Adaptive Response Behavior in the Pursuit of Unpredictably Moving Sounds

Contains fulltext : 236376.pdf (Publisher’s version ) (Open Access

A retrospective comparison between non-conveyed and conveyed patients in ambulance care

Contains fulltext : 197717.pdf (publisher's version ) (Open Access

IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice

AbstractBackgroundInterleukin 15 (IL-15) is a pro-inflammatory cytokine involved in inflammatory diseases and IL-15 is expressed in atherosclerotic plaques.MethodsTo establish the role of IL-15 in atherosclerosis we studied the effect of IL-15 on atherosclerosis associated cells in vitro and in vivo by neutralizing IL-15 using a DNA vaccination strategy.ResultsUpon feeding a Western type diet LDLr−/− mice do express higher levels of IL-15 within the spleen and the number of IL-15 expressing cells among blood leukocytes and spleen cells is increased. Addition of IL-15 to macrophages induces the expression TNF-α and CCL-2. After the mice were vaccinated against IL-15, we observe a reduction in plaque size of 75% plaque. Unexpectedly, the relative number of macrophages within the plaque was 2-fold higher in IL-15 vaccinated mice than in control mice. Vaccination against IL-15 leads to an increased cytotoxicity against IL-15 overexpressing target cells, resulting in a reduction in IL-15 expressing cells and macrophages in blood and spleen and a decreased CD4/CD8 ratio.ConclusionHypercholesterolemia leads to upregulation of IL-15 within spleen and blood. DNA vaccination against IL-15 does markedly reduces atherosclerotic lesion size, but does not promote lesion stability

KLF2 suppresses TGF-β signaling in endothelium through induction of Smad7 and inhibition of AP-1

OBJECTIVE - The flow-responsive Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial cell quiescence. Here, we describe its detailed effects on transforming growth factor-β (TGF-β) signaling, which normally has proatherogenic effects on endothelium. METHODS AND RESULTS - In-depth analysis of genome-wide expression data shows that prolonged lentiviral-mediated overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) diminishes the expression of a large panel of established TGF-β-inducible genes. Both baseline and TGF-β-induced expression levels of plasminogen activator inhibitor 1 (PAI-1) and thrombospondin-1 are greatly diminished by KLF2. Using a combination of ectopic expression, small interfering RNA-mediated knockdown, and promoter activity assays, we show that KLF2 partly inhibits the phosphorylation and subsequent nuclear accumulation of Smad2, thereby suppressing the TGF-β-induced Smad4-mediated transcriptional activity. This is achieved through TGF-β-independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF-β signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF-β-dependent transcription of many genes. CONCLUSIONS - The concerted mechanism by which KLF2 inhibits TGF-β signaling through induction of inhibitory Smad7 and attenuation of AP-1 activity provides a novel mechanism by which KLF2 contributes to sustaining a quiescent, atheroprotective status of vascular endothelium