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- van Dijk, Jesper R., et al.
(author)
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Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization
- 2014
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 459:1, s. 27-36
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Journal article (peer-reviewed)abstract
- Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, and processes that are regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. The PA (protease-associated) domain E3 ligases, such as Godzilla(CG10277) in Drosophila melanogaster and RNF167 (RING finger protein 167) in humans, have been implicated in the regulation of cellular endosome trafficking. In the present study, we have characterized point mutations in the RING (really interesting new gene) domain of human RNF13 and RNF167, which have been identified in human tumour samples, that abrogate ubiquitin ligase activity as well as function. In the present study, we have also identified a functional role for the PA domain, which is required for endosomal localization of these proteins. Although the PA domain point mutations of RNF13 and RNF167 identified in human tumours are ligase active, the resultant mutant proteins are mislocalized within the cell. Thus the PA domain E3 ligases examined in the present study appear to require both E3 ligase activity as well as an intact PA domain to efficiently target and ubiquitylate their cellular substrates.
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- Blomskog, Stig, 1951-, et al.
(author)
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An Analysis of a Sustainability Index
- 2021
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In: Sustainable Consumption and Production, Volume I. - Cham : Palgrave Macmillan. - 9783030563707 - 9783030563738 - 9783030563714 ; , s. 39-63
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Book chapter (other academic/artistic)abstract
- In this chapter, we perform a conceptual analysis of a household sustainable consumption index, whose construction is based on guidelines in a handbook issued by OECD. We conclude in our analysis that the designers of the index treat the concept ‘sustainable consumption’ as a descriptive concept, and argue that this interpretation is a conceptual mistake. A consequence of this mistake is that the construction of the index is treated as a kind of statistical and empirical problem only. Instead, we argue that sustainable consumption is a specific kind of value concept named intermediate concept, whose function is to link descriptive grounds with normative consequences, and thus that the construction of the index is a normative problem. That is, the construction of a sustainable consumption index should be regarded as a normative multi-attribute decision process. A policy implication of our study is that when measuring sustainability, a decision analytic approach based on an adequate interpretation of the concept sustainability as an intermediate concept should be employed. In order to avoid low validity of sustainability indices as a result of making a conceptual mistake, it is possible to explicitly treat the construction of a sustainability index as a normative multi-attribute decision process that can be aided by decision support tools. The relevance of our analysis to policymakers and other stakeholders is that it contributes to a deeper understanding of what kind of concept sustainability is and what it means to measure such concepts. Without a proper understanding of the nature of this concept, there is an obvious risk of low validity of its measurement.
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- Ahlkvist, Linda
(author)
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Novel insights into the regulation of insulin secretion by GLP-1, GIP and glucagon
- 2015
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Doctoral thesis (other academic/artistic)abstract
- There are many contributing factors to the development of type 2 diabetes, however, failure of beta-cells to sufficiently secrete insulin is the key component. The underlying mechanism of beta-cell failure is not fully established. In this thesis, we examined the role of high glucagon levels, i.e. hyperglucagonemia, for the development of beta-cell dysfunction in pre-diabetic mice. We found that induction of 2 week hyperglucagonemia leads to defective insulin secretion. To enhance beta-cell function, there are several therapeutic strategies. One important strategy is based on the gut incretin hormone glucagon-like peptide 1 (GLP-1), which potently stimulates insulin secretion. In the clinic, GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for degradation of GLP-1, are currently used. A new concept of GLP-1 based therapies is to increase also endogenous GLP-1 secretion. In this thesis, we explored the importance of meal macronutrient composition for GLP-1 and insulin responses in healthy mice. We found that intake of mixed macronutrients compared to isocaloric glucose leads to a synergistic increase in GLP-1 and insulin levels. We also explored the effects of a novel GPR119 receptor agonist on GLP-1 and insulin levels after meal intake in healthy and glucose intolerant mice. GPR119 activation markedly increased GLP-1 and insulin responses to meal intake, however, only in glucose intolerant mice. Furthermore, we examined the mechanisms behind the effects of DPP-4 inhibition and found that vagal nerve signaling is important for the insulinotropic effects of DPP-4 inhibition. To conclude, the work in this thesis shed new light on possible ways to increase GLP-1 and insulin secretion, on the mechanism behind the effects of DPP-inhibition and on glucagon as a possible factor that may contribute to beta-cell failure.
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- Andersson, Niklas, 1976, et al.
(author)
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A Study of Mach 0.75 Jets and Their Radiated Sound Using Large-Eddy Simulation
- 2004
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In: AIAA 2004-3024, proc. of 10th AIAA/CEAS Aeroacoustics Conference, May 10-12, 2004.
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Conference paper (peer-reviewed)abstract
- Large-Eddy Simulations (LES) of a compressible nozzle/jet configuration have been carried out. Two jets were simulated, an isothermal jet and a jet with a higher temperature than the quiescent surrounding air. The Mach number was in both cases 0.75 and the jet Reynolds number was 50,000. Sound pressure levels in far-field observer locations were evaluated using Kirchhoff surface integration. The Favre filtered Navier-Stokes equations were solved using a finite volume method solver with a low-dissipation third-order upwind scheme for the convective fluxes, a second-order centered difference approach for the viscous fluxes and a three-stage second-order Runge-Kutta technique in time. The computational domain was discretized using a block structured boundary fitted mesh with approximately 3,000,000 cells. The calculations were performed on a parallel computer, using message-passing interface (MPI). A compressible form of Smagorinsky's subgrid scale model was used for computation of the subgrid scale stresses. Absorbing boundary conditions based on characteristic variables were adopted for all free boundaries. Velocity components specified at the entrainment boundaries were estimated from corresponding Reynolds Averaged Navier-Stokes (RANS) calculations, which enable the use of a rather narrow domain. This, furthermore, ensures that the correct amount of fluid is entrained into the domain. Two-point space-time correlations were obtained for locations in the shear layer center, from which length and time scales of turbulence structures were evaluated. Predicted near-field flow statistics and far-field sound pressure levels (SPL) are both in good agreement with experiments. Predicted (SPL) are for all observers locations, where evaluated, within a 3.0 [dB] deviation from measured levels and for most locations within a 1.0 [dB] deviation. Experimental data used for validation were provided by Laboratoire dEtude Aeròdynamiques, Poitiers, France.
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