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

PTt history from kyanite-sillimanite migmatites and garnet-staurolite schists from the Bayankhongor area, Mongolia indicates suprasubduction switching from extension to compression during Rodinia assembly

The tectonometamorphic evolution of the peri-Siberian tract of the Central Asian Orogenic Belt is mainly characterized by Baikalian Late Proterozoic - Early Cambrian cycle related to amalgamation of Proterozoic oceanic and continent fragments to Siberain landmass. Here we present in-situ monazite geochronology linked to P−T modelling of micashischsts and migmatite gneisses at the northern part of the Precambrian Baydrag block (central Mongolia) previously considered as a part of Baikalian metamorphic belt. Garnet-sillimanite-kyanite gneiss records first burial to the sillimanite stability at ~725 °C and 6.5 kbar, followed by burial to the kyanite stability at ~650 °C and ~8 kbar. The garnet-staurolite schist records burial to the staurolite-stability at ~620 °C and 6 kbar, followed by a nearly isothermal burial to ~580 °C and 9 kbar. The monazite data yield a continuum of 207Pb-corrected 238U/206Pb dates of c. 926−768 Ma in the Grt−Sil−Ky gneiss, and c. 937−754 Ma in the Grt-St schist. Based on monazite textural positon and internal zoning, the time of prograde burial and peak under a thermal gradient of 28-32 °C/km is estimated at c. 870−890 Ma. It is not clear whether such high grade conditions prevailed until a phase of further burial under a geothermal gradient of 18-22 °C/km and dated at 800−820 Ma. Additionally, monazite with dates of c. 568−515 Ma occurs as whole grains or as rims with sharp boundaries on Grenvillean monazite in Grt-St schist testifying for minor Baikalian overprint. Metamorphic zircon rims with Th/U ratio ~0.01-0.06 in Grt−Sil−Ky gneiss with 877 ± 7 Ma age, together with lower intercepts of zircon discordia lines in both Grt-Sil-Ky gneiss and Grt-St schist further support the Tonian age of high grade metamorphism. The P−T and geochronology data show anticlockwise P−T evolution from c. 930 to 750 Ma which is interpreted as a result of thickening of suprasubduction extensional and hot edifice - probably of back arc or arc type. This kind of prograde metamorphism was so far described only on the northern part of the Tarim block and interpreted as a result of initiation of peri-Rodinian subduction of Mirovoi Ocean. Here, we further discuss geodynamic consequences of a unique discovery of Tonian metamorphism in term of tectonic switch related to initiation of peri-Rodinian oceanic subduction during supercontinent assembly followed by strong mechanical coupling potentially related to onset of Rodinia splitting

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements