Proteomic and transcriptomic analysis of heart failure due to volume overload in a rat aorto-caval fistula model provides support for new potential therapeutic targets - monoamine oxidase A and transglutaminase 2

<p>Abstract</p> <p>Background</p> <p>Chronic hemodynamic overloading leads to heart failure (HF) due to incompletely understood mechanisms. To gain deeper insight into the molecular pathophysiology of volume overload-induced HF and to identify potential markers and targets for novel therapies, we performed proteomic and mRNA expression analysis comparing myocardium from Wistar rats with HF induced by a chronic aorto-caval fistula (ACF) and sham-operated rats harvested at the advanced, decompensated stage of HF.</p> <p>Methods</p> <p>We analyzed control and failing myocardium employing iTRAQ labeling, two-dimensional peptide separation combining peptide IEF and nano-HPLC with MALDI-MS/MS. For the transcriptomic analysis we employed Illumina RatRef-12v1 Expression BeadChip.</p> <p>Results</p> <p>In the proteomic analysis we identified 2030 myocardial proteins, of which 66 proteins were differentially expressed. The mRNA expression analysis identified 851 differentially expressed mRNAs.</p> <p>Conclusions</p> <p>The differentially expressed proteins confirm a switch in the substrate preference from fatty acids to other sources in the failing heart. Failing hearts showed downregulation of the major calcium transporters SERCA2 and ryanodine receptor 2 and altered expression of creatine kinases. Decreased expression of two NADPH producing proteins suggests a decreased redox reserve. Overexpression of annexins supports their possible potential as HF biomarkers. Most importantly, among the most up-regulated proteins in ACF hearts were monoamine oxidase A and transglutaminase 2 that are both potential attractive targets of low molecular weight inhibitors in future HF therapy.</p

Toll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14(+)Sirp alpha (+) population of monocyte-derived dendritic cells (CD14(+)moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14(+)moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25(+)Foxp3(+) Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14(+)moDC, the generation of Tregs, and thereby the establishment of central tolerance. Immune tolerance is mediated by the deletion of autoreactive T cells via medullary thymic epithelial cells (mTEC) and dendritic cells (DC), and by the induction of regulatory T cells (Treg). Here the authors show that mTEC receiving toll-like receptor signaling control the recruitment of CD14(+)Sirp alpha (+) DC population that is capable of inducing Treg for establishing tolerance

CAVER Analyst 1.0: graphic tool for interactive visualization and analysis of tunnels and channels in protein structures

ABSTRACT Summary: The transport of ligands, ions or solvent molecules into proteins with buried binding sites or through the membrane is enabled by protein tunnels and channels. CAVER Analyst is a software tool for calculation, analysis and real-time visualization of access tunnels and channels in static and dynamic protein structures. It provides an intuitive graphic user interface for setting up the calculation and interactive exploration of identified tunnels/channels and their characteristics. Availability and Implementation: CAVER Analyst is a multi-platform software written in JAVA. Binaries and documentation are freely available for non-commercial use at http://www.caver.cz

Thermodynamics of Molten Salts for Nuclear Applications - JRC-ITU-TN-2008/40

The molten salt reactor (MSR) is one of the six reactor concepts of the Generation IV initiative, an international collaboration to study the next generation nuclear power reactors. The fuel of the MSR is based on the dissolution of the fissile material (235U, 233U or 239Pu) in a matrix of a molten salt that must fulfill several requirements with respect to its physical properties. These requirements are very well satisfied by the various systems containing alkali metal and alkali earth fluorides. In this study in total 32 binary fluoride systems have been thermodynamically assessed in order to predict the fuel properties in terms of the melting behaviour, the vapour pressure and the solubility of the actinides in the fuel matrix. Based on these properties, in total eight fuel compositions for the MSR have been proposed. As part of the experimental study, two gas tight crucibles have been developped in order to measure the fluoride samples up to high temperatures. One is designed for a drop calorimeter used to measure the heat capacity of the (Li,Na)F liquid solution, whereas the other one is designed for a Differential Scanning Calorimeter (DSC) which was used to determine the equilibrium data points of the NaNO3-KNO3, RbF-CsF and CaF2-ThF4 binary systems. The data of the two latter systems were used to improve our thermodynamic database. The Schottky contributions of the UPd3 sample were measured by the drop calorimeter and a very good correlation to the theoretical curve has been obtained. This measurement also confirmed that the drop calorimetry is in general a very sensitive method to determine relatively small energies. An approach of obtaining the excess Gibbs energies of the solutions ab initio has been demonstrated in the case of (Rb,Cs)F solid solution and a very good correlation with the measured solidus and liquidus data has been observed.JRC.E.3-Materials researc

Thermodynamic Study of LiF-BeF2-ZrF4-UF4 System

In this work the three binary phase diagrams LiF¿ZrF4, BeF2¿ZrF4 and UF4¿ZrF4 were thermodynamically assessed. The three ternary phase diagrams LiF¿BeF2¿ZrF4, BeF2¿ZrF4¿UF4 and LiF¿ZrF4¿UF4 were approximated on the basis of binary data. A pseudo-ternary LiF¿BeF2¿ZrF4 system with constant amount of UF4 set to 0.83 mol% was calculated as well, typical for molten salt reactor fuel. Based on this diagram a suggestion for the composition of the fuel in this system was made.JRC.E.3-Materials researc

The heat capacity of NpO2 at high temperatures: the effect of oxygen Frenkel pair formation

The contribution of oxygen Frenkel pair formation to the high-temperature heat capacity of NpO2 has been calculated from its formation enthalpy and entropy obtained by interpolation of the values for ThO2, UO2 and PuO2 derived from an analysis of experimental heat capacity data.JRC.E.3-Materials researc

Thermodynamic assessment of the LiF-CeF3-ThF4 system: Prediction of PuF3 concentration in a molten salt reactor fuel

A thermodynamic description of the LiF-CeF3-ThF4 system is made in this study using a two-sublattice model for the description of the solid solution and a quasi-chemical model based on quadruplet approximation for the liquid phase. New calorimetric experimental data of the binary LiF-CeF3, CeF3-ThF4 and ternary LiF-CeF3-ThF4 systems have been obtained in this work justifying the calculated phase diagrams. Using the obtained thermodynamic assessment the concentration of PuF3 in the LiF-ThF4 melt was estimated based on the similarities with CeF3 and the melting behaviour of the initial molten salt fast reactor fuel was discussed.JRC.E.3-Materials researc