Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies

Brugada syndrome (BrS) is an inherited ion channel channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Originally believed to be predominantly associated with mutations in SCN5A encoding for the cardiac sodium channel, mutations of 18 genes other than SCN5A have been implicated in the pathogenesis of BrS to date. Diagnosis is based on the presence of a spontaneous or drug-induced coved-type ST segment elevation. The predominant electrophysiological mechanism underlying BrS remains disputed, commonly revolving around the three main hypotheses based on abnormal repolarization, depolarization or current-load match. Evidence from computational modelling, pre-clinical and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening ventricular arrhythmic events. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers. Current treatment options include pharmacological therapy to reduce the occurrence of arrhythmic events or to abort these episodes, and interventions such as implantable cardioverter-defibrillator insertion or radiofrequency ablation of abnormal arrhythmic substrate

Simulation-guided nanofabrication of high-quality practical tungsten probes

Micro/nanoscale tungsten probes are widely utilized in the fields of surface analysis, biological engineering, etc. amongst several others. This work performs comprehensive dynamic simulations on the influences of electric field distribution, surface tension and the bubbling situation on electrochemical etching behaviors, and then the tip dimension. Results show that the etching rate is reliant on the electric field distribution determined by the cathode dimension. The necking position lies in the meniscus rather than at the bottom of the meniscus. A bubble-free condition is mandatory to stabilize the distribution of OH- and WO4 2- ions for a smooth tungsten probe surface. Such simulation-guidance enables the nanofabrication of probes with a high aspect ratio (10 : 1), ultra-sharp tip apex (40 nm) and ultra-smooth surface. These probes have been successfully developed for high-performance application with Scanning Tunneling Microscopy (STM). The acquired decent atomic resolution images of epitaxial bilayer graphene robustly verify the feasibility of the practical level application of these nanoscale probes. Therefore, these nanoscale probes would be of great benefit to the development of advanced analytical science and nano-to-atomic scale experimental science and technology.G. M. gratefully acknowledges funding from National Natural Science Foundation of China (51977169, 51607138) and the Fundamental Research Funds for the Central University (xzy012019030). Z. Y. gratefully acknowledges the support from the ANU Futures Scheme (Q4601024) and the Australian Research Council (DP190100295, LE190100014). Y. P. gratefully acknowledges the support from the National Natural Science Foundation of China (11704303) and the National Key R&D Program of China (2017YFA0206202). The authors also acknowledge funding supported by State Key Laboratory of Electrical Insulation and Power Equipment (EIPE19203)

Inhibition of Wdr5 Attenuates Ang-II-Induced Fibroblast-to-Myofibroblast Transition in Cardiac Fibrosis by Regulating Mdm2/P53/P21 Pathway

Cardiac fibrosis is an important pathological process in many diseases. Wdr5 catalyzes the trimethylation of lysine K4 on histone H3. The effects of Wdr5 on the cardiac fibrosis phenotype and the activation or transformation of cardiac fibroblasts were investigated by Ang-II-infused mice by osmotic mini-pump and isolated primary neonatal rat cardiac fibroblasts. We found that the Wdr5 expression and histone H3K4me3 modification were significantly increased in Ang-II-infused mice. By stimulating primary neonatal rat cardiac fibroblasts with Ang II, we detected that the expression of Wdr5 and H3K4me3 modification were also significantly increased. Two Wdr5-specific inhibitors, and the lentivirus that transfected Sh-Wdr5, were used to treat primary mouse cardiac fibroblasts, which not only inhibited the histone methylation by Wdr5 but also significantly reduced the activation and migration ability of Ang-II-treated fibroblasts. To explore its mechanism, we found that the inhibition of Wdr5 increased the expression of P53, P21. Cut&Tag-qPCR showed that the inhibition of Wdr5 significantly reduced the enrichment of H3K4me3 in the Mdm2 promoter region. For in vivo experiments, we finally proved that the Wdr5 inhibitor OICR9429 significantly reduced Ang-II-induced cardiac fibrosis and increased the expression of P21 in cardiac fibroblasts. Inhibition of Wdr5 may mediate cardiac fibroblast cycle arrest through the Mdm2/P53/P21 pathway and alleviate cardiac fibrosis