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BackgroundSudden cardiac death due to malignant ventricular arrhythmia is a devastating manifestation of cardiac hypertrophy. Sarcomere protein myosin binding protein C is functionally related to cardiac diastolic function and hypertrophy. Zebrafish is a better model to study human electrophysiology and arrhythmia than rodents because of the electrophysiological characteristics similar to those of humans.Methods and ResultsWe established a zebrafish model of cardiac hypertrophy and diastolic dysfunction by genetic knockdown of myosin binding protein C gene (mybpc3) and investigated the electrophysiological phenotypes in this model. We found expression of zebrafish mybpc3 restrictively in the heart and slow muscle, and mybpc3 gene was evolutionally conservative with sequence homology between zebrafish and human mybpc3 genes. Zebrafish with genetic knockdown of mybpc3 by morpholino showed ventricular hypertrophy with increased myocardial wall thickness and diastolic heart failure, manifesting as decreased ventricular diastolic relaxation velocity, pericardial effusion, and dilatation of the atrium. In terms of electrophysiological phenotypes, mybpc3 knockdown fish had a longer ventricular action potential duration and slower ventricular diastolic calcium reuptake, both of which are typical electrophysiological features in human cardiac hypertrophy and heart failure. Impaired calcium reuptake resulted in increased susceptibility to calcium transient alternans and action potential duration alternans, which have been proved to be central to the genesis of malignant ventricular fibrillation and a sensitive marker of sudden cardiac death.Conclusionsmybpc3 knockdown in zebrafish recapitulated the morphological, mechanical, and electrophysiological phenotypes of human cardiac hypertrophy and diastolic heart failure. Our study also first demonstrated arrhythmogenic cardiac alternans in cardiac hypertrophy.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway.

BackgroundROCKET AF and its East Asian subanalysis demonstrated that rivaroxaban was non‐inferior to warfarin for stroke/systemic embolism (SE) prevention in patients with non‐valvular atrial fibrillation (NVAF), with a favorable benefit–risk profile. XANAP investigated the safety and effectiveness of rivaroxaban in routine care in Asia‐Pacific.MethodsXANAP was a prospective, real‐world, observational study in patients with NVAF newly starting rivaroxaban. Patients were followed at ~3‐month intervals for 1 year, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding events, adverse events (AEs), serious AEs and all‐cause mortality; secondary outcomes included stroke/SE. Major outcomes were adjudicated centrally.ResultsXANAP enrolled 2273 patients from 10 countries: mean age was 70.5 years and 58.1% were male. 49.8% of patients received rivaroxaban 20 mg once daily (od), 43.8% 15 mg od and 5.9% 10 mg od. Mean treatment duration was 296 days, and 72.8% of patients had received prior anticoagulation therapy. Co‐morbidities included heart failure (20.1%), hypertension (73.6%), diabetes mellitus (26.6%), prior stroke/non‐central nervous system SE/transient ischemic attack (32.8%) and myocardial infarction (3.8%). Mean CHADS2, CHA2DS2‐VASc and HAS‐BLED scores were 2.3, 3.7 and 2.1, respectively. The rates (events/100 patient‐years [95% confidence interval]) of treatment‐emergent major bleeding, stroke and all‐cause mortality were 1.5 (1.0‐2.1), 1.7 (1.2‐2.5) and 2.0 (1.4‐2.7), respectively. Persistence was 66.2% at the study end.ConclusionsThe real‐world XANAP study demonstrated low rates of stroke and bleeding in rivaroxaban‐treated patients with NVAF from Asia‐Pacific. The results were consistent with the real‐world XANTUS study and ROCKET AF.

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In this article, a robust decentralized tracking control scheme for a large-scale unmanned aerial vehicle (UAV) formation team networked control system (NCS) is proposed to overcome a non-scalable or even infeasible design problem due to high computational complexity by the centralized control. At the outset, wind external disturbance, intrinsic fluctuation, coupling from other UAV subsystems, timevarying network-induced delay and packet dropout are taken into account in the design procedure of large-scale team formation UAV network system. Moreover, an event-triggered mechanism is embedded in NCS to reduce the number of transmitted control signals to save the network traffic especially for a large-scale team formation network of UAVs. To effectively reduce the above uncertainties, a robust H ∞ decentralized tracking controller is proposed for the large-scale UAV team formation NCS which is constructed by virtual leader-follower tracking network of UAV subsystems. By the Takagi-Sugeno (T-S) fuzzy interpolation method, the H ∞ robust virtual leader-follower decentralized tracking control design problem of the large-scale UAV team formation NCS is transformed to an independent Hamilton-Jacobin inequality (HJI)-constrained optimization problem for each UAV, which is effectively solved by a linear matrix inequality (LMI)-constrained optimization problem. Finally, a large-scale UAV team formation example of 25 UAVs is proposed to validate the effectiveness of the proposed robust decentralized tracking controller of large-scale UAV team formation NCS.INDEX TERMS Unmanned aerial vehicle (UAV) networked control system (NCS), event-triggered control, stochastic control, virtual structure formation control, decentralized stochastic robust H ∞ fuzzy tracking control.

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Mutations or loss of heterozygosity of p53 are detected in approximately 50% of bladder cancers. E1B-55 kD-deleted adenovirus has been shown to kill tumour cells with defective p53 function while sparing normal cells. Here, we examined the cytolytic effect and replication of E1B-55 kD-deleted adenovirus, designated Ad5WS1, on human bladder cancer cell lines with various p53 status. Ad5WS1 caused more severe cytolytic effect and replicated more efficiently in J82 and TCC-SUP bladder cancer cells carrying mutant p53 compared with TSGH-8301 and BFTC-905 bladder cancer cells retaining wild-type p53. Introduction of dominant negative p53 into BFTC-905 cells rendered them more susceptible to Ad5WS1-induced cytolysis. Furthermore, cells susceptible to lysis caused by Ad5WS1 were not attributable to their greater infectability by adenovirus. Finally, Ad5WS1 suppressed the growth of TCC-SUP bladder tumour xenografts, which could be augmented when combined with replication-defective adenoviral vector encoding kringles 1 -5 of plasminogen (K1 -5), an angiogenic inhibitor. Taken together, our results show that E1B-55 kD-deleted adenovirus replicates and hence lyses bladder cancer cells with mutant p53 much more efficient than those with wild-type p53. Thus, E1B-deleted adenovirus may have therapeutic potential, especially in combination with adenoviral vector expressing K1 -5, for the treatment of bladder cancer.