Objective To evaluate the effects of dexmedetomidine on action potential in isolated rabbit sinoatrial node cells.Methods Twenty-four healthy New Zealand rabbits of both sexes,weighing 1.5-2.5 kg,were sacrificed.Their hearts were removed and sinoatrial nodes were dissected and placed in Tyrode solution.Sixty isolated sinoatrial nodes were randomly divided into 6 groups (n =10 each):control group (group C),0.5 ng/ml dexmedetomedine group (group D1),5.0 ng/ml dexmedetomedine group (group D2),dexmedetomidine 5.0 ng/ml + yohimbine 1 μmol/L (alpha 2-adrenoreceptor antagonist) group (group D2 + Y),dexmedetomidine 5.0 ng/ml + 2 mmol/L CsCl (blocker of pacemaker current) group (group D2 + C),and dexmedetomidine 50.0 ng/ml group (group D3).After perfusion with the Tyrode' s solution for 60 min,C group was perfused with Tyrode' s solution for another 40 min,D1-3 groups were perfused with Tyrode's solution cont(a)ining dexmedetomedine 0.5,5.0 and 50.0 ng/ml,respectively,for40 min,and D2 + Y and D2 + C groups were perfused with Tyrode' s solution containing 1 μmol/L yohimbine and 2 mmol/L CsCl,respectively,for 20 min,and then 5.0 ng/ml dexmedetomedine was added and sinoatrial nodes were perfused for 20 min.Maximal rate of depolarization (Vmax),amplitude of action potential (APA),action potential duration at 50％ and 90％ repolarization (APDso and APD90),velocity of diastolic (phase 4) depolarization (VDD),and rate of pacemaker firing (RPF) were recorded at 60 min of perfusion with Tyrode' s solution (T1),20 min of perfusion with yohimbine or CsCl (T2) and termination of perfusion with dexmedetomedine (T3).Results Compared with group C,APA,VDD and RPF were gradually decreased at T2,3 in groups D1-3 (P ＜ 0.05),and there was no significant difference in Vmax,APD50 and APD9o among C and D1-3 groups (P ＞ 0.05).VDD and RPF at T2 in group D2 + C and APA,VDD and RPF at T3 in groups D2 + Y and D2 + C were significantly lower than those at T1 (P ＜ 0.05).APA,VDD and RPF in group D2 + Y and APA in group D2 + C were significantly lower at T3 than at T2 (P ＜ 0.05).Conclusion Dexmedetomidine can decrease the sinoatrial node autorhythmicity in a concentration-dependent manner in rabbits,and the mechanism may be related to the inhibition of pacemaker current,but not alpha 2-adrenoreceptor.

In the original publication Fig. 1D and supplementary material is incorrect. The correct figure and supplementary material is provided in this correction.

Recently we have established a new culture condition enabling the derivation of extended pluripotent stem (EPS) cells, which, compared to conventional pluripotent stem cells, possess superior developmental potential and germline competence. However, it remains unclear whether this condition permits derivation of EPS cells from mouse strains that are refractory or non-permissive to pluripotent cell establishment. Here, we show that EPS cells can be robustly generated from non-permissive NOD-scid Il2rg mice through de novo derivation from blastocysts. Furthermore, these cells can also be efficiently generated by chemical reprogramming from embryonic NOD-scid Il2rg fibroblasts. NOD-scid Il2rg EPS cells can be expanded for more than 20 passages with genomic stability and can be genetically modified through gene targeting. Notably, these cells contribute to both embryonic and extraembryonic lineages in vivo. More importantly, they can produce chimeras and integrate into the E13.5 genital ridge. Our study demonstrates the feasibility of generating EPS cells from refractory mouse strains, which could potentially be a general strategy for deriving mouse pluripotent cells. The generation of NOD-scid Il2rg EPS cell lines permits sophisticated genetic modification in NOD-scid Il2rg mice, which may greatly advance the optimization of humanized mouse models for biomedical applications.

One major strategy to generate genetically modified mouse models is gene targeting in mouse embryonic stem (ES) cells, which is used to produce gene-targeted mice for wide applications in biomedicine. However, a major bottleneck in this approach is that the robustness of germline transmission of gene-targeted ES cells can be significantly reduced by their genetic and epigenetic instability after long-term culturing, which impairs the efficiency and robustness of mouse model generation. Recently, we have established a new type of pluripotent cells termed extended pluripotent stem (EPS) cells, which have superior developmental potency and robust germline competence compared to conventional mouse ES cells. In this study, we demonstrate that mouse EPS cells well maintain developmental potency and genetic stability after long-term passage. Based on gene targeting in mouse EPS cells, we established a new approach to directly and rapidly generate gene-targeted mouse models through tetraploid complementation, which could be accomplished in approximately 2 months. Importantly, using this approach, we successfully constructed mouse models in which the human interleukin 3 (IL3) or interleukin 6 (IL6) gene was knocked into its corresponding locus in the mouse genome. Our study demonstrates the feasibility of using mouse EPS cells to rapidly generate mouse models by gene targeting, which have great application potential in biomedical research.