Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’lives.However,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures.To accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h PCMs.Accordingly,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.

Modelling and simulation study on dynamic pollution accumulation process of composite insulator

With the widespread application of composite insulators in transmission lines,exploring the accumulation mechanism of pollution particles on composite insulator surfaces is of importance to ensure the safe and steady operation of the power system.Addressing the current theoretical shortcomings,this study categorises the accumulation process of particles on the insulator surface into three stages,namely‘spatial motion’,‘surface collision’,and‘surface motion’.The motion and rotation velocities in a multi-physics field are calculated in the spatial motion stage.In the surface collision stage,a parameter called‘neck height’is introduced to determine the optimum mechanics theory,and the normal deposition criterion is established.For the surface motion stage,the sliding displacement and rolling displacement on the surface are calculated based on the rotation speed of the particles.A dynamic pollution accumulation model of the composite insulator is estab-lished based on the normal deposition criterion and tangential displacement.Finally,numerical simulations are performed by using the finite element method.Simulation results show that the proposed model agrees with the actual insulator pollution accu-mulation,and the deposition model is still applicable for various types of composite insulators operating in different applied voltages.The deposition probability of particles increases with the increasing particle size.In the surface motion stage,particle displacement increases with particle size and wind velocity.

Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-α

Allergic asthma,a chronic inflammatory airway disease associated with type 2 cytokines,often originates in early life.Immune responses at an early age exhibit a Th2 cell bias,but the precise mechanisms remain elusive.Plasmacytoid dendritic cells(pDCs),which play a regulatory role in allergic asthma,were shown to be deficient in neonatal mice.We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model.Adoptive transfer of pDCs or administration of IFN-αto neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/−mice.Similarly,adult mice developed more severe allergic inflammation when pDCs were depleted.The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20,GM-CSF,and IL-33,which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway.In asthmatic patients,the percentage of pDCs and the level of IFN-αwere lower in children than in adults.These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergeninduced allergic airway inflammation.