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We previously reported that dysregulation of histone deacetylase 2 (Hdac2) was associated with the prognosis of sudden sensorineural hearing loss. However, the underlying molecular mechanisms are poorly understood. In the present study, we developed an acute hearing loss animal model in guinea pigs by infusing lipopolysaccharides (LPS) into the cochlea and measured the expression of Hdac2 in the sensory epithelium. We observed that the level of Hdac2 was significantly decreased in the LPS-infused cochleae. The levels of apoptosis-inhibition genes Bcl-2 and Bcl-xl were also decreased in the cochlea and correlated positively with the levels of Hdac2. Caspase3 or TUNEL-positive spiral ganglion neurons, hair cells, and supporting cells were observed in the LPS-infused cochleae. These in vivo observations were recapitulated in cell culture experiments. Based on bioinformatics analysis, we found miR-204-5p was engaged in the regulation of Hdac2 on Bcl-2. Molecular mechanism experiments displayed that miR-204-5p could be regulated by Hdac2 through interacting with transcription factor Sp1. Taken together, these results indicated that the Hdac2/Sp1/miR-204-5p/Bcl-2 regulatory axis mediated apoptosis in the cochlea, providing potential insights into the progression of acute hearing loss. To our knowledge, the study describes a miRNA-related mechanism for Hdac2-mediated regulation in the cochlea for the first time., Graphical Abstract, Dysregulation of histone deacetylase 2 (Hdac2) was associated with the prognosis of sudden sensorineural hearing loss. However, the underlying molecular mechanisms are poorly understood. This study revealed a role of Hdac2/miR-204-5P/Bcl-2 axis in the apoptosis of cochlear cells and provided a potential insight into the pathogenesis of acute hearing loss.

Introduction: A significant number of sensorineural hearing loss (SSNHL) patients had no noticeable hearing improvement after glucocorticoid (GC) treatment. In the present study, we examined expression of the nuclear factor erythroid 2-related factor 2 (NRF2) and histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) of refractory SSNHL patients to study the role of NRF2-HDAC2 pathway in GC insensitivity hearing improvement after GC treatment, which is usually referred to as refractory SSNHL or GC insensitivity. Materials and Methods: Forty-four refractory SSNHL patients were treated by intratympanic GC infusion. Hearing was tested in all patients before and after treatment by pure tone hearing test. NRF2/HDAC2 mRNA and protein levels were examined in PBMCs of refractory SSNHL patients before and after treatment. PBMCs from healthy volunteers were used as normal controls. Results: According to the hearing improvement after treatment, patients were assigned into 2 groups: the intratympanic GC sensitive (IGCS) group (hearing recovery ≥15 dB HL) and the intratympanic GC insensitive (IGCI) group (hearing recovery Conclusion: Low response of NRF2/HDAC2 proteins is associated with GC insensitivity in SSNHL. We speculate that the NRF2-HDAC2 pathway affects GC sensitivity in SSNHL patients.

An ongoing theme of the COVID-19 pandemic is the need for widespread availability of accurate and efficient diagnostic testing for detection of SARS-CoV-2 and antiviral antibodies in infected indiv...

With the steadily increasing amount of leadless pacemaker implantations performed worldwide, it has called attention to the delivery difficulty in patients with severe large right heart. Nevertheless, limited studies have reported leadless pacemaker implantation in patients with tricuspid stenosis. Here, we report the successful implantation of leadless pacemaker in a 60-year-old female patient with giant right atrium and tricuspid valve stenosis. It is highlighted that leadless pacemaker should not be discouraged even if there are tricuspid valve stenosis and giant right atrium.

Background: As the most common primary bone tumor in adolescents and children, osteosarcoma commonly occurs with high mortality rate and metastasis. Emerging evidence has illustrated that circular RNAs (circRNAs) are important regulatory RNAs that are involved in multiple biological activities of carcinomas. Circ-FOXM1 (hsa_circ_0025033) is a recently found circRNA and promotes the cellular activities of several cancers. However, the function and molecular mechanism of circ-FOXM1 in osteosarcoma have not been interrogated yet. Methods: The qRT-PCR was utilized to test the expression of circ-FOXM1 in osteosarcoma cell lines. Loss-of-function assays including CCK-8, EdU, TUNEL, transwell and western blot assays were conducted to measure cell proliferation, cell migration, EMT process and cell apoptosis. Luciferase reporter assay and RIP assay were utilized to detect the interaction of circ-FOXM1 and RNAs. Results：We discovered the high expression of circ-FOXM1 in osteosarcoma cells. Besides, it was indicated that circ-FOXM1 knockdown inhibited cell proliferation, cell migration and EMT process, as well as induced cell apoptosis of osteosarcoma cells. Furthermore, circ-FOXM1 was discovered to upregulate the expression level of forkhead box M1 (FOXM1) at post-transcriptional level. Moreover, it was proved that circ-FOXM1 sponged miR-320a and miR-320b so as to increase FOXM1 expression. Additionally, circ-FOXM1 could activate Wnt signaling pathway through upregulating FOXM1. In the end, rescue assays certified that FOXM1 overexpression could totally rescue the circ-FOXM1 silence-repressed cellular activities of osteosarcoma cells.Conclusion: Circ-FOXM1 facilitated the progression of osteosarcoma cells via relieving FOXM1 from the inhibition by miR-320a and miR-320b.

Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E2. Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.

Background: There are numerous clinical reports of oral tumors in children. However, the clinical features and management of oral nonodontogenic masses in children were rare reported. The aim of this article is to present a large series of oral nonodontogenic masses in children, analyzing the clinical characteristics of such masses and reviewing the relevant procedures for treatment.Methods: We conducted an observational retrospective study, reviewing medical records of 171 patients who were treated for oral nonodontogenic masses between 2014 and 2019 at the Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University. Data collected included age, gender, site, pathologic diagnosis and treatment strategy.Results: All patients were hospitalized in our department. Of the 171 cases, all of them were benign, however, only 1 case diagnosed as inflammatory myofibroblastic tumor showed a malignant process. The most frequent type was hemangioma (63.7%), followed by lymphangioma (16.4%), ranula (7.6%). The most common location of oral masses in the buccal mucosa. The second common location was in tongue. 16 cases of hemangioma were located in two or more sites in cavity. And 29 patients (26.6%) of hemangioma and 11 patients (39.3%) lymphangioma of were found other extraoral lesions. With regard to some cases of hemangioma, the other patients commonly undergone surgical resections or sclerotherapy. The follow-up period ranged from 1 to 5 years. The recurrence rate of hemangioma and lymphangioma were 8.3%, 17.9%, respectively.Conclusion: Most of oral nonodontogenic masses are benign, few oral masses are malignant or mimic a malignant process. Surgical resections are the most common treatment with excellent success.

The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10F/F mice (cFat10−/−). Compared with their wild-type littermates, cFat10−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scien...

Melatonin is involve in plant development and abiotic stress responses. In the present study, the effects of exogenous melatonin on chilling in tea plant were investigated. Compared to control, decreasing chlorophyll contents and increasing malondialdehyde levels in leaves were observed in tea plants treated with chilling at 4 °C. Interestingly, compared to chilling treatment, chlorophyll contents were increased significantly and malondialdehyde levels were dramatically decreased in tea leaves after melatonin treatments. Moreover, exogenous melatonin enhanced the anti-oxidation ability by increasing the activities of superoxide dismutase, catalase and peroxidase. It was also observed that there is increased the contents of reduced glutathione (GSH), decreased the contents of oxidized glutathione (GSSG), increased the ratio of GSH/GSSG, and increased the activity of ascorbate peroxidase and glutathione reductase in tea leaves after melatonin treatments. Meanwhile, the genes expression of CsGSHS, CsGR, and CsAPX were significantly up-regluated after the treatment of melatonin comparison with chilling treatment. Therefore, these data indicated that exogenous melatonin can attenuate the cold damage via enhancing anti-oxidation ability in tea plant.

Background Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias. Methods and results In this study, Sprague-Dawley rats (male, 200-230 g) were treated with a single high-dose of streptozotocin (STZ, 80 mg/kg) to generate a rat model of diabetes. STZ-induced 3-month diabetic rats displayed increased susceptibility to ventricular arrhythmias. The elevated O-GlcNAc modification was correlated with decreases in both total and cytoplasmic Nav1.5 expression in vivo and in vitro. In addition, both co-immunoprecipitation and immunostaining assays demonstrated that hyperglycemia could increase the O-GlcNAc-modified Nav1.5 levels and decrease the interaction between Nav1.5 and Nav1.5-binding proteins Nedd4–2/SAP-97. Furthermore, patch-clamp measurements in HEK-293 T cells showed that Nav1.5 current densities decreased by 30% after high-glucose treatment, and the sodium currents increased via O-GlcNAc inhibition. Conclusion Our data suggested that hyperglycemia increased the O-GlcNAc modification of Nav1.5 expression and decreased the interaction between Nav1.5 and Nedd4–2/SAP-97, which led to the abnormal expression and distribution of Nav1.5, loss of function of the sodium channel, and prolongation of the PR/QT interval. Excessive O-GlcNAc modification of Nav1.5 is a novel signaling event, which may be an underlying contributing factor for the development of the arrhythmogenesis in DH.

Background Self-incompatibility (SI) is a major barrier that obstructs the breeding process in most horticultural plants including tea plants (Camellia sinensis). The aim of this study was to elucidate the molecular mechanism of SI in tea plants through a high throughput transcriptome analysis. Results In this study, the transcriptomes of self- and cross-pollinated pistils of two tea cultivars ‘Fudingdabai’ and ‘Yulv’ were compared to elucidate the SI mechanism of tea plants. In addition, the ion components and pollen tube growth in self- and cross-pollinated pistils were investigated. Our results revealed that both cultivars had similar pollen activities and cross-pollination could promote the pollen tube growth. In tea pistils, the highest ion content was potassium (K+), followed by calcium (Ca2+), magnesium (Mg2+) and phosphorus (P5+). Ca2+ content increased after self-pollination but decreased after cross-pollination, while K+ showed reverse trend with Ca2+. A total of 990 and 3 common differentially expressed genes (DEGs) were identified in un-pollinated vs. pollinated pistils and self- vs. cross-pollinated groups after 48 h, respectively. Function annotation indicated that three genes encoding UDP-glycosyltransferase 74B1 (UGT74B1), Mitochondrial calcium uniporter protein 2 (MCU2) and G-type lectin S-receptor-like serine/threonine-protein kinase (G-type RLK) might play important roles during SI process in tea plants. Conclusion Ca2+ and K+ are important signal for SI in tea plants, and three genes including UGT74B1, MCU2 and G-type RLK play essential roles during SI signal transduction. Electronic supplementary material The online version of this article (10.1186/s12864-018-4674-1) contains supplementary material, which is available to authorized users.

The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single-nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (PG, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B-cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti-apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD.

Sensorineural hearing loss is a health problem with global prevalence. Aminoglycoside antibiotics, for instance gentamicin, may cause ototoxicity in mammals as a result of apoptosis and elevated oxidative stress in cochlear hair cells. Our study aimed to examine the potential effects of theophylline, an HDAC2 agonist, on gentamicin-induced cytotoxicity to sensory hair cells. Mouse cochlear explants and HEI-OC1 cells were in vitro cultured and challenged by gentamicin to induce ototoxicity, with or without theophylline. Cochlear hair cells were evaluated by fluorescent microscopy, and their mechanotransduction was assessed by electrophysiology. Expression levels of HDAC2 and apoptosis pathway factors were also evaluated following gentamicin and theophylline treatments. The functional role of HDAC2 in this setting was investigated by siRNA targeted silencing. Theophylline protected cochlear hair cells from ototoxicity induced by gentamicin, in terms of preserving cochlear structure and mechanotransduction ability, and preventing the activation of the intrinsic apoptosis pathway dose-dependently. HDAC2 expression was downregulated by gentamicin, which could be restored by theophylline. HDAC2 silencing in HEI-OC1 cells negated the beneficial effect of theophylline against gentamicin-induced growth defect and apoptosis activation. Theophylline protects sensory hair cells from gentamicin ototoxicity by maintaining HDAC2 expression. Our study thereby discovers a critical role of HDAC2 in gentamicin-induced ototoxicity, which could shine light on potential therapeutic options for treatment against sensorineural hearing loss.

Glucocorticoids have been used to treat hearing loss and vestibular dysfunction for many years. However, some reports have indicated that a subset of patients with these disorders exhibit glucocorticoid insensitivity or resistance. A reduction in histone deacetylase 2 (HDAC2) activity and expression has been reported to play a critical role in glucocorticoid resistance. Here, we investigated the protective effects of aminophylline on HDAC2 expression and glucocorticoid sensitivity in lipopolysaccharide (LPS)-induced sudden sensorineural hearing loss in guinea pigs. We assessed hearing recovery in LPS-applied guinea pigs, which were either left untreated or were systemically treated with either dexamethasone, aminophylline, or a combination of the two. We utilized fluorescence microscopy and enzyme-linked immunosorbent assay to analyze the distribution patterns of HDAC2 and detect its levels in the cochlea. We used hematoxylin-eosin staining to examine cochlear histopathological changes. In the absence of treatment, significant hearing loss was detected in LPS-exposed animals. A synergistic effect was observed between aminophylline and dexamethasone in maintaining HDAC2 expression levels, preventing hearing loss in LPS-exposed animals and reducing cochlear damage. This study indicates that aminophylline can restore glucocorticoid sensitivity, which provides a new approach to treating patients with hearing disorders who are refractory to glucocorticoids.

The benefits of implantable cardioverter defibrillator (ICD) implantation in chronic kidney disease (CKD) patients with high sudden cardiac death (SCD) risk are uncertain. To clarify the effects of receiving an ICD in CKD patients, we conducted this meta-analysis to identify the effects of ICDs on patients with CKD, including those on dialysis. We searched the Cochrane library, EMBASE, PubMed, and clinical trials for studies published before July 2016. Eleven studies including 20,196 CKD patients were considered for inclusion. The pooled analysis suggested that patients with an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m2 would benefit from receiving treatments with ICDs compared with patients without an ICD device (aHR = 0.74; 95% confidence interval [CI], 0.63 to 0.86). [corrected]. This is the first report of a subgroup analysis on the survival rate of ICD implantation in CKD patients according to an eGFR group. The subgroup analysis indicated a similar protective association of ICDs in stage 3 (aHR = 0.71; 95% CI, 0.61 to 0.82) and 5 (aHR = 0.71; 95% CI, 0.54 to 0.92) CKD patients [corrected] compared with the control group. However, there was no significant improvement in all-cause mortality in stage 4 CKD patients (aHR = 1.02; 95%CI, 0.75 to 1.37) [corrected]. This is the first meta-analysis reporting that ICD implantation reduces all-cause mortality in stage 3 and 5 [corrected] CKD patients. However, the data do not indicate there is any benefit to ICD implantation in stage 4 [corrected] CKD patients.

At present, the role of ventricular tachycardia (VT) non-inducibility after ablation in patients with non-ischemic cardiomyopathy (NICM) remains controversial. We conducted a meta-analysis of the published literature to assess whether VT non-inducibility after ablation could predict reduced VT recurrence and mortality in patients with NICM.PubMed, ScienceDirect, and the Cochrane library were searched for studies evaluating the effects of VT non-inducibility after catheter ablation on the long-term outcome in NICM patients with sustained VT. Results were analyzed using a fixed-effect model, and the data were pooled using RevMan 5.3 software.Twenty-four observational studies were identified (736 participants, mean follow-up time: 22months). NICM patients with VT inducibility after ablation had a higher risk of VT recurrence (odds ratio [OR]=5.83, 95% confidence interval [CI] 4.07-8.37; P0.00001) and all-cause mortality (OR=3.55, 95% CI 1.62-7.78; P=0.002) compared with VT non-inducibility. Similarly in the subgroup analysis, patients with VT inducibility showed a higher risk of VT recurrence from non-ischemic dilated cardiomyopathy (OR=3.92, 95% CI 2.36-6.50; P0.00001) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (OR=5.37, 95% CI 2.20-13.10; P=0.0002). Additionally, meta-analysis also showed that combined endo-epicardial ablation significantly reduced the risk of VT recurrence compared with endocardial-only ablation (OR=2.02, 95% CI 1.19-3.44; P=0.009; mean follow-up time: 22months).Recent evidence has shown that VT non-inducibility after ablation is a predictor for reduced VT recurrence and mortality compared with VT inducibility in NICM patients with sustained VT. In addition, endocardial plus adjuvant epicardial ablation provides better long-term arrhythmia-free survival than endocardial ablation alone.

Carboxylesterases, historically referred as non-specific esterases, are ubiquitous hydrolases with high catalytic efficiency. Without exceptions, all mammalian species studied contain multiple forms of carboxylesterases. While having been widely studied in humans and experimental animals, these enzymes remain to be characterized in farm animals. In this study, we showed that pig liver esterase 1 (PLE1) and pig liver esterase 6 (PLE6) were highly active toward amoxicillin (AMO) and ampicillin (AMP), two major antibiotics that are widely used in food-supplements. Mass-spectrometric analysis established that the hydrolysis occurred at the β-lactam amide bond and the hydrolysis drastically decreased or completely eliminated the antibacterial activity. Furthermore, hydrolytic activity and proteomic analysis suggested that trace PLEs existed in pig plasma and contributed little to the hydrolysis of AMO and AMP. These results suggested that carboxylesterases-based hydrolysis determines the therapeutic intensity of these and related antibiotics and the magnitude of the determination occurs in a species-dependent manner.

Objectives Mesenchymal stem cells (MSCs) have been widely used for regenerative medicine. Traditionally, the procedures of MSC isolation are usually invasive and time-consuming. Urine is merely a body waste, and recent studies have suggested that urine represents an alternative source of stem cells. We, therefore, determined whether the possibility of isolating mesenchymal-like stem cells was practical from human urine. Methods A total of 16 urine samples were collected from pediatric patients. Urine-derived cells were isolated, expanded, and identified for specific cell surface markers using flow cytometry. Cell morphology was observed by microscopy. Osteogenic and adipogenic differentiation potential were determinded by culturing cells in specific induction medium, and assessed by alkaline phosphatase and oil red O stainings, respectively. Results Clones were established and passaged successfully from primary cultures of urine cells. Cultured urine-derived cells at passage 3 were fusiform and arranged with certain directionality. Urine-derived cells at passage 5 displayed expressions of cell surface markers (CD29, CD105, CD166, CD90, and CD13). There was no expression of the general hematopoietic cell markers (CD45, CD34, and HLA-DR). Under in vitro induction conditions, urine-derived cells at passage 5 were able to differentiate into osteoblasts, but not adipocytes. Conclusions Urine may be a noninvasive source for mesenchymal-like stem cells. These cells could potentially provide a new source of autologous stem cells for regenerative medicine and cell therapy.

Several studies have investigated the role of physical fitness in atrial fibrillation (AF), but the results remain controversial. We aimed to estimate the association between physical fitness and risk of AF. We comprehensively retrieved data from the Cochrane Library, PubMed, and Embase databases until February 29, 2016, for studies evaluating the association of physical fitness with the risk of AF. Data were abstracted from included studies, and effect estimates were pooled using a random-effects model. Six studies with a total of 205 094 participants and 15 919 AF cases fulfilled the inclusion criteria. When physical fitness was assessed as a continuous variable, per incremental increase of physical fitness was associated with a 9% reduced risk of AF (risk ratio [RR]: 0.91, 95% confidence interval [CI]: 0.84-1.00, P = 0.05). When physical fitness was assessed as a categorical variable, the risk of AF was significantly reduced (RR: 0.51, 95% CI: 0.28-0.91, P = 0.02) in individuals with the highest level of physical fitness compared with those with the lowest level. The intermediate vs the lowest level of physical fitness was associated with a 28% reduced risk of AF (RR: 0.72, 95% CI: 0.56-0.93, P = 0.01). The sensitivity analysis indicated that these results were stable. Notably, there was evidence of statistical heterogeneity across studies; therefore, we should interpret the results cautiously. In conclusion, published literature supports that a higher level of physical fitness is associated with a lower risk of AF. Further studies should be performed to confirm these findings.

The errors in the following list appeared in the article titled "Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages?: An Updated Meta-Analysis" by Linghua Fu, Qiongqiong Zhou, Wengen Zhu, Lin Huang, Ying Ding, Yang Shen, Jinzhu Hu, and Kui Hong (Vol. 58, No. 3, 371-7, 2017).

FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin-proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions.

Objective To evaluate the expression of histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) from patients with sudden sensorineural hearing loss (SSNHL) who were refractory to systemic glucocorticoid treatment and to identify the relationship between the level of HDAC2 and glucocorticoid insensitivity. Study design Prospective clinical study. Setting This study was conducted in Nanjing Drum Tower Hospital, Nanjing University Medical School. Subjects and methods PBMCs were collected from 42 refractory SSNHL patients. After a 10-day intratympanic methylprednisolone perfusion (IMP) and systemic Ginkgo biloba extract treatment, the SSNHL patients were divided into 2 groups according to their hearing recovery after IMP (IMP sensitive and insensitive). Real-time polymerase chain reaction and HDAC2 protein assays were used to detect the relative expression levels of HDAC2 in PBMCs. The HDAC2 mRNA expression and protein levels in PBMCs collected from 17 volunteers were used as normal HDAC2 reference levels. Results Compared with normal reference levels, HDAC2 protein levels were significantly reduced, while the HDAC2 mRNA expression was much higher in all refractory SSNHL patients before IMP. HDAC2 mRNA expression and HDAC2 protein levels were significantly elevated in the IMP-sensitive group, while no change was observed in the IMP-insensitive group after IMP plus systemic antioxidant treatment. Conclusions Reduced HDAC2 protein levels may be 1 of the mechanistic underpinnings of corticosteroid insensitivity in refractory SSNHL patients. IMP can increase HDAC2 protein levels and the expression of HDAC2 mRNA in IMP-sensitive patients. HDAC2 protein levels might be regulated through posttranslational modifications.

The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1–3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1–3 leads and a strong family history of ARVC.

This study explored whether FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by regulating Cav-3 expression, and whether the expression of Cav-3 is stabilized by inhibiting ubiquitin-mediated cardiomyocyte degradation. Together, these findings revealed the novel role of FAT10 in protection

Liver, as the central regulator of metabolism, plays numerous functions in human body. When account acute injuries, the liver processes the specific competence to regenerate and return to a constant size. Many signaling molecules have been discovered for the initiation of liver regeneration. However, few mechanical changes have been addressed in the past in terms of liver regeneration and size control. This review discussed the mechanisms of mechanosensing molecules Yap/TAZ, 14-3-3 and their functions in liver regeneration, and how hepatocytes swelling, a physical change after acute liver injury, may initiate liver regeneration.

In this laboratory experiment, you formulate a simple liposome composed of a triacylglyceride (tripalmitin) and cholesterol. A small amount of fluorescently conjugated cholesterol is incorporated to impart fluorescence characteristics upon the liposome. The liposome is then viewed by using fluorescence microscopy.

In this laboratory experiment, you prepare a simple liposome containing a phospholipid surrounding internalized DNA. The lipid layer and DNA are fluorescently labeled or stained and then analyzed by using fluorescence microscopy.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare lethal disorder among inherited arrhythmogenic channelopathies, and would be misdiagnosed by neurologists for the analogous symptom of syncope. We aim to describe a long-term misdiagnosis case of CPVT as epilepsy caused by

Mitochondria are major cellular sources of hydrogen peroxide (H(2)O(2)), the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H(2)O(2) concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H(2)O(2) due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs) orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H(2)O(2) yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 microM H(2)O(2) increased cell proliferation in ERK1/2-dependent manner whereas high 50 microM H(2)O(2) arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei), the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs) facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H(2)O(2) level. Like this, high H(2)O(2) or directed mutation of redox-sensitive ERK2 Cys(214) impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to increase H(2)O(2) yield should disrupt synchronized MAPK oxidations and the regulation of cell cycle leading cells to remain in a proliferating phenotype.