Super-élément fini de tôles rivetées pour le calcul des structures

The thesis is made in a context which consists in improving the finite element (FE) analysis of full-scale aircraft structures subjected to crash and impact loadings. The study is focused, in particular, on the riveted assemblies modeling in structural computations, which are stress concentrations areas where ruptures initiation can occur. If the fastener rupture is mastered, the rupture modes due to perforations are, however, difficult to simulate in a complete structure computation. In order to accurately take into account the perforations influence on the mechanical response of such structures, a perforated super-element featuring 8 nodes have been formulated in a previous thesis. Nevertheless, its internal boundary is analytic and free of loads, which makes difficult the connection with a rivet element, and consequently the assembly modeling. The study proposed here consists in the developement of a perforated super-element which is, on the one hand, able to take into account the perforation influence on the mechanical fields, and which is, on the other hand, formulated such as the interaction with a rivet macro-element is possible.In order to deals with these issues, the framework in which the formulation of super-elements takes place is presented in the first chapter. The concepts necessary to the theoretical foundations understanding of super-elements are presented, and a literature review on super-elements featuring defects is made. In the second chapter, a new perforated plate super-element featuring nodes on the hole boundary is formulated in order to establish the interaction with a fastener model used for the rivet. To this end, the variational principle of the new FE is developed, the interpolation functions are defined with a complex variables method and are chosen in order to formulate a perforated super-element featuring 8 external nodes and 8 nodes on the hole boundary, and a formalism making the hole boundary loading possible is proposed. Finally, the stiffness matrix and the load vector of the new super-element are established. In the third chapter, the new super-element interpolation functions are evaluated. It is shown that they are able to describe the mechanical fields in the hole vicinity. However, a decrease in the accuracy is observed in comparison with the ones of the super-element without internal nodes. The inaccuracies origin is identified, and methods to correct them are proposed. In the last chapter, the 16-node perforated super-element is implemented in ZéBuLoN. Its capability to localise the fields in the hole vicinity when external and internal loadings are applied, its accuracy, and also its efficiency, are assessed. However, when the hole boundary is subjected to a constant and uniform pressure, the results are inconsistent. Nevertheless, some positive points observed are encouraging; so, an outlook is to improve the load vector implementation, and particularly the numerical integration on the hole boundary.La thèse s'inscrit dans un axe de recherche visant à améliorer l'analyse par éléments finis (EF) des structures aéronautiques soumises au crash et à l'impact. L'étude s'intéresse, en particulier, à la modélisation des assemblages rivetés dans les calculs de structures, qui sont des zones de concentrations de contraintes propices à l'initiation de ruptures. Si la rupture de la fixation est maîtrisée, les modes de rupture dus aux perforations sont, quant à eux, difficiles à simuler dans un calcul sur structure complète. Afin de prendre en compte avec précision l'influence des perforations sur la réponse mécanique de telles structures, un super-élément perforé à 8 noeuds a été formulé lors d'une précédente thèse. Cependant, sa frontière interne est analytique et libre de chargement, ce qui rend difficile la connexion avec un élément rivet, et donc la modélisation de l'assemblage. L'étude proposée ici consiste donc à développer un super-élément perforé qui soit capable de tenir compte de l'influence de la perforation sur les champs mécaniques, d'une part, et qui soit formulé de façon à rendre possible l'interaction avec un macro-élément rivet, d'autre part.Pour répondre à cette problématique, le cadre dans lequel s'inscrit la formulation de super-éléments est présenté dans le premier chapitre. Les concepts nécessaires à la compréhension des fondements théoriques des super-éléments sont présentés, et une synthèse bibliographique de super-éléments comportant un défaut est réalisée. Dans le deuxième chapitre, un nouveau super-élément de plaque perforée qui comporte des noeuds sur la perforation est formulé afin de pouvoir établir l'interaction avec un modèle de fixation utilisé pour le rivet. Pour cela, le principe variationnel du nouvel EF est développé, les fonctions d'interpolation sont déterminées par une méthode de variables complexes et sont choisies de façon à formuler un super-élément perforé comportant 8 noeuds externes et 8 noeuds sur la perforation, et un formalisme permettant d'appliquer des chargements sur la perforation est proposé. Enfin, la matrice de rigidité et le vecteur chargement du nouveau super-élément sont établis. Dans le troisième chapitre, les fonctions d'interpolation du nouveau super-élément sont évaluées. Il est montré qu'elles sont capables de reconstruire les champs mécaniques au voisinage de la perforation. Cependant, une diminution de la précision est observée par rapport à celles du super-élément sans noeuds internes. L'origine de ces imprécisions est identifiée, et des méthodes sont proposées pour remédier à ces écarts. Dans le dernier chapitre, le super-élément perforé à 16 noeuds est implémenté dans ZéBuLoN. Sa capacité à localiser les champs au voisinage de la perforation lorsque des chargements externes ou internes sont appliqués, sa précision, ainsi que son efficacité, sont évaluées. Le super-élément est complètement validé lorsqu'il est soumis à des chargements externes. Par contre, lorsque sa perforation est soumise à une pression constante et uniforme, les résultats présentent des incohérences. Malgré tout, plusieurs points positifs observés sont encourageants~; une perspective immédiate est donc d'améliorer l'implémentation du second membre, et en particulier l'intégration numérique sur la perforation

Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα

Adaptation to fasting involves both Glucocorticoid Receptor (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARα, using ChIP- and RNA-seq in primary hepatocytes. Our data reveal extensive chromatin co-localization of both factors with cooperative induction of genes controlling lipid/glucose metabolism. Key GR/PPAR co-controlled genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon coinciding with gene promoter recruitment of phosphorylated AMP-activated protein kinase (AMPK) and blocked by its pharmacological inhibition. In vitro interaction studies support trimeric complex formation between GR, PPARα and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRα Ser211. Phospho-AMPK chromatin recruitment at liver target genes, observed upon prolonged fasting in mice, is dampened by refeeding. Taken together, our results identify phospho-AMPK as a molecular switch able to cooperate with nuclear receptors at the chromatin level and reveal a novel adaptation mechanism to prolonged fasting

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Transcriptional Profiling Uncovers a Network of Cholesterol-Responsive Atherosclerosis Target Genes

Despite the well-documented effects of plasma lipid lowering regimes halting atherosclerosis lesion development and reducing morbidity and mortality of coronary artery disease and stroke, the transcriptional response in the atherosclerotic lesion mediating these beneficial effects has not yet been carefully investigated. We performed transcriptional profiling at 10-week intervals in atherosclerosis-prone mice with human-like hypercholesterolemia and a genetic switch to lower plasma lipoproteins (Ldlr−/−Apo100/100 Mttpflox/flox Mx1-Cre). Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated that accumulation of lipid-poor macrophages reached a point that led to the rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation supported by lesion histology. Genetic lowering of plasma cholesterol (e.g., lipoproteins) at this point all together prevented the formation of advanced plaques and parallel transcriptional profiling of the atherosclerotic arterial wall identified 37 cholesterol-responsive genes mediating this effect. Validation by siRNA-inhibition in macrophages incubated with acetylated-LDL revealed a network of eight cholesterol-responsive atherosclerosis genes regulating cholesterol-ester accumulation. Taken together, we have identified a network of atherosclerosis genes that in response to plasma cholesterol-lowering prevents the formation of advanced plaques. This network should be of interest for the development of novel atherosclerosis therapies

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance

The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions.

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs

Super-element for riveted plates in structural computations

La thèse s’inscrit dans un axe de recherche visant à améliorer l’analyse par éléments finis (EF) des structures aéronautiques soumises au crash et à l’impact. L’étude s’intéresse, en particulier, à la modélisation des assemblages rivetés dans les calculs de structures, qui sont des zones de concentrations de contraintes propices à l’initiation de ruptures. Si la rupture de la fixation est maîtrisée, les modes de rupture dus aux perforations sont, quant à eux, difficiles à simuler dans un calcul sur structure complète. Afin de prendre en compte avec précision l’influence des perforations sur la réponse mécanique de telles structures, un super-élément perforé à 8 nœuds a été formulé lors d’une précédente thèse. Cependant, sa frontière interne est analytique et libre de chargement, ce qui rend difficile la connexion avec un élément rivet, et donc la modélisation de l’assemblage. L’étude proposée ici consiste donc à développer un super-élément perforé qui soit capable de tenir compte de l’influence de la perforation sur les champs mécaniques, d’une part, et qui soit formulé de façon à rendre possible l’interaction avec un macro-élément rivet, d’autre part.The thesis is made in a context which consists in improving the finite element (FE) analysis of full-scale aircraft structures subjected to crash and impact loadings. The study is focused, in particular, on the rivetedassemblies modeling in structural computations, which are stress concentrations areas where ruptures initiation can occur. If the fastener rupture is mastered, the rupture modes due to perforations are, however, difficult to simulate in a complete structure computation. In order to accurately take into account the perforations influence on the mechanical response of such structures, a perforated super-element featuring 8 nodes have been formulated in a previous thesis. Nevertheless, its internal boundary is analytic and free of loads, which makes difficult the connection with a rivet element, and consequently the assembly modeling. The study proposed here consists in the developement of a perforated super-element which is, on the one hand, able to take into account the perforation influence on the mechanical fields, and which is, on the other hand, formulated such as the interaction with a rivet macro-element is possible

L'Insuffisance veineuse chronique primaire

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Vers la modélisation des assemblages rivetés par super-éléments finis en dynamique rapide

La prédiction de la rupture des zones d’assemblages rivetés dans les modèles numériques de structures aéronautiques soumises à impact nécessite l'utilisation d'éléments finis adaptés (échelle structure >> échelle assemblage ; avion complet ≈ 100000 rivets). Des super-EF, de rivet et de plaque perforée, ont donc été développés pour la représentation des assemblages. Cependant, ces éléments ne peuvent être liés à l'heure actuelle. Les travaux se focalisent donc sur leur association. Le super-élément perforé à 8 nœuds (frontière externe) existant repose sur un principe variationnel hybride déplacement (compatibilité avec les EF voisins), et sur des fonctions d’interpolation tronquées à l’ordre 4 (série de Laurent) qui permettent de tenir compte de la perforation. Or, la frontière interne est analytique et libre de chargements. Afin de gérer l’interaction fixation/perforation, cette dernière doit alors être matérialisée par des nœuds. Le développement d’un super-EF de plaque perforée à 16 nœuds (8 externes, 8 internes) consiste en deux étapes. D’abord, l’ordre de la série doit être fixé à 8 car celui-ci est lié au nombre de nœuds de l’EF. Pour s’assurer de la précision des fonctions d’interpolation tronquées à l’ordre 8, une étude complète en fonction de l’ordre et de la disposition des nœuds est proposée. Dans l’ensemble, la précision des résultats diminue avec l'augmentation de l'ordre, sans impact majeur. Par contre, d’autres résultats plus inattendus sont soulignés et confrontés à la littérature. Ensuite, il s’agit de développer un principe variationnel dans lequel les ddls de la perforation interviennent, et, la compatibilité des déplacements n’est assurée que sur la frontière externe. La littérature permet de formuler des EF totalement hybride (compatibilité externe et interne) ou semi-analytique (sans compatibilité). Ici, il est proposé d’évaluer la possibilité de formuler un élément partiellement hybride et semi-analytique, via l’étude des conditions de stationnarité