Can a continuous mineral foam explain the stiffening of aged bone tissue? A micromechanical approach to mineral fusion in musculoskeletal tissues

Recent experimental data revealed a stiffening of aged cortical bone tissue, which could not be explained by common multiscale elastic material models. We explain this data by incorporating the role of mineral fusion via a new hierarchical modeling approach exploiting the asymptotic (periodic) homogenization (AH) technique for three-dimensional linear elastic composites. We quantify for the first time the stiffening that is obtained by considering a fused mineral structure in a softer matrix in comparison with a composite having non-fused cubic mineral inclusions. We integrate the AH approach in the Eshelby-based hierarchical mineralized turkey leg tendon model (Tiburtius et al 2014 Biomech. Model. Mechanobiol. 13 1003–23), which can be considered as a base for musculoskeletal mineralized tissue modeling. We model the finest scale compartments, i.e. the extrafibrillar space and the mineralized collagen fibril, by replacing the self-consistent scheme with our AH approach. This way, we perform a parametric analysis at increasing mineral volume fraction, by varying the amount of mineral that is fusing in the axial and transverse tissue directions in both compartments. Our effective stiffness results are in good agreement with those reported for aged human radius and support the argument that the axial stiffening in aged bone tissue is caused by the formation of a continuous mineral foam. Moreover, the proposed theoretical and computational approach supports the design of biomimetic materials which require an overall composite stiffening without increasing the amount of the reinforcing material

Ubiquitin and endocytic internalization in yeast and animal cells.

Endocytosis is involved in a wide variety of cellular processes, and the internalization step of endocytosis has been extensively studied in both lower and higher eukaryotic cells. Studies in mammalian cells have described several endocytic pathways, with the main emphasis on clathrin-dependent endocytosis. Genetic studies in yeast have underlined the critical role of actin and actin-binding proteins, lipid modification, and the ubiquitin conjugation system. The combined results of studies of endocytosis in higher and lower eukaryotic cells reveal an interesting interplay in the two systems, including a crucial role for ubiquitin-associated events. The ubiquitylation of yeast cell-surface proteins clearly acts as a signal triggering their internalization. Mammalian cells display variations on the common theme of ubiquitin-linked endocytosis, according to the cell-surface protein considered. Many plasma membrane channels, transporters and receptors undergo cell-surface ubiquitylation, required for the internalization or later endocytic steps of some cell-surface proteins, whereas for others, internalization involves interaction with the ubiquitin conjugation system or with ancillary proteins, which are themselves ubiquitylated. Epsins and Eps15 (or Eps15 homologs), are commonly involved in the process of endocytosis in all eukaryotes, their critical role in this process stemming from their capacity to bind ubiquitin, and to undergo ubiquitylation

A time-domain method to solve transient elastic wave propagation in a multilayer medium with a hybrid spectral-finite element space approximation

International audienceThis paper introduces a new numerical hybrid method to simulate transient wave propagation in a multilayer semi-infinite medium, which can be fluid or solid, subjected to given transient loads. The medium is constituted of a finite number of unbounded layers with finite thicknesses. The method has a low numerical cost and is relatively straightforward to implement, as opposed to most available numerical techniques devoted to similar problems. The proposed method is based on a time-domain formulation associated with a 2D-space Fourier transform for the variables associated with the two infinite dimensions and uses a finite element approximation in the direction perpendicular to the layers. An illustration of the method is given for an elasto-acoustic wave propagation problem: a three-layer medium constituted of an elastic layer sandwiched between two acoustic fluid layers and excited by an acoustic line source located in one fluid layer

A coinductive semantics of the Unlimited Register Machine

We exploit (co)inductive specifications and proofs to approach the evaluation of low-level programs for the Unlimited Register Machine (URM) within the Coq system, a proof assistant based on the Calculus of (Co)Inductive Constructions type theory. Our formalization allows us to certify the implementation of partial functions, thus it can be regarded as a first step towards the development of a workbench for the formal analysis and verification of both converging and diverging computations

Formal Verification of Hardware Synthesis

Original manuscript: January 21, 2013We report on the implementation of a certified compiler for a high-level hardware description language (HDL) called Fe-Si (FEatherweight SynthesIs). Fe-Si is a simplified version of Bluespec, an HDL based on a notion of guarded atomic actions. Fe-Si is defined as a dependently typed deep embedding in Coq. The target language of the compiler corresponds to a synthesisable subset of Verilog or VHDL. A key aspect of our approach is that input programs to the compiler can be defined and proved correct inside Coq. Then, we use extraction and a Verilog back-end (written in OCaml) to get a certified version of a hardware design.United States. Defense Advanced Research Projects Agency (Agreement FA8750-12-2-0110

Computed tomography porosity and spherical indentation for determining cortical bone millimetre-scale mechanical properties

The cortex of the femoral neck is a key structural element of the human body, yet there is not a reliable metric for predicting the mechanical properties of the bone in this critical region. This study explored the use of a range of non-destructive metrics to measure femoral neck cortical bone stiffness at the millimetre length scale. A range of testing methods and imaging techniques were assessed for their ability to measure or predict the mechanical properties of cortical bone samples obtained from the femoral neck of hip replacement patients. Techniques that can potentially be applied in vivo to measure bone stiffness, including computed tomography (CT), bulk wave ultrasound (BWUS) and indentation, were compared against in vitro techniques, including compression testing, density measurements and resonant ultrasound spectroscopy. Porosity, as measured by micro-CT, correlated with femoral neck cortical bone’s elastic modulus and ultimate compressive strength at the millimetre length scale. Large-tip spherical indentation also correlated with bone mechanical properties at this length scale but to a lesser extent. As the elastic mechanical properties of cortical bone correlated with porosity, we would recommend further development of technologies that can safely measure cortical porosity in vivo. Introductio

A formally verified compiler back-end

This article describes the development and formal verification (proof of semantic preservation) of a compiler back-end from Cminor (a simple imperative intermediate language) to PowerPC assembly code, using the Coq proof assistant both for programming the compiler and for proving its correctness. Such a verified compiler is useful in the context of formal methods applied to the certification of critical software: the verification of the compiler guarantees that the safety properties proved on the source code hold for the executable compiled code as well

Mejoras operativas en la valoración genética del ganado caprino lechero de raza murciano-granadina

Se compararon diferentes modelos para la evaluación de cabras lecheras para su uso en un programa de mejora genética establecido entre la Asociación de Ganaderos de Caprino de Raza Murciano-Granadina de la Comunidad Valenciana y el Centro de Investigación y Tecnología Animal del Instituto Valenciano de Investigaciones Agrarias. Se compararon en primer lugar dos modelos mixtos con diferente estructura de covarianzas. También se realizaron comparaciones entre modelos que incluyeron otros efectos sistemáticos: edad de la hembra en el momento del parto y días desde el parto hasta el primer control de la lactación. Se consideraron los caracteres estandarizados producción de leche y porcentajes de grasa y proteína. Las comparaciones se realizaron considerando criterios estadísticos de información. Los resultados indican que el modelo de repetibilidad es el más adecuado al tener en cuenta las covarianzas entre medidas de una cabra. La inclusión del efecto edad de la hembra al parto sólo fue ventajosa para el carácter producción de leche. La consideración del efecto tiempo desde el parto al primer control lechero fue positiva para los caracteres de producción de leche y de porcentaje de proteína. Ninguno de los efectos incluidos mejoró el modelo actualmente utilizado para porcentaje de grasa

Regulation of the Na,K-ATPase Gamma-Subunit FXYD2 by Runx1 and Ret Signaling in Normal and Injured Non-Peptidergic Nociceptive Sensory Neurons

Dorsal root ganglia (DRGs) contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury