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Bomer N.,LUMC | Den Hollander W.,LUMC | Ramos Y.F.M.,LUMC | Bos S.D.,LUMC | And 16 more authors.
Annals of the Rheumatic Diseases | Year: 2015

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 (â=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (â=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-2á/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.


Jongmans S.-S.T.Q.,CWI | Arbab F.,LIACS
Scientific Annals of Computer Science | Year: 2012

Over the past decades, coordination languages have emerged for the specification and implementation of interaction protocols for communicating software components. This class of languages includes Reo, a platform for compositional construction of connectors. In recent years, many formalisms for describing the behavior of Reo connectors have emerged. In this paper, we give an overview of all these classes of semantic models. Furthermore, we investigate the expressiveness of two more prominent classes, constraint automata and coloring models, in detail. © Scientific Annals of Computer Science 2012.


Jaghoori M.M.,LIACS
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2012

Concurrent objects encapsulate a processor each and communicate by asynchronous message passing; therefore, they can be composed to naturally model distributed and embedded systems. We model real-time concurrent objects using timed automata and provide each object with a context-specific scheduling policy. The envisioned usage and guaranteed deadlines of each object is specified in its behavioral interface, given also in timed automata. Furthermore, multiple objects can be composed only if they are compatible, i.e., if they respect the expected use patterns given in the behavioral interfaces of each other. In this paper, we define refinement of timed automata with inputs and outputs from a new perspective and we take account of deadlines in the refinement theory. Within this framework, we study composition and compatibility of real-time concurrent objects, and apply it in the context of compositional schedulability analysis of multiple-processor systems. © 2012 Springer-Verlag.


Bomer N.,LUMC | den Hollander W.,LUMC | Ramos Y.F.M.,LUMC | Bos S.D.,Leiden University | And 15 more authors.
Annals of the Rheumatic Diseases | Year: 2014

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. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.


Emmerich M.T.M.,LIACS | Deutz A.H.,LIACS | Kruisselbrink J.W.,LIACS
Studies in Computational Intelligence | Year: 2013

This chapter reviews indicators that can be used to compute the quality of approximations to level sets for black-box functions. Such problems occur, for instance, when finding sets of solutions to optimization problems or in solving nonlinear equation systems. After defining and motivating level set problems from a decision theoretic perspective, we discuss quality indicators that could be used to measure how well a set of points approximates a level set. We review simple indicators based on distance, indicators from biodiversity, and propose novel indicators based on the concept of Hausdorff distance. We study properties of these indicators with respect to continuity, spread, and monotonicity and also discuss computational complexity. Moreover, we study the use of these indicators in a simple indicatorbased evolutionary algorithm for level set approximation. © Springer Berlin Heidelberg 2013.


Winter J.,CWI | Bonsangue M.M.,LIACS | Rutten J.,CWI
Logical Methods in Computer Science | Year: 2013

In this article, we provide three coalgebraic characterizations of the class of context-free languages, each based on the idea of adding coalgebraic structure to an existing algebraic structure by specifying output-derivative pairs. Final coalgebra semantics then gives an interpretation function into the final coalgebra of all languages with the usual output and derivative operations. The first characterization is based on systems, where each derivative is given as a finite language over the set of nonterminals; the second characterization on systems where derivatives are given as elements of a term-algebra; and the third characterization is based on adding coalgebraic structure to a class of closed (unique) fixed point expressions. We prove equivalences between these characterizations, discuss the generalization from languages to formal power series, as well as the relationship to the generalized powerset construction. © J. Winter, M. M. Bonsangue, and J. Rutten.

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