The COP9 signalosome (originally described as the COP9 complex) is an essential multi-subunit repressor of light-regulated development in plants [1] [2]. It has also been identified in mammals, though its role remains obscure [3] [4] [5]. This complex is similar to the regulatory lid of the proteasome and eIF3 [5] [9] [10] [11] [12] and several of its subunits are known to be involved in kinase signaling pathways [4] [6] [7] [8]. No proteins homologous to COP9 signalosome components were identified in the Saccharomyces cerevisiae genome, suggesting that the COP9 signalosome is specific for multi-cellular differentiation [13]. In order to reveal the developmental function of the COP9 signalosome in animals, we have isolated Drosophila melanogaster genes encoding eight subunits of the COP9 signalosome, and have shown by co-immunoprecipitation and gel-filtration analysis that these proteins are components of the Drosophila COP9 signalosome. Yeast two-hybrid assays indicated that several of these proteins interact, some through the PCI domain. Disruption of one of the subunits by either a P-element insertion or deletion of the gene caused lethality at the late larval or pupal stages. This lethality is probably a result of numerous pleiotropic effects. Our results indicate that the COP9 signalosome is conserved in invertebrates and that it has an essential role in animal development.

Viral myocarditis (VM) can be a life-threatening event resulting in cardiac failure, chronic cardiomyopathy, and death. VM typically includes three phases, i.e., acute, subacute, and resolution/chronic. We prospectively investigated cardiac- and inflammatory-associated plasma-circulating miRNA levels in eight pediatric patients with VM during the three stages of the disease. The level of cardiac-associated miR-208a was significantly elevated during the acute phase compared with the subacute and resolution/chronic phases. The level of cardiac- and inflammatory-associated miR-21 was significantly elevated during the acute phase compared to the resolution/chronic phase. Moreover, cardiac-associated miR-208b levels during the subacute phase correlated with systolic left ventricular function recovery as measured during the resolution/chronic phase. The findings of our study demonstrate an association between cardiac damage and the inflammatory response and the expression of miR-208a and miR-21 during the pathological progression of myocarditis. We also found that miR-208b levels exhibit a prognostic significance for left ventricular functional recovery.

Regulating gene expression is part of a cell's response to hypoxia. A-to-I RNA editing is an epigenetic phenomenon that can contribute to RNA and protein levels and to isoform diversity. In this study, we identified alterations in the levels of RNA editing following hypoxic stress in three genes: MED13, STAT3, and F11R. Changes in editing levels were associated with changes in RNA levels. These results suggest that A-to-I RNA editing may be one of the mechanisms used by cells to regulate changes in gene expression after hypoxia. These findings could lead to a novel therapeutic approach and better health care for children with hypoxemia.

BackgroundThe immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins‐4 and ‐13 are anti‐inflammatory type‐2 cytokines, signaling via the common interleukin‐13 receptor α1 chain and the type‐2 interleukin‐4 receptor. The role of interleukin‐13 receptor α1 in the heart is unknown.Methods and ResultsWe analyzed myocardial samples from human donors (n=136) and patients with end‐stage heart failure (n=177). We found that the interleukin‐13 receptor α1 is present in the myocardium and, together with the complementary type‐2 interleukin‐4 receptor chain Il4ra, is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1‐deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild‐type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P=0.004, left ventricular end‐diastolic diameter 4.2±0.2 versus 3.92±0.3; P=0.03). A bioinformatic analysis of mouse hearts indicated that interleukin‐13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=−2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure‐overload conditions.ConclusionsThe results of our studies in humans and mice indicate, for the first time, a role of interleukin‐13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.