Mechanical link between durotaxis, cell polarity and anisotropy during cell migration.

Cell migration, a fundamental mechanobiological process, is highly sensitive to the biochemical and mechanical properties of the environment. Efficient cell migration is ensured by the intrinsic polarity of the cell, which triggers a transition from an isotropic to an anisotropic configuration of the acto-mysion filaments responsible for the protrusion-contraction movement of the cell. Additionally, polarity may be highly influenced by the substrate rigidity, which results in a phenomenon called durotaxis. In the present work, we propose a two-dimensional finite element model able to capture three main features of cell migration: durotaxis, cell polarity and anisotropy. The cell is modelled as a continuum able to develop cyclic active strains regulated by the polymerization and depolymerization of the acto-myosin filaments and synchronized with the adhesion forces between the cell and the substrate underneath. A generalized Maxwell model is used to describe the viscoelastic behaviour of the cell constituted by a solid anisotropic branch with active strains (i.e. the acto-myosin filaments) and a fluid viscoelastic branch (i.e. the cytoplasm). Several types of substrate have been tested which are homogeneously soft or stiff or include both regions. The numerical results have been qualitatively compared with experimental observations showing a good agreement and have allowed us to find the mechanical link between durotaxis, cell polarity and anisotropy.

On the mechanical interplay between intra- and inter-synchronization during collective cell migration: a numerical investigation.

Collective cell migration is a fundamental process that takes place during several biological phenomena such as embryogenesis, immunity response, and tumorogenesis, but the mechanisms that regulate it are still unclear. Similarly to collective animal behavior, cells receive feedbacks in space and time, which control the direction of the migration and the synergy between the cells of the population, respectively. While in single cell migration intra-synchronization (i.e. the synchronization between the protrusion-contraction movement of the cell and the adhesion forces exerted by the cell to move forward) is a sufficient condition for an efficient migration, in collective cell migration the cells must communicate and coordinate their movement between each other in order to be as efficient as possible (i.e. inter-synchronization). Here, we propose a 2D mechanical model of a cell population, which is described as a continuum with embedded discrete cells with or without motility phenotype. The decomposition of the deformation gradient is employed to reproduce the cyclic active strains of each single cell (i.e. protrusion and contraction). We explore different modes of collective migration to investigate the mechanical interplay between intra- and inter-synchronization. The main objective of the paper is to evaluate the efficiency of the cell population in terms of covered distance and how the stress distribution inside the cohort and the single cells may in turn provide insights regarding such efficiency.

Comparison of ultrasonic attenuation within two- and three-dimensional polycrystalline media.

An analytical approach to develop explicit formulas of attenuation coefficient in both 2D and 3D cases is proposed. It results in a better understanding of the grain scattering mechanisms within a polycrystalline material and the grain size effects on the attenuation of an ultrasonic wave. It is based on the Stanke and Kino's model and uses the Born approximation. An explicit formula is deduced for untextured polycrystals with equiaxed grains of cubic symmetry and allows a rigorous comparison of the attenuation coefficient between both 2D and 3D cases. It confirms that the attenuation in the Rayleigh region is higher in 2D simulation than in 3D one, while very similar coefficients are obtained in the stochastic region for both cases. The study of the explicit formula allows the decomposition of the attenuation coefficient into various scattering-induced components, which leads to a better understanding of different grain scattering mechanisms. The reflection/transmission at grain boundaries between wave modes of a same type mainly explains a same attenuation coefficient in the stochastic region for both 2D and 3D modelings. The conversion at grain boundaries between different types of wave modes provides some explanations for a higher attenuation value given by the 2D modeling in the Rayleigh region. The effect of the grain size on the attenuation coefficient is then predicted by the 2D analytical calculation and by the FE simulation. The analytical-numerical comparison validates the numerical calculations and the approach suggests a way of using the 2D FE calculations to predict the evolution of the attenuation coefficient with the wave frequency in 3D.

Finite element modeling of grain size effects on the ultrasonic microstructural noise backscattering in polycrystalline materials.

The correlation between ultrasonic wave propagation and polycrystalline microstructures has significant implications in nondestructive evaluation. An original numerical approach using the finite element method to quantify in both time and frequency domains the ultrasonic noise scattering due to the elastic heterogeneity of polycrystalline microstructures is presented. Based on the reciprocity theorem, it allows the scattering evaluation using mechanical data recorded only on the boundary of polycrystal instead of within its volume and is applicable to any polycrystalline aggregate regardless of its crystallographic or morphological characteristics. Consequently it gives a more realistic and accurate access of polycrystalline microstructures than the classical analytical models developed under the assumption of single scattering and the Born approximation. The numerical approach is proposed within the same unified theoretical framework as the classical analytical models, so it is possible to validate it in the cases of idealized microstructures for which the considered analytical models remain relevant. As an original result, assuming single phase, untextured and equiaxed microstructures, two-dimensional (2D) theoretical formulas are developed and a frequency-dependent coefficient is found compared to the classical three-dimensional (3D) formulas. 2D numerical simulations are then performed for idealized microstructures composed of hexagonal grains with a uniform grain-size. Three grain sizes are considered herein and involve different scattering regions. Good comparisons are obtained between theoretical and numerical estimates of the backscattering coefficient, which validate the numerical approach. Effects of the grain boundary orientations are analyzed by modeling an irregular hexagonal grain morphology and a random grain morphology generated by an established Voronoi approach. The origin of the significant oscillation level of backscattering is then investigated and discussed.

Spin polarisation with electron Bessel beams.

The theoretical possibility to use an electron microscope as a spin polarizer is studied. It turns out that a Bessel beam passing a standard magnetic objective lens is intrinsically spin polarized when post-selected on-axis. In the limit of infinitely small detectors, the spin polarisation tends to 100%. Increasing the detector size, the polarisation decreases rapidly, dropping below 10-4 for standard settings of medium voltage microscopes. For extremely low voltages, the Figure of Merit increases by two orders of magnitude, approaching that of existing Mott detectors. Our findings may lead to new desings of spin filters, an attractive option in view of its inherent combination with the electron microscope, especially at low voltage.

Spin polarisation with electron Bessel beams.

The theoretical possibility to use an electron microscope as a spin polarizer is studied. It turns out that a Bessel beam passing a standard magnetic objective lens is intrinsically spin polarized when post-selected on-axis. In the limit of infinitely small detectors, the spin polarisation tends to 100%. Increasing the detector size, the polarisation decreases rapidly, dropping below 10-4 for standard settings of medium voltage microscopes. For extremely low voltages, the Figure of Merit increases by two orders of magnitude, approaching that of existing Mott detectors. Our findings may lead to new desings of spin filters, an attractive option in view of its inherent combination with the electron microscope, especially at low voltage.

Effect of microstructure on the mechanical properties of Haversian cortical bone.

The mechanical properties of cortical bone have been extensively studied at the macrostructural scale. However, knowledge of the macroscopic mechanical properties is not sufficient to predict local phenomena, such as damage or bone remodeling, both of which are dependent on local mechanical behavior. The objective of this study is to quantify the mechanical properties of cortical bone at several length scales, with emphasis on the microstructure of Haversian systems. Samples of mature bovine cortical bone, with a Haversian microstructure, were obtained from the posterior area of the mid-femoral diaphysis. A nanoindentation technique was used to measure the local Young's modulus. The distribution of the bone mineral content was obtained by backscattered electron imaging using a scanning electron microscope. A novel compression device employing microextensometry techniques was developed to quantify local strains. Digital image correlation was performed on the microstructure imaged by optical microscopy during compression tests. This study demonstrated that the local Young's modulus and strain were heterogeneous at the scale of an osteon. For both properties, the ratio between the maximum and minimum values was approximately two. The local Young's modulus and bone-mineral content were reasonably correlated (r2 = 0.75; P < 0.0001), but this was not the case for the distribution of local strains versus bone mineral content (r2 = 0.395; P < 0.0001). Hence, local strains cannot be described simply in terms of the bone mineral content, as the Haversian canal and osteonal microstructure have a major influence on these properties. In conclusion, the microstructure must be considered in evaluating the local strain and stress fields of cortical bone.

A computational mechanics approach to assess the link between cell morphology and forces during confined migration.

Confined migration plays a fundamental role during several biological phenomena such as embryogenesis, immunity and tumorogenesis. Here, we propose a two-dimensional mechanical model to simulate the migration of a HeLa cell through a micro-channel. As in our previous works, the cell is modelled as a continuum and a standard Maxwell model is used to describe the mechanical behaviour of both the cytoplasm (including active strains) and the nucleus. The cell cyclically protrudes and contracts and develops viscous forces to adhere to the substrate. The micro-channel is represented by two rigid walls, and it exerts an additional viscous force on the cell boundaries. We test four channels whose dimensions in terms of width are i) larger than the cell diameter, ii) sub-cellular, ii) sub-nuclear and iv) much smaller than the nucleus diameter. The main objective of the work is to assess the necessary conditions for the cell to enter into the channel and migrate through it. Therefore, we evaluate both the evolution of the cell morphology and the cell-channel and cell-substrate surface forces, and we show that there exists a link between the two, which is the essential parameter determining whether the cell is permeative, invasive or penetrating.

[Treatment of pharyngeal disease in general and pediatric practice]. / Das Vorgehen bei Affektionen des Rachenraums in der allgemeinärztlichen und pädiatrischen Praxis.

Based on 1351 reports by 180 physicians, it was found that pediatricians and younger physicians conducted more diagnostic tests and judged a tonsillectomy as necessary less frequently than GP's, especially those without board certification, and older physicians.

Three-dimensional pore-scale modelling of dentinal infiltration.

Dentine is the fundamental substrate of restorative dentistry, and its properties and characteristics are the key determinants of restorative processes. In contemporary restorative techniques, bonding to Dentine is created by the impregnation of the demineralised dentine by blends of resin monomers. In this paper, a numerical model of dentinal infiltration is proposed. The aim is to follow the resin front and to point out the optimal parameter set. The main tool is a level set technique to follow the evolving interface. It is coupled with the Navier-Stokes equation where capillary effect gives rise to the appearance of a new term in the variational approach than discretised by finite elements. Using an appropriate geometry representing demineralised dentine, the moving front is observed. First, a simulation of porosimetry test is achieved in order to validate the model. The two expected pore sizes are detected and the simulation also points out limitations of mercury intrusion porosimetry test in an educational way. Then a wetting fluid (representing the dental resin) is numerically infiltrated. In the dentinal porous network, capillarity is taken into account in our model by including a capillary term. A crucial conclusion is drawn from this study: resin application time by practitioners is sufficient if, in the infiltration process, the wetting phase is the resin.

Diffusion-reaction model for Drosophila embryo development.

During the early stages of gastrulation in Drosophila embryo, the epithelial cells composing the single tissue layer of the egg undergo large strains and displacements. These movements have been usually modelled by decomposing the total deformation gradient in an (imposed or strain/stress dependent) active part and a passive response. Although the influence of the chemical and genetic activity in the mechanical response of the cell has been experimentally observed, the effects of the mechanical deformation on the latter have been far less studied, and much less modelled. Here, we propose a model that couples morphogen transport and the cell mechanics during embryogenesis. A diffusion-reaction equation is introduced as an additional mechanical regulator of morphogenesis. Consequently, the active deformations are not directly imposed in the analytical formulation, but they rather depend on the morphogen concentration, which is introduced as a new variable. In this study, we show that strain patterns similar to those observed during biological experiments can be reproduced by properly combining the two phenomena. In addition, we use a novel technique to parameterise the embryo geometry by solving two Laplace problems with specific boundary conditions. We apply the method to two morphogenetic movements: ventral furrow invagination and germ band extension. The matching between our results and the observed experimental deformations confirms that diffusion-reaction of morphogens can actually be controlling large morphogenetic movements.

An extensive numerical simulation of the cephalic furrow formation in Drosophila embryo.

Here, we propose a new finite element model of the Drosophila embryo to simulate the cephalic furrow (CF) formation. Two different 3D geometries are introduced to reproduce the embryo. The two of them are parametrised through a novel system of curvilinear coordinates, well adapted for biological structures, which is obtained by three fictive electrostatic potentials. A gradient decomposition method is used to take into account both the active and the passive deformations occurring to the cells. Four simulations of the CF are proposed, which in turn considers singular and coupled aspects of the problem.

A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants.

There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional capacity of human hematopoietic stem/progenitor cells both in in vitro and in in vivo transplantation models. These findings highlight the potential use of MegaFasL as an ex-vivo purging agent in ASCT.

Simulation of multiple morphogenetic movements in the Drosophila embryo by a single 3D finite element model.

The present work describes a 3D finite element model of the Drosophila embryo designed to simulate three morphogenetic movements during early gastrulation: ventral furrow invagination, cephalic furrow formation and germ band extension. The embryo is represented by a regular ellipsoid and only the mesoderm is modeled. Additionally, the parametric description of the biological structure in a special curvilinear system provides mesh-independent endogenous strains. A deformation gradient decomposition is used to couple an active deformation, specific for each morphogenetic movement, together with a passive deformation, which is due to the response of the continuous mesoderm. Boundary conditions such as the rigid contact with the external vitelline membrane and the yolk pressure are also taken into account. The results suggest that the number of active strains responsible for the morphogenetic events can be less than that deduced from direct experimental observations. Finally, the estimation of the non-local pressures induced during morphogenetic movements is in good agreement with the experimental data.

Separating the racemic and meso diastereomers of a binucleating tetraphosphine ligand system through the use of nickel chloride.

The reaction of a 1:1 mixture of rac- and meso-et,ph-P4 (et,ph-P4 = (Et(2)PCH(2)CH(2))(Ph)PCH(2)P(Ph)CH(2)CH(2)PEt(2)) with 2 equiv of NiCl(2).6H(2)O in EtOH produces soluble rac-Ni(2)Cl(4)(et,ph-P4) and precipitates meso-Ni(2)Cl(4)(et,ph-P4), allowing facile isolation of each bimetallic complex. Subsequent reaction with more than 250 equiv of NaCN in H(2)O/MeOH releases the et,ph-P4 ligand and [Ni(CN)(4)](2-). The rac,trans- and meso,trans-Ni(CN)(2)(eta(2.5)-et,ph-P4) form as intermediates in the cyanolysis of rac- and meso-Ni(2)Cl(4)(et,ph-P4). These have been characterized by X-ray crystallography. The unusual partial isomerization of the meso- to rac-et,ph-P4 ligand via the monometallic trans-Ni(CN)(2)(eta(2.5)-et,ph-P4) intermediate complex is discussed.