745 research outputs found

    First Principles for Virginia\u27s Fifth Century

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    Noise may be music to bionic ears

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    Bionic ear implants could be improved by introducing noise to mimic biological unpredictability

    ‘Values clans’: how clusters of the electorate have shaped the political landscape

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    To explain the divisions which permeate UK politics, Paula Surridge, Michael Turner, Robert Struthers, and Clive McDonnell introduce an approach that takes the dimensionality of voters’ preferences more seriously; and in a second piece they illustrate the political behaviour of two of these groups in more detail

    The ‘cross-pressured clans’ of British politics: a quarter of the electorate and their values

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    Having explained how clusters of the electorate have shaped the UK political landscape, Paula Surridge, Michael Turner, Robert Struthers, and Clive McDonnell focus on two of the most ‘cross-pressured’ of these groups. They analyse their political behaviour in order to illustrate why understanding voters according to their values on multiple dimensions rather than on the traditional ‘left-right’ divide is more crucial than ever

    The Role of NPM-ALK Signaling in Tumor Cell Metabolism.

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    NPM-ALK is a fusion tyrosine kinase that drives oncogenesis in a subset of anaplastic large cell lymphoma. Based on the role of NPM-ALK in cancer initiation and progression, we pursued a mass spectrometry-based phosphoproteomic approach aimed at the unbiased identification of novel mediators of NPM-ALK signaling. The analysis of cell lines under differing NPM-ALK activation conditions revealed a significant number of proteins that regulate cellular metabolism to be affected by NPM-ALK signaling. We therefore, pursued an untargeted metabolomic screen aimed at the identification of specific metabolites and metabolic pathways that are regulated by NPM-ALK. This analysis revealed significant alterations in pathways implicated in the Warburg effect and biomass production, including glycolysis, the pentose phosphate pathway, pyrimidine metabolism, etc. Metabolic flux analysis revealed an NPM-ALK-driven up-regulation of these pathways and down-regulation of energy production. We hypothesized that PKM2 and GSK3β, both identified in the phosphoproteomic study, mediate the metabolic changes. Biochemical studies revealed that NPM-ALK directly phosphorylated PKM2, decreasing its enzymatic activity and driving a metabolic shift away from energy production and toward biomass production. Chemical activation of PKM2 or expression of a mutant PKM2 resulted in a reversal of this metabolic shift and decreased tumorigenesis. The phosphoproteomic analysis identified another candidate mediator of NPM-ALK signaling, GSK3beta. Through the PI3K/AKT pathway, NPM-ALK regulated pS9-GSK3beta, inhibited its activity and provided proteasomal protection for Mcl-1, CDC25A and GYS. This pathway increased proliferation and survival, while increasing glycogen production as a form of metabolic regulation. Studies described in this dissertation globally characterize the ALK driven phosphoproteome and metabolome while providing mechanistic discoveries of two novel NPM-ALK driven pathways. This work provides significant advances to our understanding of oncogenesis and will lead to advances in targeted therapies for ALK driven neoplasms.PHDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97975/1/scottmcd_1.pd

    Prevalence of Illicit Tobacco use and Tobacco Tax Avoidance in Pregnancy

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    Background Smoking during pregnancy is associated with adverse maternal and fetal outcomes. Tobacco tax avoidance and tax evasion undermine the effectiveness of tobacco tax policies, resulting in cheaper prices for smokers and increased tobacco usage. Aims The purpose of this study was to explore the purchasing habits of pregnant smokers with regard to tobacco expenditure anduse of illicit tobacco. Methods Prospective cohort study. Face to face interviews were conducted with 90 attendees (age range 18–42 years; mean age28 years) of a smoking cessation antenatal clinic in a large Irish tertiary level maternity hospital. Information regarding smoking habits, quantity of tobacco smoked, and location of purchase of tobacco was collected in addition to socioeconomic details. Tobacco products were examined to establish whether these were purchased from legitimate sources. Results 76.6% of women smoked 10 or fewer cigarettes per day. The mean weekly spend on tobacco was €39. Seventeen women (18.8%) smoked roll-your-own tobacco. One woman (1.1%) currently possessed a pack of illicit tobacco, while another 5.5% ofparticipants had purchased illicit tobacco in the past. Four women (4.4%) practiced tobacco tax avoidance by purchasing tobacco abroad or in Duty Free.Conclusions Use of illicit tobacco is low and only a minority of women engaged in tobacco tax avoidance. As the average price of tobacco in Ireland increases, weekly expenditure on tobacco products is a significant financial impact on low-income women. Smoking cessation would deliver significant financial gains in addition to health benefit
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