Melatonin inhibits atrazine-induced mitochondrial impairment in cerebellum of mice: Modulation of cGAS-STING-NLRP3 axis-dependent cell pyroptosis.

The global prevalence of Neurological disorders has increased alarmingly in response to environmental and lifestyle changes. Atrazine (ATZ) is a difficult to degrade soil and water pollutant with well-known neurotoxicity. Melatonin (MT), an antioxidant with chemoprotective properties, has a potential therapeutic effect on cerebellar damage caused by ATZ exposure. The aim of this study was to explore the effects and underlying mechanisms of MT on the cerebellar inflammatory response and pyroptosis induced by ATZ exposure. In this study, C57BL/6J mice were treated with ATZ (170 mg/kg BW/day) and MT (5 mg/kg BW/day) for 28 days. Our results revealed that MT alleviated the histopathological changes, ultrastructural damage, oxidative stress and decrease of mitochondrial membrane potential (ΔΨm) in the cerebellum induced by ATZ exposure. ATZ exposure damaged the mitochondria leading to release of mitochondrial DNA (mtDNA) to the cytoplasm, MT activated the cyclic GMP-AMP synthetase interferon gene stimulator (cGAS-STING) axis to alleviate inflammation and pyroptosis caused by ATZ exposure. In general, our study provided new evidence that the cGAS-STING-NLRP3 axis plays an important role in the treatment of ATZ-induced cerebellar injury by MT.

Predictive value of pre-procedural N-terminal pro-B-type natriuretic peptide level for atrial fibrillation recurrence after radiofrequency catheter ablation.

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been demonstrated as a valuable risk marker for mortality and morbidity of cardiovascular disease. Recurrence after atrial fibrillation (AF) radiofrequency catheter ablation remains common. Aim: We investigated the predictive value of the pre-procedural level of NT-proBNP to differentiate high-risk patients for post-ablation AF recurrence. Material and methods: 326 individuals with nonvalvular AF and preserved systolic function after enduring an initial radiofrequency catheter ablation (RFCA) between March 2018 and December 2019 were categorized into a recurrent group and a non-AF recurrent group. The serum NT-proBNP levels were examined before the ablation procedure. The researchers used multivariate logistic regression to find the determinants of AF recurrence. Results: During a 14-month (interquartile range (IQR): 12-16) median follow-up, AF recurred in 84 (25.8%) patients. Patients in the recurrence group had considerably greater pre-ablation NT-proBNP levels (389.4 vs. 141.7 pg/ml, p < 0.001 in non-paroxysmal AF and 348.0 vs. 99.4 pg/ml, p < 0.001 in paroxysmal AF) as well as a greater left atrium (40 vs. 36 mm, p = 0.01 in non-paroxysmal AF and 38 vs. 36 mm, p = 0.01 in paroxysmal AF) than the non-AF recurrence group. A cut-off value of NT-proBNP ≥ 168.05 pg/ml identified AF recurrence with a sensitivity of 78.6% and specificity of 53.7% (area under ROC curve 0.68, 95% confidence interval (CI) 0.62-0.74, p < 0.001). Kaplan-Meier examination revealed that the elevated NT-proBNP (≥ 168.05 pg/ml) group presented a considerably shorter period without an occurrence compared to the low-NT-proBNP group (18.4 vs. 22.2 months, log-rank p = 0.001). Multivariate cox regression investigation showed that a level of NT-proBNP ≥ 168.05 pg/ml (hazard ratio (HR): 2.89, 95% CI: 1.71-4.903, p < 0.001) was a reliable predictor of AF recurrence after RFCA. Conclusions: A high pre-ablation NT-proBNP level was associated with AF recurrence, and it was also discovered to be a prognostic factor of recurrence of AF following RFCA.

Identification and validation of key genes associated with atrial fibrillation in the elderly.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and significantly increases the risk of stroke and heart failure (HF), contributing to a higher mortality rate. Increasing age is a major risk factor for AF; however, the mechanisms of how aging contributes to the occurrence and progression of AF remain unclear. This study conducted weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes and determine their potential associations with aging-related AF. Materials and methods: WGCNA was performed using the AF dataset GSE2240 obtained from the Gene Expression Omnibus, which contained data from atrial myocardium in cardiac patients with permanent AF or sinus rhythm (SR). Hub genes were identified in clinical samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed. Results: Green and pink were the most critical modules associated with AF, from which nine hub genes, PTGDS, COLQ, ASTN2, VASH1, RCAN1, AMIGO2, RBP1, MFAP4, and ALDH1A1, were hypothesized to play key roles in the AF pathophysiology in elderly and seven of them have high diagnostic value. Functional enrichment analysis demonstrated that the green module was associated with the calcium, cyclic adenosine monophosphate (cAMP), and peroxisome proliferator-activated receptors (PPAR) signaling pathways, and the pink module may be associated with the transforming growth factor beta (TGF-ß) signaling pathway in myocardial fibrosis. Conclusion: We identified nine genes that may play crucial roles in the pathophysiological mechanism of aging-related AF, among which six genes were associated with AF for the first time. This study provided novel insights into the impact of aging on the occurrence and progression of AF, and identified biomarkers and potential therapeutic targets for AF.

Clinical effect of total thoracoscopic mitral valve surgery combined with atrial fibrillation radiofrequency ablation in patients with different left atrium diameter-a single center prospective observational cohort study.

Background: Mitral valve surgery combined with atrial fibrillation (AF) radiofrequency ablation (AFRA) is recommended as the first-line strategy for valvular disease-related AF. There are relatively few reports on the effect of AFRA combined with total thoracoscopic mitral valve surgery. This article aimed to analyze the clinical data and prognostic outcomes of patients with diverse left atrium diameter (LAD) (>50 or ≤50 mm) who underwent total thoracoscopic mitral valve surgery combined with AFRA. Methods: We conducted a prospective analysis of patients who underwent AFRA from January 2021 to June 2022 in the Department of Cardiovascular Surgery at the Chinese PLA General Hospital. The inclusion criteria were: (I) aged 40-70 years; (II) diagnosed with valvular heart disease and concomitant long-term persistent AF (>1 year); (III) patients who underwent total thoracoscopic mitral valve surgery; (IV) with a left ventricular end-diastolic diameter of ≤70 mm; (V) with a LAD ≤65 mm; and (VI) left ventricular ejection fraction (LVEF) ≥50%. The included patients were assigned to group A and B depend up on the LAD. All patients were followed up at 3 and 6 months timepoints postoperatively. The prime endpoint was the recovery rate of sinus rhythm. Results: There were 24 cases in group A (LAD >50 mm) and 16 cases in group B (LAD ≤50 mm). The two groups exhibited no statistical differences in terms of age, gender proportion, preoperative comorbidities, AF duration, preoperative heart function, and type of valve disease (P>0.05). The LAD, pulmonary artery pressure, and left ventricular diameter of group A were significantly greater than those of group B (P<0.05). There were no new cerebrovascular incidents during the perioperative and follow-up periods. The sinus rhythm conversion rates in group A after surgery and at 6 months were 75% and 66.7%, respectively; meanwhile, both of these values were 87.5% in group B, and the difference between the groups was statistically significant (P<0.05). Conclusions: Total thoracoscopic mitral valve surgery with AFRA is more effective in maintaining sinus rhythm in patients with LAD ≤50 mm than in those with LAD >50 mm without increased risk of adverse events. Further studies are warranted to validate our findings.

The transformation of atrial fibroblasts into myofibroblasts is promoted by trimethylamine N-oxide via the Wnt3a/ß-catenin signaling pathway.

Background: Atrial fibrosis is an important pathophysiological mechanism in the development and maintenance of atrial fibrillation. Trimethylamine N-oxide (TMAO) is one of the most widely studied microbial metabolites involved in the promotion of cardiac fibrosis. TMAO promotes phenotypic transformation, proliferation, and migration and increases collagen secretion in cardiac fibroblasts. The Wnt/ß-catenin pathway also plays a key role in the promotion of cardiac fibroblasts into myofibroblasts. Methods: The expression of Alpha-smooth muscle actin (α-SMA) was determined to identify the formation of myofibroblasts. The effects of TMAO on the proliferation and migration of atrial fibroblasts were detected by cell counting kit 8, and transwell assays, respectively. Western blot and immunofluorescence were used to detect the activation of the ß-catenin pathway by TMAO and the phenotypic transformation and collagen secretion of the atrial fibroblasts. Western blot and immunofluorescence assays were performed to detect the effects of exogenous Wnt3a and TMAO on the activation of ß-catenin pathway and the phenotypic transformation of atrial fibroblasts. Results: TMAO promoted the proliferation and migration of atrial fibroblasts. TMAO also promoted the phenotypic transformation, migration, and collagen secretion of the atrial fibroblasts by activating the ß-catenin pathway. Exogenous Wnt3a and TMAO synergistically promoted the activation and phenotypic transformation of the ß-catenin pathway in atrial fibroblasts. Conclusions: TMAO promotes the transformation of atrial fibroblasts into myofibroblasts by activating Wnt3a/ß-catenin signaling pathway.

POSH regulates assembly of the NMDAR/PSD-95/Shank complex and synaptic function.

Mutation or disruption of the Shank/ProSAP family of genes is a high risk factor for autism spectrum disorders (ASDs) and intellectual disability. N-methyl-D-aspartate glutamate receptor (NMDAR) dysfunction contributes to the development of autism-like behaviors. However, the molecular mechanism of Shank-mediated NMDAR modulation is still not clear. Here, we show that the scaffold protein plenty of SH3s (POSH) directly interacts with two other scaffold proteins, PSD95 and SHANK2/3, at excitatory synapses. In POSH conditional knockout (cKO) mice, normal synaptic clustering of NMDAR/PSD-95/SHANK complex is disrupted, accompanied by abnormal dendritic spine development and glutamatergic transmission in hippocampal neurons. POSH cKO mice display profound autism-like behaviors, including impairments in social interactions, social communication, repetitive behaviors, and deficits in learning and memory. Thus, POSH clusters at the postsynaptic density (PSD) with PSD-95 and SHANK2/3 and plays important roles in the signaling mechanisms of the NMDAR/PSD-95/POSH/SHANK complex as well as in spine development and brain function.

The prognostic significance of left atrial appendage peak flow velocity in the recurrence of persistent atrial fibrillation following first radiofrequency catheter ablation.

BACKGROUND: Atrial fibrillation (AF) relapse following radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (PeAF) continues to be a concern. This study establishes a connection between left atrial appendage peak flow velocity (LAAV) and recurrence of AF in individuals having PeAF following first RFCA. METHODS: We retrospectively studied 164 successive PeAF patients who had first RFCA between January 2018 and December 2019. Before the ablation, the LAAV was recorded using transesophageal echocardiography (TEE). The demographic and clinical data of the individuals were gathered. Participants were monitored at regular intervals to monitor for recurrence of AF. We employed Cox proportional hazards regression to determine if LAAV, as well as other clinical indicators, were predictive of AF recurrence in follow-up. RESULTS: In this study, AF relapse was seen in 43 patients (26.2%) following a median follow-up of 15 [interquartile range (IQR): 12-18] months. It was shown that the LAAV was decreased in individuals who had recurrences of AF (0.36±0.05 vs. 0.45±0.17 m/s, P=0.004). Using Kaplan-Meier analysis, it was discovered that the low LAAV (0.37 m/s) group had a poorer event-free survival rate compared to the high LAAV (>0.37 m/s) group (17.6 vs. 21.2 months, log-rank P=0.002) group. Based on the results of the multivariate Cox regression analysis, a LAAV of fewer than 0.37 m/s [hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.177-4.227; P=0.014] was shown to be an independent predictor of AF recurrence following RFCA. CONCLUSIONS: A low LAAV is associated with AF relapse, and it is a predictor of AF relapse following the first RFCA for PeAF. This discovery may be useful in the optimization of treatment strategies and the care of patients with PeAF.

Road crack segmentation using an attention residual U-Net with generative adversarial learning.

This paper proposed an end-to-end road crack segmentation model based on attention mechanism and deep FCN with generative adversarial learning. We create a segmentation network by introducing a visual attention mechanism and residual module to a fully convolutional network(FCN) to capture richer local features and more global semantic features and get a better segment result. Besides, we use an adversarial network consisting of convolutional layers as a discrimination network. The main contributions of this work are as follows: 1) We introduce a CNN model as a discriminate network to realize adversarial learning to guide the training of the segmentation network, which is trained in a min-max way: the discrimination network is trained by maximizing the loss function, while the segmentation network is trained with the only gradient passed by the discrimination network and aim at minimizing the loss function, and finally an optimal segmentation network is obtained; 2) We add the residual modular and the visual attention mechanism to U-Net, which makes the segmentation results more robust, refined and smooth; 3) Extensive experiments are conducted on three public road crack datasets to evaluate the performance of our proposed model. Qualitative and quantitative comparisons between the proposed method and the state-of-the-art methods show that the proposed method outperforms or is comparable to the state-of-the-art methods in both F1 score and precision. In particular, compared with U-Net, the mIoU of our proposed method is increased about 3%~17% compared with the three public datasets.

Surgical treatment of congenital left ventricular diverticulum.

BACKGROUND: Congenital left ventricular diverticulum (LVD) is a rare cardiac malformation. Its prevalence rate is less than 0.1% of the congenital heart diseases requiring surgery. Some scholars suggest that all LVD should be actively removed to prevent possible risks, including diverticulum rupture, arterial embolism, and malignant arrhythmia. However, others believe that asymptomatic LVD can be followed up without immediate surgery. We reviewed and reported the diagnosis, clinical features, and surgical treatment of four cases of congenital LVD to provide clinical experience and a reference for the treatment of such patients. METHODS: Four patients (aged 3-32 years old) were diagnosed with congenital LVD and received surgical treatment at the Department of Cardiovascular Surgery of PLA General Hospital, Beijing, China from September 2009 to July 2019. All four patients had complete long-term postoperative follow-up data, including echocardiogram, enhanced cardiac computed tomography (CT), and electrocardiogram to monitor changes in left ventricular structure, heart function, and heart rhythm. RESULTS: In the first case, the fibrodiverticulum under the aortic valve squeezed the right ventricular outflow tract and the right main coronary artery; the morphology of the right ventricle and coronary artery returned to normal after surgery. The second patient was complicated with a huge lipoma in the apex of the left ventricle and underwent lipoma resection during LVD resection surgery. The third and fourth cases had muscular diverticula in the left ventricular apexes and received LVD removal surgery. All four patients recovered well after surgery and their left ventricular morphology and cardiac function were normal without adverse complications, such as atrial fibrillation, ventricular arrhythmia, and cerebrovascular accident. CONCLUSIONS: Although the morphology and character of congenital LVD were different in each case, the use of effective diagnostic and follow-up tools, including echocardiogram, enhanced CT, and magnetic resonance imaging (MRI), allowed for successful surgical treatment of the left ventricular diverticula and symptoms or other malformations. We propose that congenital LVD should be actively treated with surgery, especially considering effectiveness and low risk associated with this therapeutic option.

A potential treatment for COVID-19 based on modal characteristics and dynamic responses analysis of 2019-nCoV.

The 2019-nCoV is ravaging the world, taking lots of lives, and it is emergent to find a solution to deal with this novel pneumonia. This paper provides a potential treatment for COVID-19 utilizing resonance to destroy the infection ability of 2019-nCoV. Firstly, the geometry size of 2019-nCoV is scaled up by 10,000 times. The additional mass is used to represent the effect of the fluid around a spike protein. The finite element analysis (FEA) is used to study the modal characteristics of the tuned 2019-nCoV model and mistuned 2019-nCoV model in blood, respectively. Based on FEA, the lumped parameter mechanical model of 2019-nCoV is established. Then, the dynamic responses of mistuned 2019-nCoV are investigated through harmonic response and dynamical analysis. Finally, a potential method utilizing 360° sweep excitation to cure COVID-19 is put forward.

Short-term and mid-term effects of radiofrequency ablation in mitral valve surgery in patients with different left atrial sizes.

BACKGROUND: To evaluate the efficacy of atrial fibrillation radiofrequency ablation (AFRA) in patients with chronic valvular atrial fibrillation (AF) with different left atrial sizes [left atrial diameter (LAD) >45 or ≤45 mm]. METHODS: Between May 2016 and January 2019, 264 patients who underwent cardiac operations with modified bipolar AFRA in the Department of Cardiovascular Surgery, PLA General Hospital, were enrolled. The clinical data of the patients were analysed, and inclusion and exclusion criteria were implemented. A propensity score was given for two groups of different left atrial sizes: group A (75 patients with LAD >45 mm) and group B (75 patients with LAD ≤45 mm). Preoperative general data, operative indicators, postoperative mortality, complications, and sinus rhythm recovery were analysed and compared between the two groups. RESULTS: The rates of sinus rhythm recovery in group A (LAD >45 mm) at 1 week, 6 months, 1 year, and 2 years after surgery were 84.0%, 81.33%, 73.33%, and 69.33%, respectively, compared with 90.67.0%, 88.00%, 86.67%, and 84.00% at 1 week, 6 months, 1 year, and 2 years after surgery, respectively, in group B (LAD ≤45 mm). The difference between the two groups was statistically significant at the two points in time of 1 year, and 2 years (P<0.05). Warfarin anticoagulation, the standard therapy, was applied after surgery. No new cerebrovascular events occurred in either group during short- and medium-term postoperative follow-up. CONCLUSIONS: Mitral valve surgery using improved Cox-Maze IV bipolar radiofrequency ablation was effective in treating chronic long-term persistent valvular AF and had an excellent sinus rhythm recovery rate. However, the larger the LAD, the less likely a patient was to maintain sinus rhythm as time passed after surgery.

Contribution of the polymorphism rs1800469 of transforming growth factor ß in the development of myocardial infarction: meta-analysis of 5460 cases and 8413 controls (MOOSE-compliant article).

Studies investigating the association between transforming growth factor (TGF-ß-509C/T, rs1800469) promoter polymorphism and myocardial infarction (MI) risk reported inconsistent results. The aim of our study was to assess the association between the 509C/T polymorphism of the TGF-ß gene (rs1800469) and MI risk.A total of 5460 cases and 8413 controls in 7 case-control studies were incorporated in our current meta-analysis. The original studies were selected through searching the databases of the PubMed and EMBASE. The odds ratio (OR) and 95% confidence interval (95% CI) of TGF-ß 509C/T (rs1800469) for MI risk were applied to estimate the strength of the association.Our results showed that T allele carriers had a 13% increased risk of MI, when compared with the C allele carriers (OR = 1.13, 95% CI: 1.00-1.27). In the subset analysis by the type of MI, significantly elevated risk of MI was associated with the homozygote TT and heterozygote C/T in no-AMI subjects, when compared with the CC homozygote carriers (OR = 1.12, 95% CI:1.02-1.23).Our meta-analysis shows that the polymorphism with homozygote TT and heterozygote C/T of TGF-ß 509C/T (rs1800469) is significantly associated with the increased risk of MI.

MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis.

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.

Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice.

Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Disturbances in hippocampal dendritic spine development, aberrant composition of glutamatergic receptor subunits, and abnormal excitatory synaptic transmission were detected in heterozygous mutants. Remarkably, these defects are selectively unilateral. Our results support a notion that Sh3rf2 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis most likely resulting from deficits in synaptic function in the left hemisphere of the brain.

Comparison of postoperative quality of life for patients who undergo atrial myxoma excision with robotically assisted versus conventional surgery.

BACKGROUND: Robotically assisted cardiac surgery is an alternative to conventional, open-chest surgery. Although studies have been done on the clinical effect, morbidity, and mortality of robotically assisted atrial myxoma excision, few have addressed surgical outcomes, such as pain, quality of life (QOL), and length of sick leave from work. In this study, our aim was to evaluate these clinical variables among patients after they undergo robotically assisted atrial myxoma excision surgery. METHODS: Between January 2007 and January 2013, a total of 93 patients underwent either conventional sternotomy or robotically assisted atrial myxoma excision in our unit. The 36-item Medical Outcomes Study Short Form Survey was used to assess the clinical outcomes in these patients postoperatively, at day 30 and 6 months. RESULTS: The QOL scores for 7 of 8 variables in the robotically assisted group were significantly higher than those in the conventional group at postoperative day 30 (P < .05). The degree of pain and its influence on work or life was lower in the robotically assisted group (P < .05), and these patients returned to work after 0.9 ± 0.1 months, whereas those in the conventional group needed a sick leave of 3.3 ± 0.4 months. CONCLUSIONS: The level of restoration of normal QOL within 30 days after atrial myxoma surgery is excellent with the robotically assisted approach, which may enable early return to employment and satisfactory recovery.

[Efficacy of oral bosentan for treatment of congenital heart disease-associated pulmonary arterial hypertension].

OBJECTIVE: To investigate the effect of oral bosentan in the treatment of congenital heart disease-associated pulmonary arterial hypertension. METHODS: 24 patients with congenital heart disease-associated pulmonary arterial hypertension, including 4 receiving heart surgery and 20 with surgical contraindications, were enrolled in this study. All the patients were given oral bosentan and followed up regularly for analyzing the outcomes and side effects. RESULTS: One patient was lost to follow up and one patient died. Systolic pulmonary artery pressure showed no significant changes at 2 (93.6 ± 17.2 mmHg) and 4 months (85.7 ± 25.5 mmHg) of bosentan treatment compared to that before the medication (97.8 ± 14.9 mmHg) (P=0.096), but decreased significantly after a 6-month therapy (80.9 ± 25.0 mmHg, P=0.029). The 6-minute walking distance increased significantly after a 2, 4, and 6-month therapy [(488 ± 98.8, 496.3 ± 89.0, and 491.3 ± 114.2 m, respectively; P=0.004, 0.003, and 0.004 vs the distance before medication (317.0 ± 134.1)]. The New York heart functional classification was improved significantly after a 2, 4, and 6-month therapy [(2.0 ± 0.5, 1.8 ± 0.4, and 1.7 ± 0.5, respectively; P<0.001 vs pre-medication score (2.9 ± 0.5)). Hepatic and renal function remained normal, and ALT and AST showed no significant variations during the medication (P>0.05). CONCLUSION: Oral bosentan can effectively relieve the symptoms, decrease pulmonary artery hypertension, and improve exercise tolerance and cardiac function classification in patients with pulmonary artery hypertension associated with congenital heart disease with good safety and mild side effects.

Totally robotic atrial septal defect closure: 7-year single-institution experience and follow-up.

OBJECTIVES: Robotic technology has been applied to atrial septal defect (ASD) repair for more than 10 years, but the number of cases reported is limited and results of long-term follow-up are not clear. This study reports on a large group of patients who underwent totally robotic ASD repair on an arrested or beating heart at a single institution with a 7-year follow-up. METHODS: From 2007 to 2013, 160 patients (median age, 36 years; range, 11-66 years) at our centre underwent selective repair of secundum-type ASD using the da Vinci robotic system. The first 54 cases were performed on an arrested heart (arrested-heart group, n = 54) and the remainder on a beating heart (beating-heart group, n = 106). The mean diameter of defects was 2.9 cm (range, 1.1-4.1 cm). Cardiopulmonary bypass was achieved via cannulation of the femoral vessels and the right internal jugular vein. Blood cardioplegic arrest was induced using a transthoracic Chitwood clamp in the arrested-heart group. With the assistance of a robotic surgical system, atrial septal defect repairs were performed with or without tricuspid valvuloplasty via three 8-mm ports, a camera port and a working port in the right chest. Transoesophageal echocardiography was used to evaluate surgical results and follow-up. RESULTS: Complete ASD closure was verified by intraoperative transoesophageal echocardiography in all patients. None of the procedures was converted to an alternate technique and there were no major complications. There were significant learning curves for cross-clamp time, operative duration and cardiopulmonary bypass time. The beating-heart group had significantly shorter operative and cardiopulmonary bypass durations than the arrested-heart group (P = 0.000). The two groups had similar durations of mechanical ventilation and intensive care unit and hospital stays, and similar drainage volumes. During the 39 ± 21 months of follow-up, no patient required reoperation because of a residual shunt or tricuspid valve regurgitation. CONCLUSIONS: ASD can be performed safely and effectively on an arrested or beating heart with the assistance of robotic technology. This totally endoscopic approach represents an option for patients seeking a reliable, minimally invasive ASD repair with an excellent long-term result.

BMP2-SMAD signaling represses the proliferation of embryonic neural stem cells through YAP.

Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.

Pharmacokinetics and pharmacodynamics of recombinant human EPO-Fc fusion protein in vivo.

In this study, the in vivo pharmacokinetics and pharmacodynamics of a novel recombinant human erythropoietin (rhEPO) Fc fusion protein, rhEPO-Fc, were studied in both rodents and rhesus monkeys. Animal models of anemia induced by irradiation, cyclophosphamide and partial renal ablation were used to evaluate therapeutic effects of rhEPO-Fc. We have demonstrated that serum half-life of rhEPO-Fc was 29.5 to 38.9 h at doses of 8, 25, 80 µg/kg in rhesus monkeys and 35.5 to 43.5 h at doses of 16, 50, 160 µg/kg in rats. In anemia animal models, rhEPO-Fc dose-dependently (7.5-30.0 µg/kg in mice, 5.4-21.4 µg/kg in rats and 5.0-10.0 µg/kg in rhesus monkeys) increased reticulocyte level, followed by an increase of RBC count, hemoglobin and hematocrit levels. At reduced intervention frequency of weekly treatments, rhEPO-Fc showed similar hematopoietic effects as compared with rhEPO given three times a week. These results indicated that rhEPO-Fc could potentially be used in treatment of anemia and warrants future clinical trials.

A C-terminal truncated mutation of spr-3 gene extends lifespan in Caenorhabditis elegans.

The lifespan of Caenorhabditis elegans is determined by various genetic and environmental factors. In this paper, spr-3, a C. elegans homologous gene of the mammalian neural restrictive silencing factor (NRSF/REST), is reported to be an important gene regulating lifespan of C. elegans. A deletion mutation of spr-3, spr-3(ok2525), or RNAi inhibition of spr-3 expression led to the short lifespan phenotype in C. elegans. However, a nonsense mutation of spr-3, spr-3(by108), increased the lifespan by 26% when compared with that of wild-type nematode. The spr-3(by108) also showed increased resistance to environmental stress. The spr-3(by108) mutated gene encodes a C-terminal truncated protein with a structure comparable with the REST4, a splice variant of the NRSF/REST in mammalian. The long lifespan phenotype of spr-3(by108) mutant is confirmed as a gain of function and dependent on normal functions of daf-16 and glp-1. The lifespan of the spr-3(by108) can be synergistically enhanced by inducing a mutation in daf-2. Quantitative polymerase chain reaction results showed that the expression of daf-16 as well as its target gene sod-3, mtl-1, and sip-1 was up-regulated in the spr-3(by108) mutant. These results would be helpful to further understand the complex function of NRSF/REST gene in mammalian, especially in the aging process and longevity determination.