In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.
Ontology highlight
ABSTRACT:
SUBMITTER: Duverger JE
PROVIDER: S-EPMC5877903 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Collapse of homogeneous lipid monolayers is known to proceed via wrinkling/buckling, followed by folding into bilayers in water. For heterogeneous monolayers with phase coexistence, the mechanism of collapse remains unclear. Here, we investigated collapse of lipid monolayers with coexisting liquid-liquid and liquid-solid domains using molecular dynamics simulations. The MARTINI coarse-grained model was employed to simulate monolayers of ∼80 nm in lateral dimension for 10-25 μs. The monolayer minimum surface tension decreased in the presence of solid domains, especially if they percolated. Liquid-ordered domains facilitated monolayer collapse due to the spontaneous curvature induced at a high cholesterol concentration. Upon collapse, bilayer folds formed in the liquid (disordered) phase; curved domains shifted the nucleation sites toward the phase boundary. The liquid (disordered) phase was preferentially transferred into bilayers, in agreement with the squeeze-out hypothesis. As a result, the composition and phase distribution were altered in the monolayer in equilibrium with bilayers compared to a flat monolayer at the same surface tension. The composition and phase behavior of the bilayers depended on the degree of monolayer compression. The monolayer-bilayer connection region was enriched in unsaturated lipids. Percolation of solid domains slowed down monolayer collapse by several orders of magnitude. These results are important for understanding the mechanism of two-to-three-dimensional transformations in heterogeneous thin films and the role of lateral organization in biological membranes. The study is directly relevant for the function of lung surfactant, and can explain the role of nanodomains in its surface activity and inhibition by an increased cholesterol concentration.
| S-EPMC4156665 | biostudies-literature
Project description:Several theoretical studies indicate that a substantial fraction of the measured seismic anisotropy could be interpreted as extrinsic anisotropy associated with compositional layering in rocks, reducing the significance of strain-induced intrinsic anisotropy. Here we quantify the potential contribution of grain-scale and rock-scale compositional anisotropy to the observations by (i) combining effective medium theories with realistic estimates of mineral isotropic elastic properties and (ii) measuring velocities of synthetic seismic waves propagating through modeled strain-induced microstructures. It is shown that for typical mantle and oceanic crust subsolidus compositions, rock-scale compositional layering does not generate any substantial extrinsic anisotropy (<1%) because of the limited contrast in isotropic elastic moduli among different rocks. Quasi-laminated structures observed in subducting slabs using P and S wave scattering are often invoked as a source of extrinsic anisotropy, but our calculations show that they only generate minor seismic anisotropy (<0.1-0.2% of Vp and Vs radial anisotropy). More generally, rock-scale compositional layering, when present, cannot be detected with seismic anisotropy studies but mainly with wave scattering. In contrast, when grain-scale layering is present, significant extrinsic anisotropy could exist in vertically limited levels of the mantle such as in a mid-ocean ridge basalt-rich lower transition zone or in the uppermost lower mantle where foliated basalts and pyrolites display up to 2-3% Vp and 3-6% Vs radial anisotropy. Thus, seismic anisotropy observed around the 660-km discontinuity could be possibly related to grain-scale shape-preferred orientation. Extrinsic anisotropy can form also in a compositionally homogeneous mantle, where velocity variations associated with major phase transitions can generate up to 1% of positive radial anisotropy.
| S-EPMC6472509 | biostudies-literature
Project description:As a new two-dimensional (2D) material, GeSe2 has attracted significant attention recently due to its distinctive in-plane anisotropic properties originated from the in-plane anisotropic crystal structure, high air stability and excellent performance in polarization-sensitive photodetection. However, no systematic study of the strain effect on the electronic properties and anisotropy of GeSe2 has been reported, restricting the relevant applications such as mechanical-electronic devices. Here we investigate the change of the electronic properties and anisotropy of GeSe2 monolayer under strains along x and y directions through first-principle calculations. The electronic band structure and effective mass of charge carriers are highly sensitive to the strain. Notably, through appropriate x or y directional strain, the anisotropy of the hole effective mass can even be rotated by 90°. These plentiful strain-engineering properties of GeSe2 give it many opportunities in novel mechanical-electronic applications.
| S-EPMC9086578 | biostudies-literature
Project description:Three-dimensional (3D) bioprinting of living structures with cell-laden biomaterials has been achieved in vitro, however, some cell-cell interactions are limited by the existing hydrogel. To better mimic tumor microenvironment, self-assembled multicellular heterogeneous brain tumor fibers have been fabricated by a custom-made coaxial extrusion 3D bioprinting system, with high viability, proliferative activity and efficient tumor-stromal interactions. Therein, in order to further verify the sufficient interactions between tumor cells and stroma MSCs, CRE-LOXP switch gene system which contained GSCs transfected with "LOXP-STOP-LOXP-RFP" genes and MSCs transfected with "CRE recombinase" gene was used. Results showed that tumor-stroma cells interacted with each other and fused, the transcription of RFP was higher than that of 2D culture model and control group with cells mixed directly into alginate, respectively. RFP expression was observed only in the cell fibers but not in the control group under confocal microscope. In conclusion, coaxial 3D bioprinted multicellular self-assembled heterogeneous tumor tissue-like fibers provided preferable 3D models for studying tumor microenvironment in vitro, especially for tumor-stromal interactions.
| S-EPMC5431218 | biostudies-literature
Project description:Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the "funny" current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome.
| S-EPMC8100125 | biostudies-literature
Project description:Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs electrophysiology biophysically-detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythmogenicity. The new Trovato2020 model incorporates detailed Purkinje-specific ionic currents and Ca2+ handling, and was developed, calibrated and validated using human experimental data acquired at multiple frequencies, both in control conditions and following drug application. Multiscale investigations were performed in a Purkinje cell, in fibre and using an experimentally-calibrated population of PCs to evaluate biological variability. Simulations demonstrate the human Purkinje Trovato2020 model is the first one to yield: (i) all key AP features consistent with human Purkinje recordings; (ii) Automaticity with funny current up-regulation (iii) EADs at slow pacing and with 85% hERG block; (iv) DADs following fast pacing; (v) conduction velocity of 160 cm/s in a Purkinje fibre, as reported in human. The human in silico PCs population highlights that: (1) EADs are caused by ICaL reactivation in PCs with large inward currents; (2) DADs and triggered APs occur in PCs experiencing Ca2+ accumulation, at fast pacing, caused by large L-type calcium current and small Na+/Ca2+ exchanger. The novel human Purkinje model unlocks further investigations into the role of cardiac Purkinje in ventricular arrhythmias through computer modeling and multiscale simulations.
| S-EPMC7294239 | biostudies-literature
Project description:Engineered monolayers created using microabrasion and micropatterning methods have provided a simplified in vitro system to study the effects of anisotropy and fiber direction on electrical propagation. Interpreting the behavior in these culture systems has often been performed using classical computer models with continuous properties. However, such models do not account for the effects of random cell shapes, cell orientations, and cleft spaces inherent in these monolayers on the resulting wavefront conduction. This work presents a novel methodology for modeling a monolayer of cardiac tissue in which the factors governing cell shape, cell-to-cell coupling, and degree of cleft space are not constant but rather are treated as spatially random with assigned distributions. This modeling approach makes it possible to simulate wavefront propagation in a manner analogous to performing experiments on engineered monolayer tissues. Simulated results are compared to previously published measured data from monolayers used to investigate the role of cellular architecture on conduction velocities and anisotropy ratios. We also present an estimate for obtaining the electrical properties from these networks and demonstrate how variations in the discrete cellular architecture affect the macroscopic conductivities. The simulations support the common assumption that under normal ranges of coupling strength, tissues with relatively uniform distributions of cell shapes and connectivity can be represented using continuous models with conductivities derived from random discrete cellular architecture using either global or local estimates. The results also reveal that in the presence of abrupt changes in cell orientation, local estimates of tissue properties predict smoother changes in conductivity that may not adequately predict the discrete nature of propagation at the transition sites.
| S-EPMC2862160 | biostudies-literature
Project description:The complex structure of cardiac tissue is considered to be one of the main determinants of an arrhythmogenic substrate. This study is aimed at developing the first mathematical model to describe the formation of cardiac tissue, using a joint in silico-in vitro approach. First, we performed experiments under various conditions to carefully characterise the morphology of cardiac tissue in a culture of neonatal rat ventricular cells. We considered two cell types, namely, cardiomyocytes and fibroblasts. Next, we proposed a mathematical model, based on the Glazier-Graner-Hogeweg model, which is widely used in tissue growth studies. The resultant tissue morphology was coupled to the detailed electrophysiological Korhonen-Majumder model for neonatal rat ventricular cardiomyocytes, in order to study wave propagation. The simulated waves had the same anisotropy ratio and wavefront complexity as those in the experiment. Thus, we conclude that our approach allows us to reproduce the morphological and physiological properties of cardiac tissue.
| S-EPMC5554264 | biostudies-literature
Project description:Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca(2+) transient firing rates and is associated with robust down-regulation of Hcn4, Cav3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO(?MHC-Cre)), and tamoxifen-inducible SAN restricted Trpm7 deletion (KO(HCN4-CreERT2)) disrupts cardiac automaticity in vivo. Telemetered and sedated KO(?MHC-Cre) and KO(HCN4-CreERT2) mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO(?MHC-Cre) mice exhibit diminished Ca(2+) transient firing rates with a blunted diastolic increase in Ca(2+). Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, I(f), are diminished in SAN from both KO(?MHC-Cre) and KO(HCN4-CreERT2) mice. Moreover, heart rates of KO(?MHC-Cre) mice are less sensitive to the selective I(f) blocker ivabradine, and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression.
| S-EPMC3740880 | biostudies-other
Project description:In traditional slope stability analyses, soil is usually approximated as isotropic. However, naturally cohesive soil deposits are inherently anisotropic, primarily due to the directional arrangement of soil particles during their deposition process. In this paper, a generalized anisotropic constitutive model for c-φ soil is introduced to evaluate the influence of varying shear strength on slope stability. In this model, the initial strength anisotropy is defined by the variety of friction angles to the direction of the principle stress. This model is utilized by two approaches to estimate the slope stability. Firstly, the upper bound limit analysis solution for slope stability is developed, and the safety factor of the slopes is studied. Secondly, this model is coupled with the finite element method to get insight of the influence of anisotropy on slope stability. One typical slope case of slope is studied by numerical analyses. It is found that the slope stability is largely overestimated when the strength anisotropy is ignored, and the overestimation, in terms of safety factors, can reach up to 32.9%. The complex interrelations between the degree of anisotropy and evolution of the ensuing safety factor are revealed by a series of parametric studies in terms of different degrees of anisotropy.
| S-EPMC9626556 | biostudies-literature