This thesis has provided more knowledge on the disease course and its determinants of outcome in hand osteoarthritis. The role of joint-specific factors and coping styles on disability, the... Show moreThis thesis has provided more knowledge on the disease course and its determinants of outcome in hand osteoarthritis. The role of joint-specific factors and coping styles on disability, the prevelance of aesthetic dissatisfaction, its impact on daily life and their determinants were evaluated. Additionally, the association between MR Imaging features with hand pain and the association of MR Imaging features with radiographic progression were investigated. Another part of the thesis focused on the association between osteoarthritis and mortality. Show less
Identifying and elucidating the functions and activation of GPCRs will provide opportunities for novel drug discovery. We confirmed that a yeast system with an extended library of G... Show more Identifying and elucidating the functions and activation of GPCRs will provide opportunities for novel drug discovery. We confirmed that a yeast system with an extended library of G proteins is very well suited for the study of GPCR activation, G protein coupling profiles, receptor-G protein binding and G protein selectivity. For example, we used a scanning mutagenesis approach of the NPxxY(x)5,6F motif and of helix 8 of the adenosine A2B receptor (A2BR), and learned among others that amino acid residues in these motifs are crucial for receptor function, since alanine mutants of these amino acid residues led to a complete loss of function. Hopefully, such findings can contribute to further drug development. We also focused on structure-kinetics relationship (SKR) studies next to the more traditional Structure-affinity relationship (SAR) studies. We found two compounds showing longer residence times than nicotinic acid, which may provide clues for further drug discovery efforts on this receptor. All in all, the variety of methods described in this thesis provided us a detailed understanding of receptor function, suggesting that novel avenues for further drug discovery on these established targets is entirely feasible. Show less
