The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein–coupled receptors

Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursors plays a critical role in this communication and often involves metalloprotease-mediated proteolysis. Stimulation of G protein–coupled receptors (GPCR) transactivates the EGF receptors (EGFRs), which occurs via a metalloprotease-dependent cleavage of heparin-binding EGF (HB-EGF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ; ADAM10), which controls Notch signaling in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain–containing protein and Gab1 on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease domain–deleted KUZ, or blocking endogenous KUZ by morpholino antisense oligonucleotides, suppresses the transactivation. The effect of KUZ on shedding of HB-EGF and consequent transactivation of the EGFR depends on its metalloprotease activity. GPCR activation enhances the association of KUZ and its substrate HB-EGF with tetraspanin CD9. Thus, KUZ regulates the relay between the GPCR and EGFR signaling pathways

Postinfarct Ventricular Septal Defect after Coronary Covered Stent Implantation

We report a case of a postinfarction ventricular septal defect caused by an acute recurrent occlusion after the implantation of a covered stent, which was performed as a rescue procedure for the ruptured left anterior descending artery during a percutaneous coronary intervention. Although the emergent implantation of a covered stent for the ruptured coronary arteries such as the left main coronary artery or the origins of the left anterior descending artery can be performed during a percutaneous coronary intervention, and a coronary bypass surgery should be considered in order to decrease the risk of complete occlusion, thus providing a superior long term patency

BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network

Several homeodomain (HD) proteins are critical for skeletal patterning and respond directly to BMP2 as an early step in bone formation. RUNX2, the earliest transcription factor proven essential for commitment to osteoblastogenesis, is also expressed in response to BMP2. However, there is a gap in our knowledge of the regulatory cascade from BMP2 signaling to the onset of osteogenesis. Here we show that BMP2 induces DLX3, a homeodomain protein that activates Runx2 gene transcription. Small interfering RNA knockdown studies in osteoblasts validate that DLX3 is a potent regulator of Runx2. Furthermore in Runx2 null cells, DLX3 forced expression suffices to induce transcription of Runx2, osteocalcin, and alkaline phosphatase genes, thus defining DLX3 as an osteogenic regulator independent of RUNX2. Our studies further show regulation of the Runx2 gene by several homeodomain proteins: MSX2 and CDP/cut repress whereas DLX3 and DLX5 activate endogenous Runx2 expression and promoter activity in non-osseous cells and osteoblasts. These HD proteins exhibit distinct temporal expression profiles during osteoblast differentiation as well as selective association with Runx2 chromatin that is related to Runx2 transcriptional activity and recruitment of RNA polymerase II. Runx2 promoter mutagenesis shows that multiple HD elements control expression of Runx2 in relation to the stages of osteoblast maturation. Our studies establish mechanisms for commitment to the osteogenic lineage directly through BMP2 induction of HD proteins DLX3 and DLX5 that activate Runx2, thus delineating a transcriptional regulatory pathway mediating osteoblast differentiation. We propose that the three homeodomain proteins MSX2, DLX3, and DLX5 provide a key series of molecular switches that regulate expression of Runx2 throughout bone formation. <br/

Opposite field septum magnet system for the separation of charged particle beams

Abstract-The Japan Hadron Facility (JHF) accelerator complex comprises a 50-GeV main synchrotron, a 3-GeV rapid-cycling synchrotron, and a 400-MeV linac. The accelerators provide high-intensity, high-energy proton beams for various scientific fields. These high-intensity, high-energy accelerators, especially the 50-GeV main synchrotron, impose tight demands on the injection/extraction septum magnets for a thin structure, large aperture and high operating field. But to manufacture high field septum magnets on the condition of a large aperture is very difficult because of its extraordinarily strong electromagnetic force due to the self-field. To cope with these tight demands, new design concepts of septa are required. An opposite-field septum magnet system is one of the solutions to realize a thin septa or very high-field septum magnets