Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle

Background: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of alpha-dystroglycan. Overexpression of LARGE induces hyperglycosylation of alpha-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored.Methodology/Principal Findings: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with alpha-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage.Conclusions/Significance: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and alpha-dystroglycan hyperglycosylation in muscle should be safe

Isogeometric FEM-BEM coupled structural-acoustic analysis of shells using subdivision surfaces

We introduce a coupled finite and boundary element formulation for acoustic scattering analysis over thin shell structures. A triangular Loop subdivision surface discretisation is used for both geometry and analysis fields. The Kirchhoff-Love shell equation is discretised with the finite element method and the Helmholtz equation for the acoustic field with the boundary element method. The use of the boundary element formulation allows the elegant handling of infinite domains and precludes the need for volumetric meshing. In the present work the subdivision control meshes for the shell displacements and the acoustic pressures have the same resolution. The corresponding smooth subdivision basis functions have the $C^1$ continuity property required for the Kirchhoff-Love formulation and are highly efficient for the acoustic field computations. We validate the proposed isogeometric formulation through a closed-form solution of acoustic scattering over a thin shell sphere. Furthermore, we demonstrate the ability of the proposed approach to handle complex geometries with arbitrary topology that provides an integrated isogeometric design and analysis workflow for coupled structural-acoustic analysis of shells

An unstructured immersed finite element method for nonlinear solid mechanics.

We present an immersed finite element technique for boundary-value and interface problems from nonlinear solid mechanics. Its key features are the implicit representation of domain boundaries and interfaces, the use of Nitsche's method for the incorporation of boundary conditions, accurate numerical integration based on marching tetrahedrons and cut-element stabilisation by means of extrapolation. For discretisation structured and unstructured background meshes with Lagrange basis functions are considered. We show numerically and analytically that the introduced cut-element stabilisation technique provides an effective bound on the size of the Nitsche parameters and, in turn, leads to well-conditioned system matrices. In addition, we introduce a novel approach for representing and analysing geometries with sharp features (edges and corners) using an implicit geometry representation. This allows the computation of typical engineering parts composed of solid primitives without the need of boundary-fitted meshes.This work was partially supported by the EPSRC (second author, Grant #EP/G008531/1), by the European Research Council (third author, Grant #ERC-2012-StG 306751), and by the Spanish Ministry of Economy and Competitiveness (third author, Grant #DPI2015-64221-C2-1-R).This is the final version of the article. It first appeared from Springer at http://dx.doi.org/10.1186/s40323-016-0077-5

Boundary element based multiresolution shape optimisation in electrostatics

We consider the shape optimisation of high-voltage devices subject to electrostatic field equations by combining fast boundary elements with multiresolution subdivision surfaces. The geometry of the domain is described with subdivision surfaces and different resolutions of the same geometry are used for optimisation and analysis. The primal and adjoint problems are discretised with the boundary element method using a sufficiently fine control mesh. For shape optimisation the geometry is updated starting from the coarsest control mesh with increasingly finer control meshes. The multiresolution approach effectively prevents the appearance of non-physical geometry oscillations in the optimised shapes. Moreover, there is no need for mesh regeneration or smoothing during the optimisation due to the absence of a volume mesh. We present several numerical experiments and one industrial application to demonstrate the robustness and versatility of the developed approach.Web of Science29759858

A generalized finite element formulation for arbitrary basis functions : from isogeometric analysis to XFEM

Many of the formulations of cm-rent research interest, including iosogeometric methods and the extended finite element method, use nontraditional basis functions. Some, such as subdivision surfaces, may not have convenient analytical representations. The concept of an element, if appropriate at all, no longer coincides with the traditional definition. Developing a new software for each new class of basis functions is a large research burden, especially, if the problems involve large deformations, non-linear materials, and contact. The objective of this paper is to present a method that separates as much as possible the generation and evaluation of the basis functions from the analysis, resulting in a formulation that can be implemented within the traditional structure of a finite clement program but that permits the use of arbitrary sets of basis functions that are defined only through the input file. Elements ranging from a traditional linear four-node tetrahedron through a higher-order element combining XFEM and isogeometric analysis may be specified entirely through an input file without any additional programming. Examples of this framework to applications with Lagrange elements, isogeometric elements, and XFEM basis functions for fracture are presented

A stable FSI algorithm for light rigid bodies in compressible flow

In this article we describe a stable partitioned algorithm that overcomes the added mass instability arising in fluid-structure interactions of light rigid bodies and inviscid compressible flow. The new algorithm is stable even for bodies with zero mass and zero moments of inertia. The approach is based on a local characteristic projection of the force on the rigid body and is a natural extension of the recently developed algorithm for coupling compressible flow and deformable bodies. Normal mode analysis is used to prove the stability of the approximation for a one-dimensional model problem and numerical computations confirm these results. In multiple space dimensions the approach naturally reveals the form of the added mass tensors in the equations governing the motion of the rigid body. These tensors, which depend on certain surface integrals of the fluid impedance, couple the translational and angular velocities of the body. Numerical results in two space dimensions, based on the use of moving overlapping grids and adaptive mesh refinement, demonstrate the behavior and efficacy of the new scheme. These results include the simulation of the difficult problem of a shock impacting an ellipse of zero mass.Comment: 32 pages, 20 figure

Enhanced goal-oriented error assessment and computational strategies in adaptive reduced basis solver for stochastic problems

This work focuses on providing accurate low-cost approximations of stochastic ¿nite elements simulations in the framework of linear elasticity. In a previous work, an adaptive strategy was introduced as an improved Monte-Carlo method for multi-dimensional large stochastic problems. We provide here a complete analysis of the method including a new enhanced goal-oriented error estimator and estimates of CPU (computational processing unit) cost gain. Technical insights of these two topics are presented in details, and numerical examples show the interest of these new developments.Postprint (author's final draft

Viscous regularization and r-adaptive remeshing for finite element analysis of lipid membrane mechanics

As two-dimensional fluid shells, lipid bilayer membranes resist bending and stretching but are unable to sustain shear stresses. This property gives membranes the ability to adopt dramatic shape changes. In this paper, a finite element model is developed to study static equilibrium mechanics of membranes. In particular, a viscous regularization method is proposed to stabilize tangential mesh deformations and improve the convergence rate of nonlinear solvers. The Augmented Lagrangian method is used to enforce global constraints on area and volume during membrane deformations. As a validation of the method, equilibrium shapes for a shape-phase diagram of lipid bilayer vesicle are calculated. These numerical techniques are also shown to be useful for simulations of three-dimensional large-deformation problems: the formation of tethers (long tube-like exetensions); and Ginzburg-Landau phase separation of a two-lipid-component vesicle. To deal with the large mesh distortions of the two-phase model, modification of vicous regularization is explored to achieve r-adaptive mesh optimization