Nox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survival

Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP 3 receptors (InsP 3R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP 3R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia–reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT. </p

Sicherheit bei Halbleiterfertigungsgeräten

Sicherheit ist ein heute recht oft verwendetes Schlagwort. Häufig versteht man darunter, je nach Standpunkt, etwas ganz anderes. Bei Halbleiterfertigungsgeräten kann man "Sicherheit" im Zusammenhang mit vier verschiedenen Aspekten gebrauchen: - Halbleiterfertigungsgeräte sollen sicher für das Bedienpersonal sein, dieses also nicht gefährden, z.B. durch Strahlung, toxische Gase oder hohe Spannungen. - Halbleiterfertigungsgeräte sollen sicher für die Umwelt sein, d.h. beispielsweise keine toxischen Gase und Chemikalien freisetzen. - Halbleiterfertigungsgeräte sollen sicher hinsichtlich des Prozeßergebnisses sein, d.h. die gewünschte Schichtdicke, Linienbreite oder Dotierungskonzentration soll reproduzierbar und homogen über die Scheibe ohne Nachregelung am Ende des Prozeßschrittes vorliegen. - Schließlich sollen Halbleiterfertigungsgeräte auch betriebssicher sein, d.h. eine möglichst hohe up-time besitzen, da die besten Prozeßergebnisse nichts nützen, wenn man nicht wirtschaftlich fertig en kann. (-z-

Analysis of contamination - a must for ultraclean technology

Contamination analysis has become more and more important in recent years. The demands for purity of liquid chemicals, gases, wafers, and processing are increasing from generation to generation. Instead of requesting the same decrease for all impurities as is frequently done, see Table 1, a more specific procedure is necessary. The transfer of impurities from materials (liquid chemicals, gases, and equipment) onto wafers has to be measured by surface analysis and correlated to the impurities in the materials. This transfer depends on the properties of the wafer surface which have to be optimized. The concentration of impurities at the wafer surface or in a surface layer has to be correlated with devices properties and yield. After further processing then it will be possible to develop specifications which avoid an increase in quality of chemicals, gases, wafers, etc. without differentation thus making ultraclean processing affordable. Of cause in this context, cleaning is of utmost imp ortance, because it can help to clean up impurities after transfer, esp. in cases where the equipment is the cause of a contamination. When investigating the influence of contamination on devices, a clear distribution between the different types of devices is necessary. MOS devices are more sensitive against surface or interface properties whereas bipolar devices are more sensitive against volume properties. All these investigations are only possible by using contamination analysis as a key tool

Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations

Heterozygous truncating variants in TTN (TTNtv), the gene coding for titin, cause dilated cardiomyopathy (DCM), but the underlying pathomechanisms are unclear and disease management remains uncertain. Truncated titin proteins have not yet been considered as a contributor to disease development. Here, we studied myocardial tissues from nonfailing donor hearts and 113 patients with end-stage DCM for titin expression and identified a TTNtv in 22 patients with DCM (19.5%). We directly demonstrate titin haploinsufficiency in TTNtv-DCM hearts and the absence of compensatory changes in the alternative titin isoform Cronos. Twenty-one TTNtv-DCM hearts in our cohort showed stable expression of truncated titin proteins. Expression was variable, up to half of the total titin protein pool, and negatively correlated with patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates, with deregulated ubiquitin-dependent protein quality control. We produced human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs), comparing wild-type controls to cells with a patient-derived, prototypical A-band-TTNtv or a CRISPR-Cas9–generated M-band-TTNtv. TTNtv-hiPSC-CMs showed reduced wild-type titin expression and contained truncated titin proteins whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR-Cas9, eliminating truncated titin proteins and raising wild-type titin content. Functional improvement also occurred when wild-type titin protein content was increased by proteasome inhibition. Our findings reveal the major pathomechanisms of TTNtv-DCM and can be exploited for new therapies to treat TTNtv-related cardiomyopathies