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221.
Yoel H. Sitbon Francisca Diaz Katarzyna Kazmierczak Jingsheng Liang Medhi Wangpaichitr Danuta Szczesna-Cordary 《The Journal of general physiology》2021,153(7)
In this study, we assessed the super relaxed (SRX) state of myosin and sarcomeric protein phosphorylation in two pathological models of cardiomyopathy and in a near-physiological model of cardiac hypertrophy. The cardiomyopathy models differ in disease progression and severity and express the hypertrophic (HCM-A57G) or restrictive (RCM-E143K) mutations in the human ventricular myosin essential light chain (ELC), which is encoded by the MYL3 gene. Their effects were compared with near-physiological heart remodeling, represented by the N-terminally truncated ELC (Δ43 ELC mice), and with nonmutated human ventricular WT-ELC mice. The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state. The HCM-A57G model promoted the switch from the SRX to DRX state and showed an ∼40% increase in myosin regulatory light chain (RLC) phosphorylation compared with the RLC of normal WT-ELC myocardium. On the contrary, the RCM-E143K–associated stabilization of the SRX state was accompanied by an approximately twofold lower level of myosin RLC phosphorylation compared with the RLC of WT-ELC. Upregulation of RLC phosphorylation was also observed in Δ43 versus WT-ELC hearts, and the Δ43 myosin favored the energy-saving SRX conformation. The two disease variants also differently affected the duration of force transients, with shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles from these pathological models, while no changes were displayed by Δ43 fibers. We propose that the N terminus of ELC (N-ELC), which is missing in the hearts of Δ43 mice, works as an energetic switch promoting the SRX-to-DRX transition and contributing to the regulation of myosin RLC phosphorylation in full-length ELC mice by facilitating or sterically blocking RLC phosphorylation in HCM-A57G and RCM-E143K hearts, respectively. 相似文献
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223.
Published data indicate that formulation of pDNA with cationic lipids could greatly enhance the response to a pDNA vaccine in larger mammals. The present work tested the influence of several pDNA:cationic lipid formulations on rabies neutralizing titers. Plasmid expressing Rabies G protein (CVS strain) was evaluated in vivo for ability to elicit neutralizing titers. pDNA:DMRIE-DOPE formulated at two DNA:cationic lipid molar ratios was compared in mice to a Vaxfectin?-pDNA formulation. Mouse data indicate that Vaxfectin? is more effective than DMRIE-DOPE in eliciting neutralizing titers. In addition, the ratio of pDNA to DMRIE-DOPE can also affect neutralizing titers. Our data show that sustained neutralizing titers (120 days) can be obtained after a single administration of DMRIE-DOPE-formulated pDNA in rabbits. 相似文献
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