Deciphering the microRNA signature of pathological cardiac hypertrophy by engineered heart tissue- and sequencing-technology

Pathological cardiac hypertrophy and fibrosis are modulated by a set of microRNAs, most of which have been detected in biologically complex animal models of hypertrophy by arrays with moderate sensitivity and disregard of passenger strand (previously "star") microRNAs. Here, we aimed at precisely analyzing the microRNA signature of cardiac hypertrophy and fibrosis by RNA sequencing in a standardized in vitro hypertrophy model based on engineered heart tissue (EHT). Spontaneously beating, force-generating fibrin EHTs from neonatal rat heart cells were subjected to afterload enhancement for 7 days (AE-EHT), and EHTs without intervention served as controls. AE resulted in reduced contractile force and relaxation velocity, fibrotic changes and reactivation of the fetal gene program. Small RNAs were extracted from control and AE-EHTs and sequencing yielded almost 750 different mature microRNAs, many of which have never been described before in rats. The detection of both arms of the precursor stem-loop (pre-miRNA), namely -3p and -5p miRs, was frequent. 22 abundantly sequenced microRNAs were > 1.3 × upregulated and 15 abundantly sequenced microRNAs downregulated to < 0.77 ×. Among the upregulated microRNAs were 3 pairs of guide and passenger strand microRNAs (miR-21-5p/-3p, miR-322-5p/-3p, miR-210-3p/-5p) and one single passenger strand microRNA (miR-140-3p). Among downregulated microRNAs were 3 pairs (miR-133a-3p/-5p, miR-30e-5p/3p, miR-30c-5p/-3p). Preincubating EHTs with anti-miR-21-5p markedly attenuated the AE-induced contractile failure, cardiomyocyte hypertrophy and fibrotic response, recapitulating prior results in whole animals. Taken together, AE-induced pathological hypertrophy in EHTs is associated with 37 differentially regulated microRNAs, including many passenger strands. Antagonizing miR-21-5p ameliorates dysfunction in this model

The Euro's Savior? Assessing the ECB's Crisis Management Performance and Potential for Crisis Resolution

This study assesses the ECB's crisis management performance and potential for crisis resolution. The study investigates the institutional and functional constraints that delineate the ECB's scope for policy action under crisis conditions and how the ECB has actually used its leeway since 2007; or might do so in the future. The study finds that the ECB may well stand out positively when compared to other important euro or national authorities involved in managing the euro crisis but that in general the bank did "too little, too late" to prevent the euro area from slipping into recession and protracted stagnation, ending up in its current predicament. The study also finds that expectations regarding the ECB's latest policy initiatives may be excessively optimistic and that proposals featuring the ECB as the euro's savior through even more radical employment of its balance sheet are misplaced hopes. Ultimately the euro's travails can only be ended and the euro crisis resolved by shifting the emphasis towards fiscal policy, by partnering up the ECB with a "Euro Treasury" as a vehicle for the central funding of public investment through common euro treasury debt securities in particular.Diese Studie bewertet das laufende Krisenmanagement der EZB sowie ihren potenziellen Beitrag zur letztlichen Krisenbewältigung. Die Studie untersucht dazu die institutionellen und funktionellen Beschränkungen, die den Umfang und die Tragweite von politische Maßnahmen der EZB unter Krisenbedingungen ausmachen, und wie die EZB tatsächlich seit 2007 von ihrem Handlungsspielraum Gebrauch gemacht hat; oder dies in der Zukunft noch tun könnte. Die Studie stellt fest, dass die EZB sich im Vergleich zu anderen, am Euro-Krisenmanagement beteiligten Eurozonen- oder nationalen Behörden durchaus positiv hervorgetan hat, dass die Zentralbank im Allgemeinen aber "zu wenig und zu spät" gehandelt hat, um das Abgleiten der Eurozone in die Rezession und ihr Verharren in lang anhaltender Stagnation zu verhindern, was dann schließlich in der aktuellen immer noch prekären Lage mündete. Die Studie stellt außerdem fest, dass etwaige Erwartungen in Bezug auf die jüngsten politischen Initiativen der EZB übermäßig optimistisch sind und dass Vorschläge, welche die EZB bei einem noch radikaleren Einsatz ihrer Bilanz gar als Retter des Euro sehen, verschwendete Hoffnungen darstellen. Letztlich kann die Mühsal des Euro nur behoben und die Euro-Krise nur wirksam überwunden werden, indem man den wirtschaftspolitischen Schwerpunkt in der Eurozone in Richtung Fiskalpolitik verlagert. Speziell sollte man der EZB dazu ein "Euro Schatzamt" als Partner zur Seite stellen, das insbesondere als Vehikel für die zentrale Finanzierung von öffentlichen Investitionen durch gemeinsame Euro-Schatzamtsanleihen dienen würde