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International audience; Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome.

Cognitive modifications over ageing can affect decision making competence (DMC). As it is a core ability in autonomy preservation, our study aims to investigate its changes in old adults and to determine if they are linked to the deterioration of executive functions and working memory. For this purpose, 50 young adults and 50 old adults were assessed with executive, working memory and DMC tasks. The latter comprised the Iowa Gambling task (IGT) and a scenarii task based on daily life-inspired situations, under risk and under ambiguity conditions. Results revealed lower performances in old adults compared to young adults for updating, inhibition and working memory tasks. The IGT failed to distinguish the two groups of age, but the scenarii task did it, as young adults were more risk and ambiguity seekers than old adults. Moreover, updating and inhibition capacities appeared to influence DMC.

The aim of this paper is to propose a symmetrical finite element formulation for the numerical treatment of thermal contact problems without any constraint on the shape, size and order of approximation of the meshes in contact. The new formulation implicitly ensures the heat balance through the contact and it is well adapted for the use of non-linear symmetric solvers minimizing the matrix storage. Examples are presented to show the relevance of the formulation developed.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder characterized by neurodevelopmental regression between 6 and 18 months of life and associated with multi-system comorbidities. Caused mainly by pathogenic variants in the MECP2 (methyl CpG binding protein 2) gene, it is the second leading genetic cause of intellectual disability in girls after Down syndrome. RTT affects not only neurological function but also a wide array of non-neurological organs. RTT-related disorders involve abnormalities of the respiratory, cardiovascular, digestive, metabolic, skeletal, endocrine, muscular, and urinary systems and immune response. Here, we review the different aspects of RTT affecting the main peripheral groups of organs and sometimes occurring independently of nervous system defects.

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.

International audience; Spraying robots are particularly expected in viticulture and arboriculture to safely target and adapt the quantities of phytosanitary products on canopy. However, to maintain a financial profitability for the farmer wishing to adopt a robotized solution, the cost must be reduced. Therefore, instead of adding expensive and redundant sensors to measure the shape of the vegetation close to the robot, this paper investigates the possibility to deflect by a rotating mirror a part of the laser beams of the horizontal 2D LiDAR positionned in front of most of the current mobile robots for security and navigation purposes. This use of the 2D LiDAR aims to obtain at low cost the required 3D information on the canopy. Experimental results on a real spraying robot enable to highlight the interest of this approach: the presence and height of the canopy can be accurately measured, and the nozzles of the spraying boom can be controlled independantly and accordingly. To focus the measurements on a certain area, the angular variations of the mirror can be reduced or on the contrary increased to have a global overview of the environment. This original approach opens new opportunities with a 2D LiDAR for other configurations and field applications.

The aim of this paper is to compute heat transfer as a function of drilling parameters with a relatively short computing time. Assuming that the geometry of the chips close to the cutting edges of the drill tool is almost the same throughout the drilling operation, a numerical strategy is developed in the second section in order to create analytically the geometry of the chips by means of the process parameters and the geometry of the drill tool. An efficient identification procedure is then presented to model the material flow. In the third section, an experimental device is detailed as well as its tomography geometrical analysis after drilling. A simple calibration strategy is developed in order to estimate the Taylor-Quinney coefficient and the thermal impact of the removal material on the hole surface. Then, an application is detailed to show the capability of the modeling proposed to simulate the temperature variation in the case of a large depth hole.

International audience; In the last few years, fleets of mobile robots have received increased interest in agriculture with the development of master/slaves control approaches. This paper proposes on the contrary a planning strategy enabling to generate beforehand the trajectory of each robot. For that, the fleet is considered as a single mobile entity with its steering and speed constraints. An admissible trajectory for this virtual entity, including maneuver phases, is generated to cover the shape of a given field. This one is next used to plan the trajectories of the actual robots. A panel of actual fields with different fleets of robots enables to highlight the relevance of the strategy proposed.

The finite element P 1 ∕ P 1 is well known for being unsuitable for the simulation of incompressible material flows. In von Mises elasto-plasticity, the volume changes can become negligible when the plastic strain grows higher than the elastic strain. Thus, the material flow is nearly incompressible even if a small volumic elastic strain persists. In this context, the finite element P 1 ∕ P 1 leads to pressure oscillations which need to be addressed for achieving satisfactory solutions. The aim of this work is to propose a stabilized formulation without introducing new degrees of freedom or stabilization parameters as for sub-grid scale techniques. Unlike to the standard SUPG method, the stabilization depends on the time step. Examples show that a first order accuracy can be obtained for the pressure and the approach developed can be well suited for cyclic loadings.

The surrogate model proposed is entirely numerical.The surrogate model has the ability to calculate residual stresses in a multi-pass weld joint.The proposed approach is based on the Gaussian process in non-linear structural mechanics. A surrogate model is developed for the mechanical analysis of welded steel pipes. The objective is to build a simple and fast model for calculating residual stresses as a function of the dimensions and the welding parameters. This model is based on numerical experiments which are made of multi-physical finite element simulations. First, the analysis of variance is used to attest the great influence of the input parameters. Then, the polynomial approach and the Gaussian process are compared for calculating the residual hoop stresses. Experience shows that the Gaussian process can be very successful for non-linear multi-physical welding applications.

Mutations in the X‐linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain‐derived neurotrophic factor (BDNF) levels, but non‐specific overexpression of BDNF only partially improves the phenotype of Mecp2‐deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF‐containing vesicles, and is under‐expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho‐mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients., BDNF is one of the most prominent deregulated factors in Rett syndrome, a severe neurodevelopmental disorder. This study reveals that huntingtin phosphorylation stimulates BDNF axonal transport and improves many features in a Rett mouse model, suggesting a possible therapeutic approach.

This paper aims at introducing a new nodal-integration-based finite element method for the numerical calculation of residual stresses induced by welding processes. The main advantage of the proposed method is to be based on first-order tetrahedral meshes, thus greatly facilitating the meshing of complex geometries using currently available meshing tools. In addition, the formulation of the problem avoids any locking phenomena arising from the plastic incompressibility associated with von Mises plasticity and currently encountered with standard 4-node tetrahedral elements. The numerical results generated by the nodal approach are compared to those obtained with more classical simulations using finite elements based on mixed displacement&ndash, pressure formulations: 8-node Q1P0 hexahedra (linear displacement, constant pressure) and 4-node P1P1 tetrahedra (linear displacement, linear pressure). The comparisons evidence the efficiency of the nodal approach for the simulation of complex thermal&ndash, elastic&ndash, plastic problems.

An original formulation is proposed in order to simulate molten metal deposition geometry with a very low CPU time. This new approach is based on the original technique proposed by Leblond et al. [C. R. Mecanique 341 (2013) 770–775] for the incorporation of surface tension in finite element calculations . The FEM simulation strategy is composed of a 2-step resolution algorithm at each time step of the deposition process . At first, the 2D mesh of the surface inflates according to the volume flux of material added. The balance of stress is then treated on the same 2D mesh by considering the interaction between the curvature effect of the surface tension and the pressure difference between the molten zone and the atmosphere which is assumed to be nearly constant. Applications are proposed to show the interest of the numerical method developed in terms of computation efficiency.

This paper details the development of the Proper Generalized Decomposition as a space–time integrator of elastoplastic problems and shows its ability to determine the elastoplastic states resulting from cyclic loadings. The first part of this paper recalls the step-by-step resolution in time of an elastoplastic problem. The implementation of the Proper Generalized Decomposition is then developed in a second part. In the last third part, applications and numerical simulations are presented to show the relevance of the method.

The aim of this paper is to propose a numerical approach for computing the shear stress amplitude during one loading cycle. The analysis is based on the material history in the space of the deviator. It is shown that the calculated maximal amplitude can be used as a satisfactory upper estimate of the amplitude obtained with critical plane theories. The main benefit of this approach is its very low CPU time consuming compared to the algorithms used in the literature. By this way, the proposed approach allows analyzing a high number of material points in the case of the FEM analysis of a structure or a high number of temporal points in the case of an experimental high frequency measurement. Examples are presented to show the relevance and the efficiency of the numerical algorithm proposed.

[Departement_IRSTEA]Ecotechnologies [TR1_IRSTEA]INSPIRE [TR2_IRSTEA]TED; International audience; Sludge is slowly moving away from providing basic by-products and towards providing value-added products (e.g. fertilisers); therefore, it is no longer perceived as waste but as a product. Consequently, wastewater treatment plants become multifunctional systems that produce two coproducts that are given a second life: sludge and “clean” water. An allocation factor in Life Cycle Assessment can partition environmental burdens of wastewater treatment between these two products, but doing so remains highly challenging. To address this challenge, we followed a four-step procedure to develop an allocation factor using a mesoscopic approach and process- and product-related parameters in a mathematical model. The first two steps consisted of determining and mathematically representing process- and product-related parameters and their associations to define a global allocation factor. The third step consisted of constructing a corrective inventory matrix to adjust the global allocation factor, since inventory flows can be specific to certain processes. The last step consisted of mathematical modelling of the final corrected allocation factor. Based on the parameters chosen, the global allocation factor equalled 45% for sludge and 55% for water. A sensitivity analysis was performed to assess the robustness of the sludge allocation factor, which varied from 39 to 49%. The allocation factor developed reflects technological performances of the system and considers environmental impacts of sludge production to assess environmental impacts of value-added sludge-based products.

Objective Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2‐deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT. Methods The trial was a 6‐month, multicenter, randomized, double‐blind, placebo‐controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2–3 mg/kg Desipramine per day (high Desipramine), 1–2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention‐to‐treat analysis was applied. Results The median change in AHI from baseline to 6 months was −31 (IQR: −37 to −11) for the high Desipramine, −17.5 (IQR: −31 to 13) for the low Desipramine, and −13 (IQR:−31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = −0.44; P = 0.0002) was underlined. Interpretation This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

International audience; BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways , including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.

A finite element algorithm is proposed to simulate steady-state diffusion–convection problems with isothermal phase changes. This technique is based on an enthalpic approach discretized by means of a finite element approximation of the enthalpy including the latent heat of transformation. The interface of phase changes is implicitly described without coupling with an interface-capturing technique. An example clearly shows the efficiency of the method developed.

An implicit enriched finite element algorithm is proposed to simulate heat transfer involving isothermal phase changes. This technique is based on a mixed variational formulation discretized by means of an enriched finite element approximation of the enthalpy in space. The interface is implicitly described without coupling with an interface-capturing technique. The time integration is carried out with an implicit (backward) Euler algorithm in time. Two examples in 1D and 2D clearly evidence the efficiency of the method developed.

The simulation of simultaneous diffusion and precipitation of a chemical element during internal oxidation phenomena is presented here, from X-FEM method. This technique seems to be really appropriate when solubility products are very low, or even almost null. In this case, a precipitation front appears and should be properly represented by the numerical simulation. The X-FEM method is then of strong interest, since it allows to know precisely the position of the front all the time of simulation, without remeshing.

Rett syndrome (RTT) is a severe postnatal neurological disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. In affected children, most biological parameters, including brain structure, are normal (although acquired microcephaly is usually present). However, in recent years, a deficit in bioaminergic metabolism has been identified at the cellular and molecular levels, in more than 200 patients. Recently available transgenic mouse strains with a defective Mecp2 gene also show abnormalities, strongly suggesting that there is a direct link between the function of the MECP2 protein and the metabolism of biogenic amines. Biogenic amines appear to have an important role in the pathophysiology of Rett syndrome, for several reasons. Firstly, biogenic amines modulate a large number of autonomic and cognitive functions. Secondly, many of these functions are affected in RTT patients. Thirdly, biogenic amines are the only neurotransmitters that have repeatedly been found to be altered in RTT patients. Importantly, pharmacological interventions can be envisaged to try to counteract the deficits observed. Here, we review the available human and mouse data and present how they have been and could be used in the development of pharmacological treatments for children affected by the syndrome. Given our current knowledge and the tools available, modulating biogenic amine metabolism may prove to be the most promising strategy for improving the life quality of Rett syndrome patients in the short term.

We previously identified an inactivating disruption of the X-linked KIAA2022 gene by a chromosomal rearrangement in two male patients with severe mental retardation. In order to determine if KIAA2022 has a role during the development of the central nervous system, we have cloned its murine ortholog, Kiaa2022, determined its genomic structure and studied its expression during mouse development. We show that Kiaa2022 is preferentially expressed in the central nervous system and that the transcript is highly expressed in postmitotic neurons. The expression of Kiaa2022 is first detectable at E10.5 to reach a maximum at P3 where it is notably expressed in the hippocampus, the entorhinal cortex and strongly in the ventral premammillary nucleus. After P3, the expression of Kiaa2022 decreases and maintains very low levels thereafter. Our results show that Kiaa2022 is expressed in the developing brain and that it may play a role in postmitotic, maturing neurons.

Methyl CpG binding protein 2 (MeCP2) is a member of the methylated DNA binding protein family able to modulate the transcription of target genes. Mutations in MECP2 lead to a wide range of neurological phenotypes and the better known of these diseases is Rett Syndrome. All patients having a mutation in MECP2 are mentally retarded and most of them exhibit dysfunctions in autonomic processes that are controlled by the brainstem. Previous studies have shown that Mecp2 is developmentally and spatially regulated throughout the rodent brain but none of them investigated the brainstem. In the present study, we have quantified the levels of expression of the Mecp2 mRNA by real time PCR and MeCP2 protein by immunoquantifications, in different areas of the mouse brainstem during the postnatal development (P0, P7, P21, P35 and P55). We focused on regions of the pons and the medulla oblongata directly involved in the regulation of autonomic functions. Our results show that the expression of MeCP2 is heterogeneously expressed throughout the postnatal mouse brainstem. MeCP2 expression in each area studied is restricted to neurones. The developmental pattern is mainly characterized by a postnatal decrease of the Mecp2 mRNA and an increase of the MeCP2 protein staining level in spite of the local variability. However, we were not able to correlate the developmental expression of MeCP2 in a given area of the brainstem with autonomic dysfunctions occurring in the presence of a mutation in Mecp2.

The chemoreflex pathway undergoes postnatal maturation, and the perinatal environment plays a critical role in shaping respiratory control system. We investigated the role of prenatal hypoxia on the maturation of the chemoreflex neural circuits regulating ventilation in rat. Effects of hypoxia (10% O(2)) from the 5th to the 20th day of gestation were studied on male offspring at birth and on postnatal days 3, 7, 21 and 68. Maturation of the respiratory control system was assessed by in vivo tyrosine hydroxylase (TH) activity measurement in peripheral chemoreceptors (carotid bodies, petrosal ganglia), and in brainstem catecholaminergic cell groups (A(2)C(2)c and A(1)C(1) areas in the medulla, A(5) and A(6) areas in the pons). Resting ventilation and ventilatory response to hypoxia were evaluated as functional sequelae. In peripheral structures, prenatal hypoxia reduced TH activity within the first postnatal week and enhanced it later. In contrast, in central areas, prenatal hypoxia upregulated TH activity within the first postnatal week and downregulated it later. The in vivo TH activity impairment is therefore tissue specific, with an opposite effect on the peripheral and central neural circuits. A shift of the effect of prenatal hypoxia occurred between 1 and 3 weeks, indicating a postnatal temporal effect of prenatal hypoxia. An important period in the development of the chemoafferent pathway occurred between the first and the third postnatal week. Functionally, prenatal hypoxia impaired resting ventilation and ventilatory response to hypoxia. The alterations of the catecholaminergic components of the chemoafferent pathway resulting from prenatal hypoxia might contribute to impair postnatal respiratory behaviour.

Rett syndrome (RS) is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein2 (MECP2) gene. No effective treatment exists. We previously showed that the Mecp2-deficient mice, a mouse model of RS, have highly variable respiratory rhythm and frequent apneas due to reduced norepinephrine (NE) content, and a drastic decrease of tyrosine hydroxylase (TH)-expressing neurons in the medulla. We showed here that treating these mice with desipramine (DMI), which specifically inhibits NE reuptake, significantly improved their respiratory rhythm during several weeks. In addition, the treatment significantly extended their lifespan. At the cellular level, we showed that the reduced number of TH-expressing neurons before treatment in the mutant animals was not due to apoptosis. Conversely, we found that DMI treatment increased the number of TH-expressing neurons in the mutant brainstem to reach wild-type levels. We showed that this increase was not due to cellular proliferation. We propose that the Mecp2-deficient TH-expressing neurons lose their ability to synthesize TH at some point during their postnatal development. Our results suggest that a pharmacological stimulation of the noradrenergic system could be a promising approach for the treatment of the respiratory dysfunction which causes a significant proportion of death in RS patients.

International audience; The aim of this paper is to propose a stabilized finite element P1/ P1 and to show that it is well suited for the finite-strain analysis of solid metals in the context of large von Mises elasto-viscoplastic or elasto-plastic transformations. The first part of this paper is dedicated to the finite element formulation which is detailed for an elasto-viscoplastic model problem. Then, a new stabilized formulation is proposed for the pressure solution. In the last part, examples are presented to show the relevance of the finite element P1/ P1 developed.