A Multiple Step Active Stiffness Integration Scheme to Couple a Stochastic Cross-Bridge Model and Continuum Mechanics for Uses in Both Basic Research and Clinical Applications of Heart Simulation

In a multiscale simulation of a beating heart, the very large difference in the time scales between rapid stochastic conformational changes of contractile proteins and deterministic macroscopic outcomes, such as the ventricular pressure and volume, have hampered the implementation of an efficient coupling algorithm for the two scales. Furthermore, the consideration of dynamic changes of muscle stiffness caused by the cross-bridge activity of motor proteins have not been well established in continuum mechanics. To overcome these issues, we propose a multiple time step scheme called the multiple step active stiffness integration scheme (MusAsi) for the coupling of Monte Carlo (MC) multiple steps and an implicit finite element (FE) time integration step. The method focuses on the active tension stiffness matrix, where the active tension derivatives concerning the current displacements in the FE model are correctly integrated into the total stiffness matrix to avoid instability. A sensitivity analysis of the number of samples used in the MC model and the combination of time step sizes confirmed the accuracy and robustness of MusAsi, and we concluded that the combination of a 1.25 ms FE time step and 0.005 ms MC multiple steps using a few hundred motor proteins in each finite element was appropriate in the tradeoff between accuracy and computational time. Furthermore, for a biventricular FE model consisting of 45,000 tetrahedral elements, one heartbeat could be computed within 1.5 h using 320 cores of a conventional parallel computer system. These results support the practicality of MusAsi for uses in both the basic research of the relationship between molecular mechanisms and cardiac outputs, and clinical applications of perioperative prediction.

Stress-driven tissue fluidization physically segments vertebrate somites

Shaping functional structures during embryonic development requires both genetic and physical control. During somitogenesis, cell-cell coordination sets up genetic traveling waves in the presomitic mesoderm (PSM) that orchestrate somite formation. While key molecular and genetic aspects of this process are known, the mechanical events required to physically segment somites from the PSM remain unclear. Combining direct mechanical measurements during somite formation, live imaging of cell and tissue structure, and computer simulations, here we show that somites are mechanically sectioned off from the PSM by a large, actomyosin-driven increase in anisotropic stress at the nascent somite-somite boundary. Our results show that this localized increase in stress drives the regional fluidization of the tissue adjacent to the forming somite border, enabling local tissue remodeling and the shaping of the somite. Moreover, we find that active tension fluctuations in the tissue are optimized to mechanically define sharp somite boundaries while minimizing somite morphological defects. Altogether, these results indicate that mechanical changes at the somite-somite border and optimal tension fluctuations in the tissue are essential physical aspects of somite formation.

Topological floppy modes in models of epithelial tissues

We find mechanical topological phases in models of epithelial tissues with active tension on cell edges, where soft modes and stress distribution exhibit exponential localization to edges and interfaces of tissues.

There Is No Such Thing as Sound Production, or Sound=Release – The Importance of Natural Movement and Its Teaching in Violin Playing

This study details an approach which, in a certain respect, simplifies violin playing and teaching in the extreme. Creating a sound is based on a very simple rule: the sound = release. Release is preceded by tension, which is released with the sounding of the note. This is true on every level, in every direction. This general rule (or view) helps to make violin playing, the sounds created relaxed, natural and beautiful. The study shows step by step, how the necessary active tension comes into being and then how it is released, how and in what forms performers can use gravity. The main elements of this process are the posture of the body and the instrument, the movements of the arms and the joints (shoulder/armpit/upper arm. elbow/lower arm, wrist/back of the hand/palm and fingers) in their natural direction, the positions of the left hand, touch and vibrato, the relationship of the bow to the string, the use of bowing positions and right bow division, and strokes. Without the appropriate teaching of these no mechanism can be established and because of these deficiencies many a talent has been lost unable to even approach their own boundaries and unable to ever become a professional player. Keywords: sound production, release, natural mechanism, freedom, gravitation, violin

Transient K+ current explains cross-species differences in the effects of myofibroblasts on myocytes

Electrical and paracrine couplings between cardiomyocytes (CMs) and myofibroblasts (MFBs) affect both physiology and pathophysiology of cardiac tissues in a range of animal models, but relating these observations to humans is a challenge because effects vary greatly across species. To address this challenge, we developed a mathematical model for mechanoelectrical interactions between CM and MFB, considering both electrical and paracrine couplings between CMs and MFBs, with the aim of identifying the sources of cross-species variation and extrapolating animal models to predicted effects in humans. Our results revealed substantial differences across species in how these couplings modulate excitation-contraction coupling and Ca2+ transients of CMs. Both classes of couplings prolong action potential and increase APD in rat CMs, but shorten action potential and decrease APD in human CMs. Electrical coupling attenuates Ca2+ transients and active tension generation in human CMs, but has no significant effect on rat CMs. Paracrine coupling reduces Ca2+ transients and active tension in both human and rat CM. The results suggest that the variance of functional interactions between CM and MFB in cross-species may be explained by differences in the transient outward K+ currents associated with the KCND2 gene, and thus suggest potential therapeutic pathways for fibrotic cardiomyopathy.

Clinically relevant concentrations of dexmedetomidine may reduce oxytocin-induced myometrium contractions in pregnant rats

Background: Recently, there have been some trials to use dexmedetomidine in the obstetric field but concerns regarding the drug include changes in uterine contractions after labor. We aimed to evaluate the effects of dexmedetomidine on the myometrial contractions of pregnant rats.Methods: In a pilot study, the contraction of the myometrial strips of pregnant Sprague-Dawley rats in an organ bath with oxytocin at 1 mU/ml was assessed by adding dexmedetomidine from 10-6 to 10-2 M accumulatively every 20 min, and active tension and the number of contractions were evaluated. Then, changes in myometrial contractions were evaluated from high doses of dexmedetomidine (1.0 × 10−4 to 1.2 × 10−3 M). The effective concentrations (EC) for changes in uterine contractions were calculated using a probit model.Results: Active tension and the number of contractions were significantly decreased at 10-3 M and 10-4 M dexmedetomidine, respectively (P < 0.05). A complete loss of contractions was seen at 10-2 M. Dexmedetomidine (1.0 × 10−4 to 1.2 × 10−3 M) decreased active tension and the number of contractions in a concentration-dependent manner. The EC95 of dexmedetomidine for inhibiting active tension and the number of contractions was 5.16 × 10-2 M and 2.55 × 10-5 M, respectively.Conclusions: Active tension of the myometrium showed a significant decrease at concentrations of dexmedetomidine higher than 10-3 M. Thus, clinical concentrations of dexmedetomidine may inhibit uterine contractions. Further research is needed for the safe use of dexmedetomidine in the obstetrics field.

The asynchronous growth and movement reconstruction of the early molting animals

Epithelium is one of the basic types of animal tissue, and forms tissue boundaries that act as physical barriers to separate adjacent cell clusters. However, tissue boundaries at cellular resolutions can hardly be found in the fossil record. Here we focus on the growth and movement patterns of early Ecdysozoans by quantifying cell-level forces in the epithelium of two worms from the early Cambrian and Ordovician period. The arrangement of the epithelium cells (that do not necessarily represent biological cells) separating the body rings of these early Ecdysozoans indicates precise morphological patterning at the cellular level was established in the early Cambrian. The force distribution patterns on the body ring further suggest that the boundary cells helped maintain a pressure gradient between the rings, consistent with a role in movement. Finally, the active tension field of the worms plates throughout their ontogeny, and steady state of their epithelium cells, indicate these molting animals employed an asynchronous growth pattern in their epithelium.

Early myocardial changes induced by doxorubicin in the nonfailing dilated ventricle

Several studies have demonstrated that administration of doxorubicin (DOXO) results in cardiotoxicity, which eventually progresses to dilated cardiomyopathy. The present work aimed to evaluate the early myocardial changes of DOXO-induced cardiotoxicity. Male New Zealand White rabbits were injected intravenously with DOXO twice weekly for 8 wk [DOXO-induced heart failure (DOXO-HF)] or with an equivolumetric dose of saline (control). Echocardiographic evaluation was performed, and myocardial samples were collected to evaluate myocardial cellular and molecular modifications. The DOXO-HF group presented cardiac hypertrophy and higher left ventricular cavity diameters, showing a dilated phenotype but preserved ejection fraction. Concerning cardiomyocyte function, the DOXO-HF group presented a trend toward increased active tension without significant differences in passive tension. The myocardial GSSG-to-GSH ratio and interstitial fibrosis were increased and Bax-to- Bcl-2 ratio presented a trend toward an increase, suggesting the activation of apoptosis signaling pathways. The macromolecule titin shifted toward the more compliant isoform (N2BA), whereas the stiffer one (N2B) was shown to be hypophosphorylated. Differential protein analysis from the aggregate-enriched fraction through gel liquid chromatography-tandem mass spectrometry revealed an increase in the histidine-rich glycoprotein fragment in DOXO-HF animals. This work describes novel and early myocardial effects of DOXO-induced cardiotoxicity. Thus, tracking these changes appears to be of extreme relevance for the early detection of cardiac damage (as soon as ventricular dilation becomes evident) before irreversible cardiac function deterioration occurs (reduced ejection fraction). Moreover, it allows for the adjustment of the therapeutic approach and thus the prevention of cardiomyopathy progression. NEW & NOTEWORTHY Identification of early myocardial effects of doxorubicin in the heart is essential to hinder the development of cardiac complications and adjust the therapeutic approach. This study describes doxorubicin-induced cellular and molecular modifications before the onset of dilated cardiomyopathy. Myocardial samples from doxorubicin-treated rabbits showed a tendency for higher cardiomyocyte active tension, titin isoform shift from N2B to N2BA, hypophosphorylation of N2B, increased apoptotic genes, left ventricular interstitial fibrosis, and increased aggregation of histidine-rich glycoprotein.