Regulatory Light Chains in Cardiac Development and Disease

The role of regulatory light chains (RLCs) in cardiac muscle function has been elucidated progressively over the past decade. The RLCs are among the earliest expressed markers during cardiogenesis and persist through adulthood. Failing hearts have shown reduced RLC phosphorylation levels and that restoring baseline levels of RLC phosphorylation is necessary for generating optimal force of muscle contraction. The signalling mechanisms triggering changes in RLC phosphorylation levels during disease progression remain elusive. Uncovering this information may provide insights for better management of heart failure patients. Given the cardiac chamber-specific expression of RLC isoforms, ventricular RLCs have facilitated the identification of mature ventricular cardiomyocytes, opening up possibilities of regenerative medicine. This review consolidates the standing of RLCs in cardiac development and disease and highlights knowledge gaps and potential therapeutic advancements in targeting RLCs.     

Cardioinotropic Effects in Subchronic Intoxication of Rats with Lead and/or Cadmium Oxide Nanoparticles

Subchronic intoxication was induced in outbred male rats by repeated intraperitoneal injections with lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles (NPs) 3 times a week during 6 weeks for the purpose of examining its effects on the contractile characteristics of isolated right ventricle trabeculae and papillary muscles in isometric and afterload contractions. Isolated and combined intoxication with these NPs was observed to reduce the mechanical work produced by both types of myocardial preparation. Using the in vitro motility assay, we showed that the sliding velocity of regulated thin filaments drops under both isolated and combined intoxication with CdO–NP and PbO–NP. These results correlate with a shift in the expression of myosin heavy chain (MHC) isoforms towards slowly cycling β–MHC. The type of CdO–NP + PbO–NP combined cardiotoxicity depends on the effect of the toxic impact, the extent of this effect, the ratio of toxicant doses, and the degree of stretching of cardiomyocytes and muscle type studied. Some indices of combined Pb–NP and CdO–NP cardiotoxicity and general toxicity (genotoxicity included) became fully or partly normalized if intoxication developed against background administration of a bioprotective complex.     

花椒毒酚对豚鼠离体心房肌生理特性的影响

目的 研究花椒毒酚对豚鼠离体心肌生理特性的影响。 方法 采用豚鼠离体心房, 测定花椒毒酚对豚鼠心房率, 心肌收缩力, 左心房的兴奋性的影响。 结果 在心肌收缩力的实验中, 给花椒毒酚20,40, 80 μmol·L^-1 15 min后, 左心房的收缩力分别为0.85、0.68、0.48 g, 与对照组比较, 花椒毒酚明显抑制豚鼠左心房肌的收缩力(P <0.05), 并呈浓度依赖性;在对心房率的实验中, 给花椒毒酚20,40 μmol·L^-1, 30 min 后, 离体右心房的频率从90.0 次·min^-1分别下降至60.2、38.7 次·min^-1, 与对照组比较有显著的统计学意义(P <0.05);花椒毒酚对豚鼠左心房的功能性不应期和左心房兴奋性无明显影响。 结论 花椒毒酚可以降低心房自律性、抑制心房收缩力, 其负性变频和负性变力效应可能与其抑制心肌细胞外钙内流和内钙释放有关。     

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.     

The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation

The biomechanisms that govern the response of chondrocytes to mechanical stimuli are poorly understood. In this study, a series of in vitro tests are performed, in which single chondrocytes are subjected to shear deformation by a horizontally moving probe. Dramatically different probe force–indentation curves are obtained for untreated cells and for cells in which the actin cytoskeleton has been disrupted. Untreated cells exhibit a rapid increase in force upon probe contact followed by yielding behaviour. Cells in which the contractile actin cytoskeleton was removed exhibit a linear force–indentation response. In order to investigate the mechanisms underlying this behaviour, a three-dimensional active modelling framework incorporating stress fibre (SF) remodelling and contractility is used to simulate the in vitro tests. Simulations reveal that the characteristic force–indentation curve observed for untreated chondrocytes occurs as a result of two factors: (i) yielding of SFs due to stretching of the cytoplasm near the probe and (ii) dissociation of SFs due to reduced cytoplasm tension at the front of the cell. In contrast, a passive hyperelastic model predicts a linear force–indentation curve similar to that observed for cells in which the actin cytoskeleton has been disrupted. This combined modelling–experimental study offers a novel insight into the role of the active contractility and remodelling of the actin cytoskeleton in the response of chondrocytes to mechanical loading.     

用作填埋场替代盖层的水泥黄土工程特性

压实水泥黄土作为城市生活垃圾卫生填埋场新型替代盖层材料具有经济、易于施工等特点.掺加一定量水泥可以有效降低黄土的压缩性、收缩性以及渗透性,极大地提高黄土的力学强度.试验研究表明,随着水泥掺量的增加,水泥黄土的液限降低,塑限升高,最大干密度降低,并且最优含水率总保持比塑限大近2个百分点.黄土中掺加5%～10%水泥对改善黄土压缩性和收缩性效果显著.依据等效替代原则,通过适当增大厚度的措施,水泥黄土的渗透性完全可以控制在规范要求以内,以符合填埋场最终盖层设计要求,达到最终盖层替代的目的.     

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.     

单片式压电谐振型石英压力-温度传感器设计

提出了一种采用石英力敏谐振器(QFSR)-石英热敏谐振器(QTSR)的单片式压电谐振型石英压力-温度传感器(QPTS),设计了单片式QPTS结构、石英压力传感器的无应力封接方案以及新型压力-伸缩力变换器.单片式QPTS由QFSR和QTSR构成,均采用AT切型,厚度切变模式工作,不同的是QTSR的长边取向与石英X轴的夹角为60°.无应力封接方案使用石英、单晶硅、非晶态SiC、硼硅酸盐玻璃和柯伐合金的组合,并且利用石英化学刻蚀和物理修饰技术以及半导体的新工艺使QFSR和QTSR改性.其中,非晶态SiC层的制作是为了实现应力的缓冲:虽然硅和石英材料的热膨胀系数不匹配,可是二者之间的非晶态SiC层却能够良好地吸收其热应力,成为无应力结构.     

Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics

The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. TNNC2 has been implicated in a novel congenital myopathy, TNNI2 and TNNT3 in distal arthrogryposis (DA), and TNNT1 and TNNT3 in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca²⁺ sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies.