    LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice

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    LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins

    Vitamin D levels and menopause-related symptoms.

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    Objective: To determine whether vitamin D levels are associated with menopause-related symptoms in older women. Methods: A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women’s Health Initiative Calcium and Vitamin D (CaD) trial of postmenopausal women aged 51-80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the CaD trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women [mean age 66.2 years (SD 6.8)] were included in these analyses. Results: There were borderline significant associations between 25(OH)D levels and total number of menopausal symptoms (p values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. There were no associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue (p’s > 0.10 for fully adjusted models). Conclusions: There was no evidence of a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women
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