Shh Signaling from the Nucleus Pulposus Is Required for the Postnatal Growth and Differentiation of the Mouse Intervertebral Disc

Intervertebral discs (IVD) are essential components of the vertebral column. They maintain separation, and provide shock absorbing buffers, between adjacent vertebrae, while also allowing movements between them. Each IVD consists of a central semi-liquid nucleus pulposus (NP) surrounded by a multi-layered fibrocartilagenous annulus fibrosus (AF). Although the IVDs grow and differentiate after birth along with the vertebral column, little is known about the mechanism of this. Understanding the signals that control normal IVD growth and differentiation would also provide potential therapies for degenerative disc disease, which is the major cause of lower back pain and affects a large proportion of the population. In this work, we show that during postnatal growth of the mouse, Sonic hedgehog (Shh) signaling from the NP cells controls many aspects of growth and differentiation of both the NP cells themselves and of the surrounding AF, and that it acts, at least partly, by regulating other signaling pathways in the NP and AF. Recent studies have shown that the NP cells arise from the embryonic notochord, which acts as a major signaling center in the embryo. This work shows that this notochord-derived tissue continues to carry out a major signaling function in the postnatal body and that the IVDs are signaling centers, in addition to their already known functions in the mechanics of vertebral column function

LCA applied to perennial cropping systems: a review focused on the farm stage

International audienc

Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials

[EN] Combining several theories this paper presents a general multiphysics framework applied to the study of coupled and active materials, considering mechanical, electric, magnetic and thermal fields. The framework is based on thermodynamic equilibrium and non-equilibrium interactions, both linked by a two-temperature model. The multi-coupled governing equations are obtained from energy, momentum and entropy balances; the total energy is the sum of thermal, mechanical and electromagnetic parts. The momentum balance considers mechanical plus electromagnetic balances; for the latter the Abraham rep- resentation using the Maxwell stress tensor is formulated. This tensor is manipulated to automatically fulfill the angular momentum balance. The entropy balance is for- mulated using the classical Gibbs equation for equilibrium interactions and non-equilibrium thermodynamics. For the non-linear finite element formulations, this equation requires the transformation of thermoelectric coupling and conductivities into tensorial form. The two-way thermoe- lastic Biot term introduces damping: thermomechanical, pyromagnetic and pyroelectric converse electromagnetic dynamic interactions. Ponderomotrix and electromagnetic forces are also considered. The governing equations are converted into a variational formulation with the resulting four-field, multi-coupled formalism implemented and val- idated with two custom-made finite elements in the research code FEAP. Standard first-order isoparametric eight-node elements with seven degrees of freedom (dof) per node (three displacements, voltage and magnetic scalar potentials plus two temperatures) are used. Non-linearities and dynamics are solved with Newton-Raphson and New- mark-b algorithms, respectively. Results of thermoelectric, thermoelastic, thermomagnetic, piezoelectric, piezomag- netic, pyroelectric, pyromagnetic and galvanomagnetic interactions are presented, including non-linear depen- dency on temperature and some second-order interactions.This research was partially supported by grants CSD2008-00037 Canfranc Underground Physics, Polytechnic University of Valencia under programs PAID 02-11-1828 and 05-10-2674. The first author used the grant Generalitat Valenciana BEST/2014/232 for the completion of this work.Pérez-Aparicio, JL.; Palma, R.; Taylor, R. (2016). Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials. Archives of Computational Methods in Engineering. 23:535-583. https://doi.org/10.1007/s11831-015-9149-9S53558323Abraham M (1910) Sull’elettrodinamica di Minkowski. 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Anchoring skeletal muscle development and disease: the role of ankyrin repeat domain containing proteins in muscle physiology

The ankyrin repeat is a protein module with high affinity for other ankyrin repeats based on strong Van der Waals forces. The resulting dimerization is unusually resistant to both mechanical forces and alkanization, making this module exceedingly useful for meeting the extraordinary demands of muscle physiology. Many aspects of muscle function are controlled by the superfamily ankyrin repeat domain containing proteins, including structural fixation of the contractile apparatus to the muscle membrane by ankyrins, the archetypical member of the family. Additionally, other ankyrin repeat domain containing proteins critically control the various differentiation steps during muscle development, with Notch and developmental stage-specific expression of the members of the Ankyrin repeat and SOCS box (ASB) containing family of proteins controlling compartment size and guiding the various steps of muscle specification. Also, adaptive responses in fully formed muscle require ankyrin repeat containing proteins, with Myotrophin/V-1 ankyrin repeat containing proteins controlling the induction of hypertrophic responses following excessive mechanical load, and muscle ankyrin repeat proteins (MARPs) acting as protective mechanisms of last resort following extreme demands on muscle tissue. Knowledge on mechanisms governing the ordered expression of the various members of superfamily of ankyrin repeat domain containing proteins may prove exceedingly useful for developing novel rational therapy for cardiac disease and muscle dystrophies

Transcriptome analyses based on genetic screens for Pax3 myogenic targets in the mouse embryo

<p>Abstract</p> <p>Background</p> <p>Pax3 is a key upstream regulator of the onset of myogenesis, controlling progenitor cell survival and behaviour as well as entry into the myogenic programme. It functions in the dermomyotome of the somite from which skeletal muscle derives and in progenitor cell populations that migrate from the somite such as those of the limbs. Few Pax3 target genes have been identified. Identifying genes that lie genetically downstream of <it>Pax3 </it>is therefore an important endeavour in elucidating the myogenic gene regulatory network.</p> <p>Results</p> <p>We have undertaken a screen in the mouse embryo which employs a <it>Pax3^GFP</it>allele that permits isolation of Pax3 expressing cells by flow cytometry and a <it>Pax3^PAX3-FKHR</it>allele that encodes PAX3-FKHR in which the DNA binding domain of Pax3 is fused to the strong transcriptional activation domain of FKHR. This constitutes a gain of function allele that rescues the <it>Pax3 </it>mutant phenotype. Microarray comparisons were carried out between <it>Pax3^GFP/+</it>and <it>Pax3^{GFP/PAX3-FKHR}</it>preparations from the hypaxial dermomyotome of somites at E9.5 and forelimb buds at E10.5. A further transcriptome comparison between Pax3-GFP positive and negative cells identified sequences specific to myogenic progenitors in the forelimb buds. Potential Pax3 targets, based on changes in transcript levels on the gain of function genetic background, were validated by analysis on loss or partial loss of function <it>Pax3 </it>mutant backgrounds. Sequences that are up- or down-regulated in the presence of PAX3-FKHR are classified as somite only, somite and limb or limb only. The latter should not contain sequences from Pax3 positive neural crest cells which do not invade the limbs. Verification by whole mount <it>in situ </it>hybridisation distinguishes myogenic markers. Presentation of potential Pax3 target genes focuses on signalling pathways and on transcriptional regulation.</p> <p>Conclusions</p> <p>Pax3 orchestrates many of the signalling pathways implicated in the activation or repression of myogenesis by regulating effectors and also, notably, inhibitors of these pathways. Important transcriptional regulators of myogenesis are candidate Pax3 targets. Myogenic determination genes, such as <it>Myf5 </it>are controlled positively, whereas the effect of <it>Pax3 </it>on genes encoding inhibitors of myogenesis provides a potential brake on differentiation. In the progenitor cell population, <it>Pax7 </it>and also <it>Hdac5 </it>which is a potential repressor of <it>Foxc2</it>, are subject to positive control by <it>Pax3</it>.</p

Zebrafish con/disp1 reveals multiple spatiotemporal requirements for Hedgehog-signaling in craniofacial development

<p>Abstract</p> <p>Background</p> <p>The vertebrate head skeleton is derived largely from cranial neural crest cells (CNCC). Genetic studies in zebrafish and mice have established that the Hedgehog (Hh)-signaling pathway plays a critical role in craniofacial development, partly due to the pathway's role in CNCC development. Disruption of the Hh-signaling pathway in humans can lead to the spectral disorder of Holoprosencephaly (HPE), which is often characterized by a variety of craniofacial defects including midline facial clefting and cyclopia <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr></abbrgrp>. Previous work has uncovered a role for Hh-signaling in zebrafish dorsal neurocranium patterning and chondrogenesis, however Hh-signaling mutants have not been described with respect to the ventral pharyngeal arch (PA) skeleton. Lipid-modified Hh-ligands require the transmembrane-spanning receptor Dispatched 1 (Disp1) for proper secretion from Hh-synthesizing cells to the extracellular field where they act on target cells. Here we study <it>chameleon </it>mutants, lacking a functional <it>disp1</it>(<it>con/disp1</it>).</p> <p>Results</p> <p><it>con/disp1 </it>mutants display reduced and dysmorphic mandibular and hyoid arch cartilages and lack all ceratobranchial cartilage elements. CNCC specification and migration into the PA primorida occurs normally in <it>con/disp1 </it>mutants, however <it>disp1 </it>is necessary for post-migratory CNCC patterning and differentiation. We show that <it>disp1 </it>is required for post-migratory CNCC to become properly patterned within the first arch, while the gene is dispensable for CNCC condensation and patterning in more posterior arches. Upon residing in well-formed pharyngeal epithelium, neural crest condensations in the posterior PA fail to maintain expression of two transcription factors essential for chondrogenesis, <it>sox9a </it>and <it>dlx2a</it>, yet continue to robustly express other neural crest markers. Histology reveals that posterior arch residing-CNCC differentiate into fibrous-connective tissue, rather than becoming chondrocytes. Treatments with Cyclopamine, to inhibit Hh-signaling at different developmental stages, show that Hh-signaling is required during gastrulation for normal patterning of CNCC in the first PA, and then during the late pharyngula stage, to promote CNCC chondrogenesis within the posterior arches. Further, loss of <it>disp1 </it>disrupted normal expression of <it>bapx1 </it>and <it>gdf5</it>, markers of jaw joint patterning, thus resulting in jaw joint defects in <it>con/disp1 </it>mutant animals.</p> <p>Conclusion</p> <p>This study reveals novel requirements for Hh-signaling in the zebrafish PA skeleton and highlights the functional diversity and differential sensitivity of craniofacial tissues to Hh-signaling throughout the face, a finding that may help to explain the spectrum of human facial phenotypes characteristic of HPE.</p

A multiscale model for magneto-elastic couplings

At the macroscopic scale two different phenomena illustrate the couplings between the elastic and magnetic behaviours of ferromagnetic materials : first, magnetisation induces a deformation mechanism called magnetostriction, and, second, stresses have an effect on the magnetic behaviour. The complexity of the non-linear relations between these phenomena is such that few realistic macroscopic constitutive equations have been proposed to model the coupled magneto-elastic behaviour of magnetic materials. Magnetisation and magnetostriction are macroscopic manifestations of the complex magnetic domain structure that is modified by applied mechanic and magnetic loads. Herein, it is proposed to use homogenisation methods to deduce the macroscopic behaviour of single crystals and polycrystals from a statistical description of the magnetic domain structure. Therefore, the macroscopic couplings naturally arise from the expression of the free energy written at the level of the magnetic domains

Influence of the texture of soft magnetic materials on their magneto-elastic behaviour

Magnetisation and magnetostriction are macroscopic manifestations of a complex magnetic doinain structure that is modified by applied mechanic and magnetic loads. In the multiscale model used in this paper this doinain structure is statistically described by a set of internal variables that are defined in each grain. This model is used to predict the evolutions of macroscopic state variables that are related to original partitions of the magnetisation and magnetostriction. This approach is used to predict the influence of the crystallographic texture of the material on its magneto-elastic behaviour

Identification of frequency effect on magnetic hysteresis and modelling with an internal variables model

In this paper, the first magnetisation response experimentally observed on 0.5 nim thick sheets made of a non-oriented silicon-iron alloy is given for different magnetic loading frequencies from 0.05 to 500 Hz. An internal variable magnetic hysteresis model is identified from the quasi-static response (from 0.05 to about 5 Hz). This model is used for finite element analyses performed to predict the electro-magnetic response of the material at higher frequencies. The comparison between the results of these structural analyses and the experimental results proves that in this case the macroscopic eddy currents are sufficient to explain the total frequency effect on the magnetic hysteresis measurements