To relate the subcellular molecular events to organ level physiology in heart, we have developed a three-dimensional finite-element-based simulation program incorporating the cellular mechanisms of excitation-contraction coupling and its propagation, and simulated the fluid-structure interaction involved in the contraction and relaxation of the human left ventricle. The FitzHugh-Nagumo model and four-state model representing the cross-bridge kinetics were adopted for cellular model. Both ventricular wall and blood in the cavity were modeled by finite element mesh. An arbitrary Lagrangian Eulerian finite element method with automatic mesh updating has been formulated for large domain changes, and a strong coupling strategy has been taken. Using electrical analog of pulmonary circulation and left atrium as a preload and the windkessel model as an afterload, dynamics of ventricular filling as well as ejection was simulated. We successfully reproduced the biphasic filling flow consisting of early rapid filling and atrial contraction similar to that reported in clinical observation. Furthermore, fluid-structure analysis enabled us to analyze the wave propagation velocity of filling flow. This simulator can be a powerful tool for establishing a link between molecular abnormality and the clinical disorder at the macroscopic level.

In contrast to processive molecular motors, skeletal myosins form a large motor ensemble for contraction of muscles against high loads. Despite numerous information on the molecular properties of skeletal myosin, its ensemble effects on collective force generation have not been rigorously clarified. Here we show 4 nm stepwise actin displacements generated by synthetic myofilaments beyond a load of 30 pN, implying that steps cannot be driven exclusively by single myosins, but potentially by coordinated force generations among multiple myosins. The simulation model shows that stepwise actin displacements are primarily caused by coordinated force generation among myosin molecules. Moreover, the probability of coordinated force generation can be enhanced against high loads by utilizing three factors: strain-dependent kinetics between force-generating states; multiple power stroke steps; and high ATP concentrations. Compared with other molecular motors, our findings reveal how the properties of skeletal myosin are tuned to perform cooperative force generation for efficient muscle contraction.

Uniaxial stress-strain data were obtained from in vitro experiments on 20 porcine livers for compressions, elongations and cycles of compression and then elongation. There were about 70 cylindrical samples, with diameter 7mm and varying height (4-11 mm). The combined compression and elongation test provide a unified framework for both compression and elongation for applications such as computer-aided surgical simulation. It enable the zero stress state of the experimental liver sample to be precisely determined. A new equation that combined both logarithmic and polynomial strain energy forms was proposed in modelling these experimental data. The assumption of incompressibility was justified from a preliminary Poisson's ratio for elongation and compression at 0.43+/-0.16 and 0.47+/-0.15, respectively. This equation provided a good fit for the observed mechanical properties of liver during compression-elongation cycles and for separate compressions or elongations. The root mean square errors were 91.92+/-17.43 Pa, 57.55+/-13.23 Pa and 29.78+/-17.67 Pa, respectively. In comparison with existing strain energy functions, this combined model was the better constitutive equation. Application of this theoretical model to small liver samples and other tissues demonstrated its suitability as the material model of choice for soft tissue.

Finding the silent skipped beat: Predicting arrhythmia-causing drugs using a high-throughput hybrid heart simulator.