Ephrin-A5 Suppresses Neurotrophin Evoked Neuronal Motility, ERK Activation and Gene Expression

During brain development, growth cones respond to attractive and repulsive axon guidance cues. How growth cones integrate guidance instructions is poorly understood. Here, we demonstrate a link between BDNF (brain derived neurotrophic factor), promoting axonal branching and ephrin-A5, mediating axonal repulsion via Eph receptor tyrosine kinase activation. BDNF enhanced growth cone filopodial dynamics and neurite branching of primary neurons. We show that ephrin-A5 antagonized this BDNF-evoked neuronal motility. BDNF increased ERK phosphorylation (P-ERK) and nuclear ERK entry. Ephrin-A5 suppressed BDNF-induced ERK activity and might sequester P-ERK in the cytoplasm. Neurotrophins are well established stimulators of a neuronal immediate early gene (IEG) response. This is confirmed in this study by e.g. c-fos, Egr1 and Arc upregulation upon BDNF application. This BDNF-evoked IEG response required the transcription factor SRF (serum response factor). Notably, ephrin-A5 suppressed a BDNF-evoked neuronal IEG response, suggesting a role of Eph receptors in modulating gene expression. In opposite to IEGs, long-term ephrin-A5 application induced cytoskeletal gene expression of tropomyosin and actinin. To uncover specific Eph receptors mediating ephrin-As impact on neurotrophin signaling, EphA7 deficient mice were analyzed. In EphA7 deficient neurons alterations in growth cone morphology were observed. However, ephrin-A5 still counteracted neurotrophin signaling suggesting that EphA7 is not required for ephrin and BDNF crosstalk. In sum, our data suggest an interaction of ephrin-As and neurotrophin signaling pathways converging at ERK signaling and nuclear gene activity. As ephrins are involved in development and function of many organs, such modulation of receptor tyrosine kinase signaling and gene expression by Ephs might not be limited to the nervous system

"Manneszucht" und "Selbstbeherrschung". Zivilgesellschaftliche Werte in der deutschen Sozialdemokratie, 1848-1878

Welskopp T. "Manneszucht" und "Selbstbeherrschung". Zivilgesellschaftliche Werte in der deutschen Sozialdemokratie, 1848-1878. In: Jessen R, Reichardt S, Klein A, eds. Zivilgesellschaft als Geschichte. Studien zum 19. und 20. Jahrhundert. Bürgergesellschaft und Demokratie. Vol 13. Wiesbaden: VS, Verl. für Sozialwiss.; 2004: 65-88

In Vivo Metabolic Imaging of [1-13C]Pyruvate-d3 Hyperpolarized By Reversible Exchange With Parahydrogen

Metabolic magnetic resonance imaging (MRI) using hyperpolarized (HP) pyruvate has shown promise as a non-invasive technique for diagnosing, staging, and monitoring response to treatment in cancer and other diseases. The clinically established method for producing HP pyruvate is dynamic nuclear polarization; however, it is rather expensive and slow. Here, we demonstrate fast (6 min), low-cost production of HP [1-13C]pyruvate-d3 in aqueous solution using Signal Amplification By Reversible Exchange (SABRE), and in vivo metabolic MRI. The injected solution was sterile, non-toxic, pH neutral and contained ≈30 mM [1-13C]pyruvate-d3 polarized to ≈11% (residual 250 mM methanol and 20 µM catalyst). It was obtained by rapid solvent evaporation and metal filtering. The procedure was well tolerated by all four mice studied here. This achievement is a significant step of making HP MRI available to a wider community. Fast, low-cost, and high-throughput parahydrogen-hyperpolarization has become a viable alternative for metabolic MRI of living organisms

Molecular changes during TGF β

Airway remodeling is an important process in response to repetitive inflammatory-mediated airway wall injuries. This is characterized by profound changes and reorganizations at the cellular and molecular levels of the lung tissue. It is of particular importance to understand the mechanisms involved in airway remodeling, as this is strongly associated with severe asthma leading to devastating airway dysfunction. In this study, we have investigated the transforming growth factor-β (TGFβ, a proinflammatory mediator)-activated fibroblast to myofibroblast transdifferentiation pathway, which plays a key role in asthma-related airway remodeling. We show that TGFβ induces fibroblast to myofibroblast transdifferentiation by the expression of αSMA, a specific myofibroblast marker. Furthermore, Smad2/Smad3 gene and protein expression patterns are different between fibroblasts and myofibroblasts. Such a change in expression patterns reveals an important role of these proteins in the cellular phenotype as well as their regulation by TGFβ during cellular transdifferentiation. Interestingly, our data show a myofibroblastic TGFβ-mediated increase in glucocorticoid receptor (GR) expression and a preferential localization of GR in the nucleus, compared to in fibroblasts. Furthermore, the GRβ (nonfunctional GR isoform) is increased relative to GRα (functional isoform) in myofibroblasts. These results are interesting as they support the idea of a GRβ-mediated glucocorticoid resistance observed in the severe asthmatic population. All together, we provide evidence that key players are involved in the TGFβ-mediated fibroblast to myofibroblast transdifferentiation pathway in a human lung fibroblast cell line. These players could be the targets of new treatments to limit airway remodeling and reverse glucocorticoid resistance in severe asthma.</p