Imagerie 3D des matériaux et modélisations numériques : application aux multi-matériaux ferroélectriques

This thesis is focused on the conception of new tunable ferroelectric/dielectric compositematerials. Dielectric granules (MgO, TiO2) obtained by spray-drying are dispersed in a ferroelectricmatrix (Ba1-xSrxTiO3). Mixing powder is then densified by Spark Plasma Sintering (SPS). An originalapproach is developed in order to determine parameters linking the microstructure to the physicalproperties for each step of the elaboration - characterization - modelling optimization procedure.The adopted strategy is based on i) specific SPS properties which provide an accurate control of theinterfaces between each components; ii) potentialities offered by X-ray microtomography to describethe internal 3D microstructure of the composite materials during the key steps of their elaboration.Associated with powerful image processing tools, it allows to obtain relevant elements guiding theoptimization and understanding of the final properties; iii) the development of a 3D numerical modelof tunability applied directly to the real geometry which has been extracted from 3Dmicrotomography images. This step is essential to understand the origin of the redistribution of theelectric field between the different phases. Numerical results are directly compared to experimentalmeasurements.Cette thèse s’intéresse à la conception de nouveaux matériaux compositesferroélectriques/diélectriques aux propriétés accordables en tension. Des granules diélectriques(MgO, TiO2) obtenues par atomisation sont dispersées dans une matrice ferroélectrique (Ba1-xSrxTiO3). Le mélange est ensuite densifié par Spark Plasma Sintering (SPS). Une approcheoriginale est développée afin de déterminer les paramètres reliant la microstructure aux propriétésphysiques pour chacune des étapes de la boucle d’optimisation élaboration - caractérisation -modélisation. La stratégie adoptée s’appuie sur i) l’utilisation des propriétés spécifiques du frittageSPS qui offre une gestion précise des interfaces entre les différents composés. Cette méthode nonconventionnellea permis l’élaboration de composites ferroélectriques architecturés, constituésd’inclusions diélectriques de géométries contrôlées ; ii) les potentialités offertes par lamicrotomographie X comme moyen de description de la microstructure 3D des matériauxcomposites aux étapes clés de leur conception. Couplée à de puissants outils de traitements desimages elle permet d’extraire les éléments pertinents guidant l’optimisation et la compréhension despropriétés finales ; iii) le développement d’un modèle numérique 3D de l’accordabilité appliquédirectement à la géométrie réelle des matériaux extraite des images de microtomographie. Cetteétape est essentielle pour comprendre l’origine de la redistribution du champ électrique entre lesphases. Les résultats numériques obtenus sont directement confrontés aux mesuresexpérimentales

Evidens i praktiken : En kvalitativ intervju- och observationsstudie om synen på alternativa behandlingsmetoder och evidens inom missbrukarvården.

Evidence in practice The aim of this study was to discover what professionals within alcohol- and drug abuse care think about alternative treating methods in comparison to evidence based care. Also, the aim was to discover if the professionals think differently about this matter depending of their professional role within the organization. To discover this, the study was based on four qualitative interviews and a participating observation at a meeting with politicians and decision makers that took place in a municipality in southern Sweden. The interviews and the participating observation focused on finding out peoples’ subjective thoughts. The findings of this study seemed to be many things, among others the fact that all participants were positive to alternative treatment methods and they claimed it to be something necessary to truly help a client to recover. The holistic perspective was something all participants advocated for. The study also showed a great variety of knowledge about and attitudes towards evidence within drug abuse care. And, furthermore the study also showed that the professionals urge for evidence based methods adjusted to meet local differences concerning values and knowledge. The analysis was based on four perspectives of the theory social constructivism and a theory of power named "pastoral power". The analysis focused on how people create knowledge depending on their environment, interests of power and the social work itself

Epigenome-Wide and Transcriptome-Wide Analyses Reveal Gestational Diabetes is Associated with Alterations in the Human Leukocyte Antigen Complex

Background: Gestational diabetes mellitus (GDM) affects approximately 10% of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM. Results: To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 BeadChips) and expression (Affymetrix transcriptome microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex (MHC) region, which were validated in an independent cohort, the Rhode Island Child Health Study. Gene ontology enrichment among gene regulation influenced by GDM revealed an over-representation of immune response pathways among differential expression, reflecting these coordinated changes in the MHC region. This differential methylation and expression may be capturing shifts in cellular composition, reflecting physiological changes in the placenta associated with GDM. Conclusions: Our study represents the largest investigation of transcriptomic and methylomic differences associated with GDM, providing comprehensive insight into how GDM shapes the intrauterine environment, which may have implications for fetal (re)programming

A rewiring model of intratumoral interaction networks.

Intratumoral heterogeneity (ITH) has been regarded as a key cause of the failure and resistance of cancer therapy, but how it behaves and functions remains unclear. Advances in single-cell analysis have facilitated the collection of a massive amount of data about genetic and molecular states of individual cancer cells, providing a fuel to dissect the mechanistic organization of ITH at the molecular, metabolic and positional level. Taking advantage of these data, we propose a computational model to rewire up a topological network of cell-cell interdependences and interactions that operate within a tumor mass. The model is grounded on the premise of game theory that each interactive cell (player) strives to maximize its fitness by pursuing a rational self-interest strategy, war or peace, in a way that senses and alters other cells to respond properly. By integrating this idea with genome-wide association studies for intratumoral cells, the model is equipped with a capacity to visualize, annotate and quantify how somatic mutations mediate ITH and the network of intratumoral interactions. Taken together, the model provides a topological flow by which cancer cells within a tumor cooperate or compete with each other to downstream pathogenesis. This topological flow can be potentially used as a blueprint for genetically intervening the pattern and strength of cell-cell interactions towards cancer control

Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity

Background: Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation. Methods and Findings: We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p\u3c0.05). Conclusions: Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment

Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice

Little is known of the environmental factors that initiate and promote disease. The aryl hydrocarbon receptor (AHR) is a key regulator of xenobiotic metabolism and plays a major role in gene/environment interactions. The AHR has also been demonstrated to carry out critical functions in development and disease. A qualitative investigation into the contribution by the AHR when stimulated to different levels of activity was undertaken to determine whether AHR-regulated gene/environment interactions are an underlying cause of cardiovascular disease. We used two congenic mouse models differing at the Ahr gene, which encodes AHRs with a 10-fold difference in signaling potencies. Benzo[a]pyrene (BaP), a pervasive environmental toxicant, atherogen, and potent agonist for the AHR, was used as the environmental agent for AHR activation. We tested the hypothesis that activation of the AHR of different signaling potencies by BaP would have differential effects on the physiology and pathology of the mouse cardiovascular system. We found that differential AHR signaling from an exposure to BaP caused lethality in mice with the low-affinity AHR, altered the growth rates of the body and several organs, induced atherosclerosis to a greater extent in mice with the high-affinity AHR, and had a huge impact on gene expression of the aorta. Our studies also demonstrated an endogenous role for AHR signaling in regulating heart size. We report a gene/environment interaction linking differential AHR signaling in the mouse to altered aorta gene expression profiles, changes in body and organ growth rates, and atherosclerosis

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth