Studies of metabolic adaptation during environmental stress have broad applications to human disease. Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. Serendipitously, a wide search for adenosine receptor A2b (Adora2b)-elicited cardio-adaptive responses identified the circadian rhythm protein period2 (Per2). Subsequent pharmacologic and genetic studies confirmed Adora2b-dependent stabilization of Per2 during myocardial ischemia. Functional studies of myocardial ischemia in Per2−/− mice revealed larger infarct sizes and abolished cardio-protection by ischemic preconditioning. Metabolic studies during myocardial ischemia uncovered a limited ability of Per2−/− mice to utilize carbohydrates via oxygen-efficient glycolysis. These metabolic alterations were associated with a failure in Per2−/− mice to stabilize hypoxia-inducible-factor Hif1a. Moreover, cardiac stabilization of Per2 via light-exposure transcriptionally enhanced glycolysis, and provided period-specific cardio-protection from ischemia. Together, these studies identify Per2 as key regulator of ischemia tolerance through reprogramming of cardiac metabolism and implicate Per2 as novel therapeutic modality during acute myocardial ischemia.

Myocardial ischemia reperfusion injury contributes to adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. Primarily, no blood flow to the heart causes an imbalance between oxygen demand and supply, named ischemia (from the greek isch-, restriction and -haema, blood), resulting in damage or dysfunction of the cardiac tissue. Instinctively, early and fast restoration of blood flow has been established to be the treatment of choice to prevent further tissue injury. Indeed, the use of thrombolytic therapy or primary percutaneous coronary intervention is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. Unfortunately, restoring blood flow to the ischemic myocardium, named reperfusion, can also induce injury. This phenomenon was therefore termed myocardial ischemia reperfusion injury. Subsequent studies in animal models of acute myocardial infarction suggest that myocardial ischemia reperfusion injury accounts for up to 50% of the final size of a myocardial infarct. Consequently many researchers aim to understand the underlying molecular mechanism of myocardial ischemia reperfusion injury to find therapeutic strategies ultimately reducing the final infarct size. Despite of the identification of numerous therapeutic strategies at the bench, many of them are just in the process of being translated to bedside. In the current review, we will discuss the most striking basic science findings made during the last decades that are currently under clinical evaluation, with the ultimate goal to treat patients who are suffering from myocardial ischemia and reperfusion associated tissue injury.

Highlights d scRNA-seq shows transcriptional profiles corresponding to E14 meningeal layers d Regional heterogeneity in E14 meningeal fibroblast gene expression d Temporal-spatial maturation of telencephalic meningeal layers d Conservation of meningeal layer enriched markers in human fetal meninges

DisAp is a novel kinetodesmal fiber component that is essential for force-dependent fiber elongation and the alignment of basal body orientation in multiciliary arrays.

Due to an imbalance in oxygen supply and demand, myocardial ischemia is associated with profound tissue hypoxia. Studies of hypoxia-elicited adaptive responses during myocardial ischemia revealed a cardioprotective role for the signaling molecule adenosine. In ischemic human hearts, the A2B adenosine receptor (ADORA2B) is selectively induced. Functional studies in genetic models show that Adora2b signaling attenuates myocardial infarction by adapting metabolism towards more oxygen efficient utilization of carbohydrates. This adenosine-mediated cardio-adaptive response involves the transcription factor hypoxia-inducible factor HIF1A and the circadian rhythm protein Per2. In the present review we discuss advances in the current understanding of adenosine-elicited cardioprotection with particular emphasis on ADORA2B, its downstream targets, and their implications on novel strategies to prevent or treat myocardial ischemia.