9 research outputs found

    Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis

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    Objectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid). Results: OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (ß=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (ß=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2a/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. Conclusions: Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach

    Searching for peace in Asia Pacific : An overview of conflict prevention and peacebuilding activities

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    Londonxvi, 848 p.; 23 cm

    From vulnerability to empowerment

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    Disaster response agencies increasingly use the concept of ‘vulnerability’ to analyse processes that lead to disasters and to identify responses. Because no common definition of ‘vulnerability’ exists, agencies use the concept in the way that best fits their practice – in other words, focusing on physical and economic vulnerability. In most assessments, however, the stories of the affected communities are not included

    The power to define resilience in social–hydrological systems : Toward a power-sensitive resilience framework

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    Abstract Since the early work on defining and analyzing resilience in domains such as engineering, ecology and psychology, the concept has gained significant traction in many fields of research and practice. It has also become a very powerful justification for various policy goals in the water sector, evident in terms like flood resilience, river resilience, and water resilience. At the same time, a substantial body of literature has developed that questions the resilience concept's systems ontology, natural science roots and alleged conservatism, and criticizes resilience thinking for not addressing power issues. In this study, we review these critiques with the aim to develop a framework for power-sensitive resilience analysis. We build on the three faces of power to conceptualize the power to define resilience. We structure our discussion of the relevant literature into five questions that need to be reflected upon when applying the resilience concept to social?hydrological systems. These questions address: (a) resilience of what, (b) resilience at what scale, (c) resilience to what, (d) resilience for what purpose, and (e) resilience for whom; and the implications of the political choices involved in defining these parameters for resilience building or analysis. Explicitly considering these questions enables making political choices explicit in order to support negotiation or contestation on how resilience is defined and used. This article is categorized under: Human Water &gt; Water Governance. Engineering Water &gt; Planning Water.QC 20191001</p
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