Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Low-molecular-weight cyclin E: the missing link between biology and clinical outcome

Cyclin E, a key mediator of transition during the G(1)/S cellular division phase, is deregulated in a wide variety of human cancers. Our group recently reported that overexpression and generation of low-molecular-weight (LMW) isoforms of cyclin E were associated with poor clinical outcome among breast cancer patients. However, the link between LMW cyclin E biology in mediating a tumorigenic phenotype and clinical outcome is unknown. To address this gap in knowledge, we assessed the role of LMW isoforms in breast cancer cells; we found that these forms of cyclin E induced genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. These findings suggest that high levels of LMW isoforms of cyclin E not only can predict failure to endocrine therapy but also are true prognostic indicators because of their influence on cell proliferation and genetic instability

Health profiles of 996 melanoma survivors: the M. D. Anderson experience

BACKGROUND: The incidence and survival of melanoma are increasing, but little is known about its long-term health effects in adult survivors. METHODS: A health survey was available from 996 melanoma survivors (577 treated with surgery alone, and 391 with combined treatments). Their medical/physiologic and psychosocial responses were analyzed and compared with those of the survivors from other cancers. RESULTS: The melanoma survivors were 44.8 ± 12.8 years of age at diagnosis (significantly younger than the survivors of other cancers) and 63.7 ± 12.8 years at survey. Melanoma survivors were less likely to report that cancer had affected their health than survivors of other cancers (15.8% vs. 34.9%). The 577 individuals treated with surgery alone reported arthritis/osteoporosis, cataracts, and heart problems most frequently (less often than survivors of other cancers). The 391 individuals who had undergone combined treatments reported circulation problems and kidney problems generally as often as survivors of other cancers. Health problems were not associated with number of decades since diagnosis but with age at diagnosis, treatment modality, and family relationships. CONCLUSION: We present information from a large cohort of long-term survivors of melanoma. As a group, they were less likely to report that cancer had affected their overall health than survivors of other cancers; a number of disease related and psychosocial factors appear to influence their health profiles

Knowledge dynamics in the tourism-social entrepreneurship nexus

Tourism is often employed as a vehicle for facilitating social-economic development, however its usefulness has been somewhat limited in relation to addressing social issues, and in particular, those issues relating to poverty. This is partly due to the lack of cross-sectoral interactions and knowledge exchange between private, public and third sectors that are needed to create effective and appropriate initiatives to leverage tourism for social benefits. Such traditional sectoral boundaries can be broken down through social entrepreneurship approaches which concomitantly, facilitate the creation and synergizing of social innovation that addresses persistent social issues. Yet to date, the utility of cross-sectoral knowledge dynamics still remains largely under-researched in both the social entrepreneurship and tourism literature. This chapter introduces readers to the concept of knowledge dynamics and discusses knowledge dynamics in the tourism and social entrepreneurship nexus via a case study of community-based tourism in Mai Hich, Vietnam. We argue that by gaining an enhanced understanding of cross-sectoral knowledge dynamics, we can strengthen the overall praxis of tourism and social entrepreneurship, and in particular, assist policymakers in fostering conditions that generate increased innovation.Griffith Business School, Department of Tourism, Sport and Hotel ManagementNo Full Tex

Measurement of the top quark mass using the matrix element technique in dilepton final states

We present a measurement of the top quark mass in pp¯ collisions at a center-of-mass energy of 1.96 TeV at the Fermilab Tevatron collider. The data were collected by the D0 experiment corresponding to an integrated luminosity of 9.7  fb−1. The matrix element technique is applied to tt¯ events in the final state containing leptons (electrons or muons) with high transverse momenta and at least two jets. The calibration of the jet energy scale determined in the lepton+jets final state of tt¯ decays is applied to jet energies. This correction provides a substantial reduction in systematic uncertainties. We obtain a top quark mass of mt=173.93±1.84  GeV

Hierarchical cluster analysis of labour market regulations and population health: a taxonomy of low- and middle-income countries

<p>Abstract</p> <p>Background</p> <p>An important contribution of the social determinants of health perspective has been to inquire about non-medical determinants of population health. Among these, labour market regulations are of vital significance. In this study, we investigate the labour market regulations among low- and middle-income countries (LMICs) and propose a labour market taxonomy to further understand population health in a global context.</p> <p>Methods</p> <p>Using Gross National Product per capita, we classify 113 countries into either low-income (n = 71) or middle-income (n = 42) strata. Principal component analysis of three standardized indicators of labour market inequality and poverty is used to construct 2 factor scores. Factor score reliability is evaluated with Cronbach's alpha. Using these scores, we conduct a hierarchical cluster analysis to produce a labour market taxonomy, conduct zero-order correlations, and create box plots to test their associations with adult mortality, healthy life expectancy, infant mortality, maternal mortality, neonatal mortality, under-5 mortality, and years of life lost to communicable and non-communicable diseases. Labour market and health data are retrieved from the International Labour Organization's Key Indicators of Labour Markets and World Health Organization's Statistical Information System.</p> <p>Results</p> <p>Six labour market clusters emerged: Residual (n = 16), Emerging (n = 16), Informal (n = 10), Post-Communist (n = 18), Less Successful Informal (n = 22), and Insecure (n = 31). Primary findings indicate: (i) labour market poverty and population health is correlated in both LMICs; (ii) association between labour market inequality and health indicators is significant only in low-income countries; (iii) Emerging (e.g., East Asian and Eastern European countries) and Insecure (e.g., sub-Saharan African nations) clusters are the most advantaged and disadvantaged, respectively, with the remaining clusters experiencing levels of population health consistent with their labour market characteristics.</p> <p>Conclusions</p> <p>The labour market regulations of LMICs appear to be important social determinant of population health. This study demonstrates the heuristic value of understanding the labour markets of LMICs and their health effects using exploratory taxonomy approaches.</p

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. TRIAL REGISTRATION: Current controlled trials ISRCTN49545035.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are