2,728 research outputs found

    Quantification of Urinary Mevalonic Acid as a Biomarker of HMG-CoA Reductase Activity by a Novel Translational LC-MS/MS Method

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    Background: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. Methods: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed-phase liquid chromatography-tandem mass spectrometry. Results: The assay had a dynamic range of 0.0156-10 µg/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Conclusion: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability

    A model of Bˉ0→D∗+ωπ−\bar{B}^0\to D^{*+}\omega\pi^- decay

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    We suggest a parameterization of the matrix element for Bˉ0→D∗+ωπ−\bar{B}^0\to D^{*+}\omega\pi^- decay using kinematic variables convenient for experimental analysis. The contributions of intermediate ωπ\omega\pi- and D∗∗D^{**}-states up to spin 3 have been taken into account. The angular distributions for each discussed hypothesis have been obtained and analysed using Monte-Carlo simulation.Comment: 24 pages, 9 figures, 1 table; V2: text in some places improved and acknowledgments adde

    Phenomenology of a light scalar: the dilaton

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    We make use of the language of non-linear realizations to analyze electro-weak symmetry breaking scenarios in which a light dilaton emerges from the breaking of a nearly conformal strong dynamics, and compare the phenomenology of the dilaton to that of the well motivated light composite Higgs scenario. We argue that -- in addition to departures in the decay/production rates into massless gauge bosons mediated by the conformal anomaly -- characterizing features of the light dilaton scenario (as well as other scenarios admitting a light CP-even scalar not directly related to the breaking of the electro-weak symmetry) are off-shell events at high invariant mass involving two longitudinally polarized vector bosons and a dilaton, and tree-level flavor violating processes. Accommodating both electro-weak precision measurements and flavor constraints appears especially challenging in the ambiguous scenario in which the Higgs and the dilaton fields strongly mix. We show that warped higgsless models of electro-weak symmetry breaking are explicit and tractable realizations of this limiting case. The relation between the naive radion profile often adopted in the study of holographic realizations of the light dilaton scenario and the actual dynamical dilaton field is clarified in the Appendix.Comment: 21 page

    The need for speed in a crisis discipline: Perspectives on peer-review duration and implications for conservation science

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    Scholarly peer review relies on rigorous yet fair assessments of articles by qualified referees in a timely manner. We considered the extent to which a prolonged peer-review process can delay the dissemination of results in a conservation context by combining insight from a survey with our own perspectives. A survey of authors who published peer-reviewed articles in biodiversity and conservation in 2012 and 2013 yielded 461 responses from participants in 119 countries. Approximately 44% of respondents thought that slow review times might hamper conservation, while only ~5% provided specific examples of how slow reviews had actually impeded conservation actions or policy formation. When queried about the value of expediting the review process for studies of high policy or conservation relevance, ca. 1/3 of respondents thought it was a worthwhile idea in principle, though mechanics of implementing such practices are unclear. Author self-identification of potentially important papers could lead to requesting a rapid review provided that a paper meets certain criteria-an approach already used by some generalist journals. Given the urgency of many conservation-oriented initiatives, we encourage the entire editor - ial team (staff, editors, referees, authors) to make a concerted effort towards improving the speed of the peer-review process while maintaining quality. Such efforts would reflect the notion that timeliness is a key component of scientific relevance to practitioners and policy makers in a crisis discipline. We conclude that there is a 'need for speed' and advocate that rapid, rigorous and thorough peer review can be accomplished and can provide collective benefits to the scientific community and global biodiversity

    Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma

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    Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM

    Analysis of stellar spectra with 3D and NLTE models

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    Models of radiation transport in stellar atmospheres are the hinge of modern astrophysics. Our knowledge of stars, stellar populations, and galaxies is only as good as the theoretical models, which are used for the interpretation of their observed spectra, photometric magnitudes, and spectral energy distributions. I describe recent advances in the field of stellar atmosphere modelling for late-type stars. Various aspects of radiation transport with 1D hydrostatic, LTE, NLTE, and 3D radiative-hydrodynamical models are briefly reviewed.Comment: 21 pages, accepted for publication as a chapter in "Determination of Atmospheric Parameters of B, A, F and G Type Stars", Springer (2014), eds. E. Niemczura, B. Smalley, W. Pyc

    Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

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    BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population. METHODS: TNF-α gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 ± 13%, and compared with a Dutch population control group of 358 subjects. RESULTS: The data showed that the TNF-α +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-α gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-α polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-α +489G/A genotype in patients without radiological emphysema (χ(2)-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION: Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-α +489G/A gene polymorphism

    A randomised controlled trial to determine the effect on response of including a lottery incentive in health surveys [ISRCTN32203485]

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    BACKGROUND: Postal questionnaires are an economical and simple method of data collection for research purposes but are subject to non-response bias. Several studies have explored the effect of monetary and non-monetary incentives on response. Recent meta-analyses conclude that financial incentives are an effective way of increasing response rates. However, large surveys rarely have the resources to reward individual participants. Three previous papers report on the effectiveness of lottery incentives with contradictory results. This study aimed to determine the effect of including a lottery-style incentive on response rates to a postal health survey. METHODS: Randomised controlled trial. Setting: North and West Birmingham. 8,645 patients aged 18 or over randomly selected from registers of eight general practices (family physician practices). Intervention: Inclusion of a flyer and letter with a health questionnaire informing patients that returned questionnaires would be entered into a lottery-style draw for £100 of gift vouchers. Control: Health questionnaire accompanied only by standard letter of explanation. Main outcome measures: Response rate and completion rate to questionnaire. RESULTS: 5,209 individuals responded with identical rates in both groups (62.1%). Practice, patient age, sex and Townsend score (a postcode based deprivation measure) were identified as predictive of response, with higher response related to older age, being female and living in an area with a lower Townsend score (less deprived). CONCLUSION: This RCT, using a large community based sample, found that the offer of entry into a lottery style draw for £100 of High Street vouchers has no effect on response rates to a postal health questionnaire
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