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Anne-Claire Gunantin Imen Jebeniani Julia Leschik Erwan Watrin Gisle Bonne Nicolas Vignier Michel Pucat 《The Journal of clinical investigation》2021,131(1)
LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy. 相似文献
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Despite the international ratification of Geneva Conventions, which define rules to protect people in situations of war, violence beyond the law of armed conflict is not uncommon. Fairly regularly, the subject makes the headlines. A notable example is the recent publication of confidential informations by Wikileaks. What is at stake is the coherence of UN mandates to western armies. This coherence contributes to the preservation of mental balance of military forces. 相似文献
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Peyrol M Sbragia P Orabona M Casalta AC Laine M Decourt A Quatre A Jacquier A Siddo ND Paganelli F 《Journal of electrocardiology》2012,45(4):394-397
Ventricular allorhythmia is an electrocardiogram feature leading to a pattern of "regularly irregular" arrhythmia mainly reported during non-life-threatening organized atrial tachycardia. We report the infrequent case of a patient presenting with ventricular allorhythmia during infarct-related ventricular tachycardia. The potential mechanisms of this tachycardia are discussed. 相似文献