Laminopathies comprise a group of inherited diseases with variable clinical phenotypes, caused by mutations in the lamin A/C gene (LMNA). A prominent feature in several of these diseases is muscle wasting, as seen in Emery-Dreifuss muscle dystrophy, dilated cardiomyopathy and limb-girdle muscular dystrophy. Although the mechanisms underlying this phenotype remain largely obscure, two major working hypotheses are currently being investigated, namely, defects in gene regulation and/or abnormalities in nuclear architecture causing cellular fragility. In this study, using a newly developed cell compression device we have tested the latter hypothesis. The device allows controlled application of mechanical load onto single living cells, with simultaneous visualization of cellular deformation and quantitation of resistance. With the device, we have compared wild-type (MEF+/+) and LMNA knockout (MEF-/-) mouse embryonic fibroblasts (MEFs), and found that MEF-/- cells show a significantly decreased mechanical stiffness and a significantly lower bursting force. Partial rescue of the phenotype by transfection with either lamin A or lamin C prevented gross nuclear disruption, as seen in MEF-/- cells, but was unable to fully restore mechanical stiffness in these cells. Our studies show a direct correlation between absence of LMNA proteins and nuclear fragility in living cells. Simultaneous recordings by confocal microscopy revealed that the nuclei in MEF-/- cells, in contrast to MEF+/+ cells, exhibited an isotropic deformation upon indentation, despite an anisotropic deformation of the cell as a whole. This nuclear behaviour is indicative for a loss of interaction of the disturbed nucleus with the surrounding cytoskeleton. In addition, careful investigation of the three-dimensional organization of actin-, vimentin- and tubulin-based filaments showed a disturbed interaction of these structures in MEF-/- cells. Therefore, we suggest that in addition to the loss of nuclear stiffness, the loss of a physical interaction between nuclear structures (i.e. lamins) and the cytoskeleton is causing more general cellular weakness and emphasizes a potential key function for lamins in maintaining cellular tensegrity.
A new method for the computational analysis of fluid-structure interaction of a Newtonian fluid with slender bodies is developed. It combines ideas of the fictitious domain and the mortar element method by imposing continuity of the velocity field along an interface by means of Lagrange multipliers. The key advantage of the method is that it circumvents the need for complicated mesh movement strategies common in arbitrary Lagrangian-Eulerian (ALE) methods, usually used for this purpose. Copyright
SynopsisThe Pom-Pom model, recently introduced by McLeish and Larson ͓J. Rheol. 42, 81-110 ͑1998͔͒, is a breakthrough in the field of viscoelastic constitutive equations. With this model, a correct nonlinear behavior in both elongation and shear is accomplished. The original differential equations, improved with local branch-point displacement, are modified to overcome three drawbacks: solutions in steady state elongation show discontinuities, the equation for orientation is unbounded for high strain rates, the model does not have a second normal stress difference in shear. The modified extended Pom-Pom model does not show the three problems and is easy for implementation in finite element packages, because it is written as a single equation. Quantitative agreement is shown with experimental data in uniaxial, planar, equibiaxial elongation as well as shear, reversed flow and step-strain for two commercial low density polyethylene ͑LDPE͒ melts and one high density polyethylene ͑HDPE͒ melt. Such a good agreement over a full range of well defined rheometric experiments, i.e., shear, including reversed flow for one LDPE melt, and different elongational flows, is exceptional.
Abstract-Current mechanical conditioning approaches for heart valve tissue engineering concentrate on mimicking the opening and closing behavior of the leaflets, either or not in combination with tissue straining. This study describes a novel approach by mimicking only the diastolic phase of the cardiac cycle, resulting in tissue straining. A novel, yet simplified, bioreactor system was developed for this purpose by applying a dynamic pressure difference over a closed tissue engineered valve, thereby inducing dynamic strains within the leaflets. Besides the use of dynamic strains, the developing leaflet tissues were exposed to prestrain induced by the use of a stented geometry. To demonstrate the feasibility of this strain-based conditioning approach, human heart valve leaflets were engineered and their mechanial behavior evaluated. The actual dynamic strain magnitude in the leaflets over time was estimated using numerical analyses. Preliminary results showed superior tissue formation and non-linear tissuelike mechanical properties in the strained valves when compared to non-loaded tissue strips. In conclusion, the strain-based conditioning approach, using both prestrain and dynamic strains, offers new possibilities for bioreactor design and optimization of tissue properties towards a tissue-engineered aortic human heart valve replacement.
The progress made during the past decade in the application of mixed finite element methods to solve viscoelastic flow problems using differential constitutive equations is reviewed. The algorithmic developments are discussed in detail. Starting with the classical mixed formulation, the elastic viscous stress splitting (EVSS) method as well as the related discrete EVSS and the so-called EVSS-G method are discussed among others. Furthermore, stabilization techniques such as the streamline upwind PetrovGalerkin (SUPG) and the discontinuous Galerkin (DG) are reviewed. The performance of the numerical schemes for both smooth and non-smooth benchmark problems is discussed. Finally, the capabilities of viscoelastic flow solvers to predict experimental observations are reviewed.
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