RETRACTED ARTICLE: Baduanjin Exercise for Insomnia: A Systematic Review and Meta-Analysis.

We, the Editors and Publisher of the journal Behavioral Sleep Medicine, have retracted the following article:Title: Baduanjin Exercise for Insomnia: A Systematic Review and Meta-AnalysisAuthors: Yun-Han Jiang, Cheng Tan & Shuai YuanDOI: 10.1080/15402002.2017.1363042Since publication, significant concerns have been raised about the appropriateness of references and reported conclusions in the article. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as "Retracted."

Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy.

AIMS: There is a large subpopulation of multinucleated polyploid cardiomyocytes (M*Pc CMs) in the adult mammalian heart. However, the pathophysiological significance of increased M*Pc CMs in heart disease is poorly understood. We sought to determine the pathophysiological significance of increased M*Pc CMs during hypoxia adaptation. METHODS AND RESULTS: A model of hypoxia-induced cardiomyocyte (CM) multinucleation and polyploidization was established and found to be associated with less apoptosis and less reactive oxygen species (ROS) production. Compared to mononucleated diploid CMs (1*2c CMs), tetraploid CMs (4c CMs) exhibited better mitochondria quality control via increased mitochondrial autophagy (mitophagy). RNA-seq revealed Prkaa2, the gene for AMPKα2, was the most obviously up-regulated autophagy-related gene. Knockdown of AMPKα2 increased apoptosis and ROS production and suppressed mitophagy in 4c CMs compared to 1*2c CMs. Rapamycin, an autophagy activator, alleviated the adverse effect of AMPKα2 knockdown. Furthermore, silencing PINK1 also increased apoptosis and ROS in 4c CMs and weakened the adaptive superiority of 4c CMs. Finally, AMPKα2-/- mutant mice exhibited exacerbation of apoptosis and ROS production via decreases in AMPKα2-mediated mitophagy in 4c CMs compared to 1*2c CMs during hypoxia. CONCLUSIONS: Compared to 1*2c CMs, hypoxia-induced 4c CMs exhibited enhanced mitochondria quality control and less apoptosis via AMPKα2-mediated mitophagy. These results suggest that multinucleation and polyploidization allow CM to better adapt to stress via enhanced mitophagy. In addition, activation of AMPKα2 may be a promising target for myocardial hypoxia-related diseases.

Systematic Review and Meta-Analysis of the Impact of Hypoxia on Infarcted Myocardium: Better or Worse?

BACKGROUND/AIMS: Patients with myocardial infarction and hypoxemia require supplemental oxygen. However, the current therapeutic paradigm is contradicted by several recent studies in which the post-infarcted heart appears to benefit from systemic hypoxia. With this systematic review and meta-analysis, we aimed to discover whether systemic hypoxia is beneficial or detrimental to the infarcted myocardium. METHODS: We conducted an electronic search of the PubMed, EMBASE, and Web of Science databases and extracted the outcomes of cardiac function, geometry, and hemodynamics. A random-effect model was applied when the I2 value of greater than 50%. The sensitivity analysis was performed by omitting one study at a time, and publication bias was assessed using Egger's test. In addition, the quality of studies was evaluated using the risk of bias tool devised by the Systematic Review Centre for Laboratory Animal Experimentation. RESULTS: Six reports comprising 14 experiments were ultimately screened from among 10,323 initially identified preclinical studies. Few studies reported the method of randomization and none described allocation concealment, random outcome assessment or blinding. Overall, chronic hypoxia was found to have a beneficial effect on the ejection fraction (standard mean difference [SMD] = 5.39; 95% confidence interval [CI], 3.83 to 6.95; P < 0.001) of the infarcted heart, whereas acute hypoxia significantly improved hemodynamics, as indicated by an increase in the maximal rate of rise of left ventricular pressure (SMD = 1.27; 95% CI, 0.27 to 2.28; P = 0.013) and cardiac output (SMD = 1.26; 95% CI, 0.34 to 2.18; P = 0.007) and a decrease in total systematic vascular resistance (SMD = -0.89; 95% CI, -1.24 to -0.53; P < 0.001). Furthermore, a reduced oxygen content increased the stroke volume (P = 0.010). However, hypoxia reduced the end-systolic (SMD = -2.67; 95% CI, -4.09 to -1.26; P < 0.001) and end-diastolic (SMD = -3.61; 95% CI, -4.65 to -2.57; P < 0.001) left ventricular diameters and increased the total pulmonary resistance (SMD = 0.76; 95% CI, 0.20 to 1.33; P = 0.008), pulmonary arterial mean pressure (SMD = 2.02; 95% CI, 0.23 to 3.81; P = 0.027), and left atrial pressure (SMD = 1.20; 95% CI, 0.57 to 1.82; P < 0.001). CONCLUSION: Hypoxia significantly improved heart function after infarction, with particular beneficial effects on systolic function and hemodynamics. However, it had slightly adverse effects on pulmonary circulation and left ventricular geometry. A lower inspired oxygen concentration may improve cardiac function, although further research is needed to determine the optimum level of hypoxia. Finally, more studies of hypoxia and myocardial infarction in larger species are required before these findings can be incorporated into therapeutic guidelines.

The molecular mechanism of CRISPR/Cas9 system and its application in gene therapy of human diseases.

CRISPR/Cas system is an adaptive immune system that confers resistance to exogenous virus or plasmid in bacteria and archaea. In recent years, the booming CRISPR/Cas9 genome editing technology modified from type2 CRISPR/Cas adaptive immune system has been widely applied to various research fields of life science and led to revolutionary changes. In this review, we summarize the origin and development of CRISPR/Cas9 genome editing technology as well as its applications in life science research. We focus on the latest application of this system in gene therapy of human diseases and the associated side/off-target effects, which may provide references for researchers in related areas.

AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation.

Increased evidence indicates that adenosine monophosphate-activated protein kinase (AMPK) plays a vital role in vascular homeostasis, especially under hypoxia, and protects against the progression of pulmonary hypertension (PH). However, the role of AMPK in the pathogenesis of PH remains to be clarified. In the present study, we confirmed that a loss of AMPKα2 exacerbated the development of PH by using hypoxia-induced PH model in AMPKα2 -/- mice. After a 4-week period of hypoxic exposure, AMPKα2 -/- mice exhibited more severe pulmonary vascular remodeling and pulmonary vascular smooth muscle cell (SMC) proliferation when compared with wild type (WT) mice. In vitro, AMPKα2 knockdown promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. This phenomenon was accompanied by upregulated Skp2 and downregulated p27kip1 expression and was abolished by rapamycin, an inhibitor of mTOR. These results indicate that AMPKα2 deficiency exacerbates hypoxia-induced PH by promoting PASMC proliferation via the mTOR/Skp2/p27kip1 signaling axis. Therefore, enhanced AMPKα2 activity might underlie a novel therapeutic strategy for the management of PH.

KLF15 is a protective regulatory factor of heart failure induced by pressure overload.

The aim of the present study was to investigate the protective effect of Kruppel­like factor 15 (KLF15) overexpression on heart failure (HF) induced by left ventricular (LV) pressure overload in mice. Wild­type (WT) mice and cardiac­specific KLF15­overexpressed transgenic (TG) mice were selected as research subjects, and an LV pressure overload model was constructed by ascending aortic constriction surgery. Changes in cardiac morphology and function, and ultrastructure and molecular expression were observed via M­mode echocardiography, histological and immunohistochemical staining, ELISA and western blotting at 2 and 6 weeks of LV overload. WT and TG mice subjected to 2 weeks of overload displayed adaptive LV hypertrophy characterized by ventricular thickness, cardiomyocyte size, ejection fraction and fractional shortening of heart­lung weight ratio and KLF15, and increases in vascular endothelial growth factor (VEGF) expression without other pathological changes. WT mice subjected to 6 weeks of overload displayed enlargement of the LV chamber, severe interstitial remodeling, and HW/LW, cardiac capillary and heart function decline, accompanied by downregulated expression of KLF15 and VEGF, and upregulated expression of connective tissue growth factor, phosphorylated p38 (p­p38) and phosphorylated Smad3 (p­Smad3). In contrast, TG mice exhibited improved resistance to 6 weeks of overload and a slighter molecular expression response compared with WT mice. KLF15 was revealed to be a critical factor regulating the expression of CTGF, VEGF, p­p38 and p­Smad3, and could alleviate the progression from adaptive LV hypertrophy to decompensatory cardiac insufficiency.

Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of ß-catenin.

Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease. Cardiac regeneration has been suggested as a promising strategy to address CM loss. Although many studies of regeneration have focused mainly on mononucleated or diploid CM, the limitations associated with the cytokinesis of polyploid and multinucleated CMs remain less well known. Here, we show that ß-catenin, a key regulator in heart development, can increase cytokinesis in polyploid multinucleated CMs. The activation of ß-catenin increases the expression of the cytokinesis-related factor epithelial cell transforming 2 (ECT2), which regulates the actomyosin ring and thus leads to the completion of cytokinesis in polyploid CMs. In addition, hypoxia can induce polyploid and multinucleated CMs by increasing factors related to the G1-S-anaphase of the cell cycle, but not those related to cytokinesis. Our study therefore reveals that the ß-catenin can promote the cytokinesis of polyploid multinucleated CMs via upregulation of ECT2. These findings suggest a potential field of polyploid CM research that may be exploitable for cardiac regeneration therapy.

Effects of transthoracic device closure on ventricular septal defects and reasons for conversion to open-heart surgery: A meta-analysis.

Transthoracic device closure (TTDC) is thought to be a promising technology for the repair of ventricular septal defects (VSDs). However, there is considerable controversy regarding the efficacy and safety of TTDC. The present study aimed to compare the benefits and safety of TTDC with those of conventional open-heart surgery (COHS) and analyze the associated factors causing complications, conversion to COHS and reoperation. Electronic database searches were conducted in PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov and several Chinese databases. A total of 5 randomized controlled trials (RCTs), 7 cohort studies, 13 case-control studies, 129 case series and 13 case reports were included. Compared to COHS, TTDC exhibited superior efficacy with a significantly lower risk of post-operative arrhythmia; however, no significant differences in other outcomes were identified. Meta-regression analysis showed that perimembranous VSDs (pmVSDs), a smaller VSD, a smaller occluder, and a median or subxiphoid approach lowered the relative risk of several post-operative complications, conversion to COHS and reoperation. The current evidence indicates that TTDC is associated with a lower risk of post-operative arrhythmia and is not associated with an increased risk of complications. PmVSDs, a smaller VSD and occluder, and a median or subxiphoid approach correlate with better outcomes when using TTDC.

Cardiac resident macrophages are involved in hypoxia­induced postnatal cardiomyocyte proliferation.

Induction of cardiomyocyte proliferation, the most promising approach to reverse myocardial attrition, has been gaining importance as a therapy for cardiovascular disease. Hypoxia and macrophages were previously independently reported to promote cardiomyocyte proliferation in mice. However, whether hypoxia promotes cardiomyocyte proliferation in humans, and the association between hypoxia and macrophages in cardiomyocyte proliferation, have not to the best of our knowledge been previously investigated. The present study investigated the cardiomyocyte proliferation in 22 acyanotic and 29 cyanotic patients. Cardiomyocyte proliferation in a hypoxic mouse model (15% O2) was subsequently performed and the macrophage subsets were analyzed. A C­C chemokine receptor type 2 (CCR2) inhibitor was used to increase the number of resident macrophages in order to investigate the effect of macrophages on cardiomyocyte proliferation. The results demonstrated that cardiomyocyte proliferation in the cyanotic infant group was significantly increased compared with the acyanotic infant group and the hypoxia­treated C57BL/6J neonates confirmed the hypoxia­induced cardiomyocyte proliferation. However, hypoxia did not induce the proliferation of isolated cardiomyocytes. Notably, hypoxia treatment increased the number of cardiac resident macrophages in neonate hearts. Furthermore, increasing the number of resident macrophages significantly enhanced cardiomyocyte proliferation. In conclusion, postnatal hypoxia promoted cardiomyocyte proliferation in humans and animals, and cardiac resident macrophages may be involved in this process. Therefore, this novel mechanism may provide a promising strategy for cardiovascular disease treatment.