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- Aad, G., et al.
(författare)
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- 2012
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 109:21
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Tidskriftsartikel (refereegranskat)
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- Krantz, Tobias, 1971-
(författare)
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Lagskydda lokalt självstyre
- 2000
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Ingår i: Upsala nya tidning. - 1104-0173.
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 8. |
- Revêchon, Gwladys
(författare)
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Molecular insights into Hutchinson-Gilford progeria syndrome and age-associated disease : from mechanisms to treatment strategy
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aging is a complex process that occurs as we grow old and is associated with a gradual decline of tissue functions. Scientists have been trying to understand the mechanisms that drive such phenomenon by studying premature aging syndromes and aging-related disorders. The Hutchinson-Gilford progeria syndrome (HGPS) is a lethal segmental genetic disease affecting children at an early age and characterized by accelerated aging-like features including alopecia, loss of subcutaneous adipose tissue and cardiovascular pathologies. This disorder primarily results from the production of a noxious protein called progerin, altering proper tissue homeostasis and functions. Strikingly, HGPS children present an accelerated vascular aging phenotype similar to that of chronic kidney disease (CKD) patients. Indeed, in addition to displaying kidney defects, CKD patients exhibit an accelerated vascular decline. Interestingly, progerin has previously been found expressed in cells and tissues from aged individuals, but its contribution to aging and aging-associated disorders remains poorly understood. Here, we investigated whether and how various levels of progerin are relevant to the development and progression of tissue pathology in HGPS, normal aging and aging-associated diseases, in order to generate a potential new treatment strategy for HGPS in particular. In paper I, to better understand the mechanisms by which progerin accumulation disrupts tissue homeostasis, a humanized HGPS mouse model with overexpression of progerin in the skin was used. We demonstrated that progerin accumulation resulted in impaired tissue homeostasis as a consequence of an aberrant increase in symmetric cell division. Further analysis suggested a potential causal role of the Wnt/β-catenin signaling, associated with mislocalization of the nuclear envelope proteins emerin and nesprin-2. In paper II, to investigate whether a small fraction of progerin-expressing cells in a tissue can lead to tissue pathology during aging, another humanized HGPS mouse model was employed. We showed that continuous expression of progerin in only a few preadipocytes and adipocytes is associated with fibrosis and lipoatrophy over time. This phenotype was combined with increased senescence, persistent DNA damage and cell death, which were found accompanied by macrophage infiltration and systemic inflammation. These results suggested that progerin, despite being expressed in only a low fraction of the cells of a tissue, has the potential to contribute to a common aging-associated phenotype. In paper III, to unravel the possible involvement of progerin expression in age-associated diseases, we used arterial biopsies and blood from CKD patients. We found that progerin was expressed at low frequencies in 70% of the CKD patients arteries (in up to 7.4% of the cells), which was associated with an increase in DNA damage. When searching for the cause of progerin expression, we identified the LMNA c.1824C>T mutation in both the blood and arteries. Our data further suggested that progerinexpressing cells might arise during vascular regeneration, by proliferation of progenitor cells. In paper IV, to examine the mechanisms associated with telomere dysfunction in HGPS, we employed various in vitro systems and a severe progeroid mouse model of skin. We demonstrated that telomere dysfunction leads to the production of non-coding RNAs, which activates the DNA damage response signaling. Treatment with telomeric sequence-specific antisense oligonucleotides not only repressed this signaling, but also significantly improved both the healthspan and lifespan of HGPS mice. This thesis provides novel findings about the complex molecular mechanisms underlying progerin expression in HGPS, and its possible contribution to aging and CKD-related early vascular aging, all of which led to the discovery of a potential new treatment approach for HGPS.
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| 9. |
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An Enterprise Architecture Based Method for Quantified Analysis of IT System Impact on Maintenance Management
- 2009
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Proceedings (redaktörskap) (refereegranskat)abstract
- This paper presents a method for quantified analysis of the impact ICT systems have on maintenance management. The method is based on Enterprise Architecture (EA) which is a model based tool enabling holistic management of an enterprise?s ICT system portfolio and its relation and support to the business. A domain where the relation between ICT systems and business processes is crucial for cost efficient operation is maintenance of asset intensive geographically distributed processes, such as distribution of electric power. Power utilities invest many monetary resources in maintenance, a large proportion of these investments being related to development and integration of ICT systems. Thus, there is a need for the power utilities to understand how the products of these investments influence the performance of the maintenance process. The degree of efficiency of these investments runs a risk of being low unless there is a clear understanding of how specific ICT system solutions affects the maintenance activities. The suggested method combines EA with the Maintenance Scorecard and introduces Extended Influence Diagrams (EIDs) to enable a quantitative analysis of how cause and effect between ICT systems and the performance of maintenance processes are related to each other. The method provides management support for rationale decisions concerning ICT systemsￜ support of the domain of maintenance management. The paper is concluded with an example of how the method can be applied to a typical maintenance process within an electric power utility
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