Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies

In-situ analysis of phase transformations in a supermartensitic stainless steel: A magnetic approach

This thesis studies in-situ the phase transformations during heat treatment of two advanced steels: a supermartensitic stainless steels (SMSS), on which the main focus of this work is, and Fe-C-Mn-Si steels. A magnetic technique, based on the analysis of saturation magnetization, is utilized as the primary analysing tool. The scientific aim of this work is twofold: (i) to study the microstructural evolution involved in thermal processing of advanced steels based on optimising retained austenite and (ii) to optimise and extend the application of magnetic methods for these steels. For SMSS, the retained austenite fraction plays an essential role in controlling mechanical properties that often have a narrow tolerance window. Magnetic techniques are of increasing interest in the steel industry for monitoring the development of austenite on the basis of different magnetic properties of the phases in the steel. A new approach is proposed for determining the austenite fraction from in-situ thermo-magnetic measurements in SMSS. The formation of austenite during heat treatment of a SMSS is investigated and the kinetics of the martensite to austenite transformation, as well as the stability of austenite was established. The analysis of the Fe-C-Mn-Si steels provides a basis to further develop the analysis of austenite formation of multi-phase steels using thermo-magnetic techniques.This research was carried out under the project number M41.5.10392 in the framework of the Research Program of the Materials innovation institute (M2i) in The Netherlands (www.m2i.nl).(OLD) MSE-

Austenite Formation from Martensite in a 13Cr6Ni2Mo Supermartensitic Stainless Steel

The influence of austenitization treatment of a 13Cr6Ni2Mo supermartensitic stainless steel (X2CrNiMoV13-5-2) on austenite formation during reheating and on the fraction of austenite retained after tempering treatment is measured and analyzed. The results show the formation of austenite in two stages. This is probably due to inhomogeneous distribution of the austenite-stabilizing elements Ni and Mn, resulting from their slow diffusion from martensite into austenite and carbide and nitride dissolution during the second, higher temperature, stage. A better homogenization of the material causes an increase in the transformation temperatures for the martensite-to-austenite transformation and a lower retained austenite fraction with less variability after tempering. Furthermore, the martensite-to-austenite transformation was found to be incomplete at the target temperature of 1223 K (950 °C), which is influenced by the previous austenitization treatment and the heating rate. The activation energy for martensite-to-austenite transformation was determined by a modified Kissinger equation to be approximately 400 and 500 kJ/mol for the first and the second stages of transformation, respectively. Both values are much higher than the activation energy found during isothermal treatment in a previous study and are believed to be effective activation energies comprising the activation energies of both mechanisms involved, i.e., nucleation and growth.Materials Science and EngineeringMechanical, Maritime and Materials Engineerin

Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy

BACKGROUND: Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a “false positive” case in which plakoglobin signal was reduced in a patient initially thought to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC, but has not previously been associated with altered desmosomal proteins. METHODS AND RESULTS: We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (non-granulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of IL-17, TNFα and IL-6, cytokines implicated in granulomatous myocarditis, caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in non-granulomatous myocarditis had no effect, even at much high concentrations. We also observed myocardial expression of IL-17 and TNFα, and elevated serum levels of inflammatory mediators including IL-6R, IL-8, MCP1 and MIP1β in ARVC patients (all p<0.0001 compared with controls). CONCLUSIONS: These results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC