390 research outputs found

    Overexpression of the scaffold WD40 protein WRAP53ÎČ enhances the repair of and cell survival from DNA double-strand breaks

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    Altered expression of the multifunctional protein WRAP53ÎČ (WD40 encoding RNA Antisense to p53), which targets repair factors to DNA double-strand breaks and factors involved in telomere elongation to Cajal bodies, is linked to carcinogenesis. While loss of WRAP53ÎČ function has been shown to disrupt processes regulated by this protein, the consequences of its overexpression remain unclear. Here we demonstrate that overexpression of WRAP53ÎČ disrupts the formation of and impairs the localization of coilin to Cajal bodies. At the same time, the function of this protein in the repair of DNA double-strand breaks is enhanced. Following irradiation, cells overexpressing WRAP53ÎČ exhibit more rapid clearance of phospho-histone H2AX (ÎłH2AX), and more efficient homologous recombination and non-homologous end-joining, in association with fewer DNA breaks. Moreover, in these cells the ubiquitylation of damaged chromatin, which is known to facilitate the recruitment of repair factors and subsequent repair, is elevated. Knockdown of the ubiquitin ligase involved, ring-finger protein 8 (RNF8), which is recruited to DNA breaks by WRAP53ÎČ, attenuated this effect, suggesting that overexpression of WRAP53ÎČ leads to more rapid repair, as well as improved cell survival, by enhancing RNF8-mediated ubiquitylation at DNA breaks. Our present findings indicate that WRAP53ÎČ and RNF8 are rate-limiting factors in the repair of DNA double-strand breaks and raise the possibility that upregulation of WRAP53ÎČ may contribute to genomic stability in and survival of cancer cells

    A dynamic and multifunctional account of middle‐range theories

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    This article develops a novel account of middle‐range theories for combining theoretical and empirical analysis in explanatory sociology. I first revisit Robert K. Merton’s original ideas on middle‐range theories and identify a tension between his developmental approach to middle‐range theorizing that recognizes multiple functions of theories in sociological research and his static definition of the concept of middle‐range theory that focuses only on empirical testing of theories. Drawing on Merton's ideas on theorizing and recent discussions on mechanism‐based explanations, I argue that this tension can be resolved by decomposing a middle‐range theory into three interrelated and evolving components that perform different functions in sociological research: (i) a conceptual framework about social phenomena that is a set of interrelated concepts that evolve in close connection with empirical analysis; (ii) a mechanism schema that is an abstract and incomplete description of a social mechanism; and (iii) a cluster of all mechanism‐based explanations of social phenomena that are based on the particular mechanism schema. I show how these components develop over time and how they serve different functions in sociological theorizing and research. Finally, I illustrate these ideas by discussing Merton’s theory of the Matthew effect in science and its more recent applications in sociology.This article develops a novel account of middle‐range theories for combining theoretical and empirical analysis in explanatory sociology. I first revisit Robert K. Merton’s original ideas on middle‐range theories and identify a tension between his developmental approach to middle‐range theorizing that recognizes multiple functions of theories in sociological research and his static definition of the concept of middle‐range theory that focuses only on empirical testing of theories. Drawing on Merton's ideas on theorizing and recent discussions on mechanism‐based explanations, I argue that this tension can be resolved by decomposing a middle‐range theory into three interrelated and evolving components that perform different functions in sociological research: (i) a conceptual framework about social phenomena that is a set of interrelated concepts that evolve in close connection with empirical analysis; (ii) a mechanism schema that is an abstract and incomplete description of a social mechanism; and (iii) a cluster of all mechanism‐based explanations of social phenomena that are based on the particular mechanism schema. I show how these components develop over time and how they serve different functions in sociological theorizing and research. Finally, I illustrate these ideas by discussing Merton’s theory of the Matthew effect in science and its more recent applications in sociology.Peer reviewe

    Impact of the degradation leachate of the polyacrylonitrile-based material UP2W on the retention of Ni(II), Eu(III) and Pu(IV) by cement

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    The uptake of 63^{63}Ni(II), 152^{152}Eu(III) and 242^{242}Pu(IV) by hardened cement paste (HCP, CEM I) in the degradation stage II (pH ≈ 12.5, [Ca] ≈ 0.02 M) was investigated in the presence of a degradation leachate of UP2W, a polyacrylonitrile-based (PAN) material used as a filter aid in nuclear power plants. The degradation leachate with a concentration of dissolved organic carbon of ∌40 ppm was obtained from the degradation of UP2W in portlandite-buffered solutions for ca. 1100 days. Redox conditions in the Pu systems were buffered with hydroquinone, which defines mildly reducing conditions (pe + pH ≈ 10) where Pu(IV) is the predominant oxidation state. The degradation leachate investigated in this work is moderately sorbed by cement, with distribution ratios (Rd_d) of (0.35 ± 0.15) m3^3 kg−1^{−1}. These values are 30 to 100 times greater than distribution ratios previously reported for proxy ligands of PAN degradation products, i.e., glutaric acid, α-hydroxyisobutyric acid and 3-hydroxybutyric acid. The presence of the degradation leachate induces a moderate decrease in the uptake of 63^{63}Ni(II), 152^{152}Eu(III) and 242^{242}Pu(IV) by cement, as compared to the sorption in the presence of the proxy ligands. Nevertheless, retention in the presence of the degradation leachate remains high for all investigated radionuclides, with Rd(63^{63}Ni(II)) ≈ 2 m3^3 kg−1^{−1}, Rd(152^{152}Eu(III)) ≈ 100 m3^3 kg−1^{−1} and Rd(242^{242}Pu(IV)) ≈ 30 m3^3 kg−1^{−1}. These observations possibly reflect that the multiple functionalities (–COOH, –OH, amide groups) expected in the macromolecules (10–15 kDa) present in the degradation leachate, can offer further binding/chelating capabilities compared to the small organic proxy ligands with at most bidentate binding

    Solubility of Ca( ii ), Ni( ii ), Nd( iii ) and Pu( iv ) in the presence of proxy ligands for the degradation of polyacrylonitrile in cementitious systems

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    The solubility of Ca(OH)2_{2}(cr), ÎČ-Ni(OH)2_{2}(cr), Nd(OH)3_{3}(s) and PuO2_{2}(ncr, hyd) was investigated in cement porewater solutions containing glutarate (GTA), α-hydroxyisobutarate (HIBA) and 3-hydroxybutarate (HBA). These ligands were proposed as probable degradation products of UP2W, a polyacrylonitrile-based filter aid used in nuclear power plants. Results obtained in this work are compared with reported solubility data in the presence of iso-saccharinic acid (ISA), a polyhydroxocarboxylic acid resulting from cellulose degradation. None of the investigated proxy ligands shows any significant impact on the solubility of Ca(II), Nd(III) or Pu(IV) in cement porewater solutions. Although the formation of binary complexes M–L (M = Ca(II), Nd(III), An(IV); L = GTA, HIBA, HBA) under acidic conditions is described in the literature, these organic ligands cannot outcompete hydrolysis under hyperalkaline conditions. GTA, HIBA and HBA induce a slight increase in the solubility of ÎČ-Ni(OH)2_{2}(cr) at [L]tot_{tot} = 0.1 M. This observation supports the formation of stable Ni(II)–GTA, –HIBA and –HBA complexes in hyperalkaline conditions, although the exact stoichiometry of these complexes remains unknown. The comparison of these results with solubility data in the presence of ISA confirms the stronger complexation properties of the latter ligand. Even though HIBA and HBA are carboxylic acids containing one alcohol group, this comparison shows that additional alcohol groups are required to efficiently chelate the metal ion and outcompete hydrolysis. This conclusion is supported by DFT calculations on the Pu(IV)-OH–L systems (L = GTA, HIBA and HBA), which indicate that the complexation with the proxy ligands takes places through the carboxylate group. XRD of selected solid phases after equilibration with proxy ligands at [L]tot_{tot} = 0.1 M confirms that Ca(II), Ni(II), Nd(III) and Pu(IV) starting solid materials remained mostly unaltered in the course of the experiments. However, the presence of new XRD features suggests the possible formation of secondary phases. These results allow assessment of the effect of the proposed proxy ligands on the solubility of key radionuclides and metal ions in cementitious systems relevant for low and intermediate level waste, and feed into on-going sorption studies evaluating the impact of UP2W degradation products on the uptake of radionuclides by cement

    Coulomb Explosion and Thermal Spikes

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    A fast ion penetrating a solid creates a track of excitations. This can produce displacements seen as an etched track, a process initially used to detect energetic particles but now used to alter materials. From the seminal papers by Fleischer et al. [Phys. Rev. 156, 353 (1967)] to the present [C. Trautmann, S. Klaumunzer and H. Trinkaus, Phys. Rev. Lett. 85, 3648 (2000)], `Coulomb explosion' and thermal spike models are treated as conflicting models for describing ion track effects. Here molecular dynamics simulations of electronic-sputtering, a surface manifestation of ion track formation, show that `Coulomb explosion' produces a `heat' spike so that these are early and late aspects of the same process. Therefore, differences in scaling are due to the use of incomplete spike models.Comment: Submitted to PRL. 4 pages, 3 figures. For related movies see: http://dirac.ms.virginia.edu/~emb3t/coulomb/coulomb.html PACS added in new versio

    Complex, but not quite complex enough : The turn to the complexity sciences in evaluation scholarship

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    This document is the Accepted Manuscript version of the following article: Chris Mowles, ‘Complex, but not quite complex enough: The turn to the complexity sciences in evaluation scholarship’. The final, definitive version of this paper has been published in Evaluation, Vol. 20 (2): 160-175, April 2014, doi: https://doi.org/10.1177/1356389014527885 , published by SAGE Publishing. All rights reserved.This article offers a critical review of the way in which some scholars have taken up the complexity sciences in evaluation scholarship. I argue that there is a tendency either to over-claim or under-claim their importance because scholars are not always careful about which of the manifestations of the complexity sciences they are appealing to, nor do they demonstrate how they understand them in social terms. The effect is to render ‘complexity’ just another volitional tool in the evaluator’s toolbox subsumed under the dominant understanding of evaluation, as a logical, rational activity based on systems thinking and design. As an alternative I argue for a radical interpretation of the complexity sciences, which understands human interaction as always complex and emergent. The interweaving of intentions in human activity will always bring about outcomes that no one has intended including in the activity of evaluation itself.Peer reviewe
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