Thermomechanical behavior of oxide-carbon refractory composites

Cette thèse avait pour objectif d’étudier les relations existant entre la microstructure de réfractaires alumine-carbone utilisés en coulée continue dans l’industrie sidérurgique et leurs propriétés thermomécaniques. Le travail réalisé ici s’inscrit dans une logique composite, en déterminant les propriétés thermomécaniques des constituants séparément et en analysant ensuite les propriétés des matériaux multiphasiques. Différents systèmes de matériaux modèles ont été étudiés en s’intéressant à deux échelles : agrégats et matrice. Ces matériaux sont constitués d’une part, d’un squelette de graphite et d’agrégats d’alumine et d’autre part d’une matrice carbonée chargée en petits grains d’alumine. La liaison carbone de ces matériaux résultant de la pyrolyse d’une résine phénolique, les propriétés thermomécaniques des matériaux modèles élaborés ont été analysées à la fois pendant et après le traitement thermique de pyrolyse. L’évolution des propriétés au cours de la pyrolyse des échantillons réticulés a mis en évidence l’apparition d’un léger endommagement en fin de montée en température, et un endommagement plus prononcé lors du refroidissement. Cet endommagement résulte d’un différentiel de dilatation thermique entre les grains d'alumine et la liaison carbone. L'influence de ces effets microstructuraux sur le comportement mécanique des matériaux pyrolysés a été étudiée grâce à des essais de traction, mettant en évidence un comportement non-linéaire assez marqué. Des relations entre la fraction volumique et les propriétés physiques clés des matériaux ont pu être établies. Par ailleurs, les résultats obtenus ont montré qu’un changement de composition relativement peu important peut modifier radicalement les propriétés thermomécaniques de ces matériaux. Cette étude sur des matériaux modèles a permis de dégager des pistes pour une amélioration des compositions industrielles.The present thesis aimed at investigating the relationships existing between the microstructure of alumina-carbon refractories used in steel continuous casting and their thermomechanical properties. The work realized here fall within a composite approach, by determining thermomechanical properties of the single constituents of the materials and analyzing then the properties of the heterogeneous composites. Different systems of double scale model materials, constituted of graphite and alumina aggregates in one hand, and of carbon matrix loaded with fine alumina grains on the other hand were studied here. The carbon bond of these materials resulting from pyrolysis of phenolic resin, the thermomechanical properties of the elaborated model materials were analyzed both during and after the pyrolysis heating treatment. The properties evolutions of the cured samples during the pyrolysis highlighted a slight damage during the end of heating and important damage during cooling, due to a thermal expansion mismatch between the alumina grains and the resin/carbon bond. The influence of the thermal damage has been investigated thanks to tensile tests on the pyrolyzed materials, which exhibit a rather strong non-linear behavior. Relationships between volume fraction and physical key-properties of the materials have been established. Besides, the obtained results highlighted that a small change in composition can drastically change the thermomechanical properties of these materials. This overall study on model materials allowed to develop some ideas in order to improve industrial compositions

Le pharmacien face aux médicaments à risque pendant l'allaitement maternel

L allaitement est très important pour le bébé et pour sa mère ; c est pourquoi la mise en place d une thérapeutique pour une femme allaitante ne doit pas être systématiquement considérée comme une barrière. Si l instauration de médicaments s avère indispensable, la décision de maintenir l allaitement dépend du médecin mais aussi du pharmacien. Celui-ci se doit notamment de détecter toute contre-indication à l allaitement s il se trouve face à un conseil ou à une prescription médicale. Le pharmacien doit dans tous les cas donner une réponse à la mère allaitante la plus fiable possible compte-tenu des connaissances actuelles. La décision devra toujours être prise en fonction du rapport entre le bénéfice pour la mère et le risque pour le nourrisson. Cette thèse a pour objet de regrouper les médicaments à risque pendant l allaitement et de guider le pharmacien dans sa prise de décision.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Compréhension élémentaire des propriétés physiques des matériaux compositesréfractaires à matrice carbonée

National audienceDe nos jours, la production d’acier avec des propriétés améliorées devient essentielle, mais presque impossiblesans le progrès dans la connaissance des matériaux réfractaires à matrice carbonée. Ces matériaux sont confrontés à desconditions sévères d’utilisations et font face à des contraintes thermomécaniques élevées et à la corrosion de l’acier enfusion. Ces matériaux réfractaires doivent donc avoir des propriétés spécifiques telles qu’une faible dilatation entempérature et un module d’Young peu élevé, une haute conductivité thermique et une faible réactivité chimique avecl’acier afin d’avoir une bonne résistance aux chocs thermiques. Certaines familles de réfractaires notamment celles àmatrice carbonée présentent un comportement mécanique non-linéaire en service, du fait de leur structure spécifique,même lorsque ces matériaux sont testés à température ambiante. Comparativement à des matériaux ayant uncomportement mécanique linéaire, cette caractéristique entraîne une valeur élevée de la déformation à la rupture,couplée avec une contrainte à la rupture plus faible. Par conséquent, une meilleure compréhension de ces matériaux, enparticulier des interactions entre leurs différents composants et de leur influence sur les propriétés thermo-physiquesmacroscopiques est vital.Afin de parvenir à cette compréhension, des matériaux modèles à matrice carbonée, utilisant des précurseursorganiques pour la matrice et des oxydes comme charge minérale ont été élaborés, en vue de comprendre lesinteractions entre la matrice carbonée et les particules d’oxyde. Les matériaux ont été étudiés grâce à différentesméthodes de caractérisation, tel que la microscopie électronique à balayage, le module d’Young et l’analyse dedilatation thermique. En fonction de la fraction volumique d’oxyde, il apparaît deux types de structures différentes : lapremière consiste en une matrice carbonée amorphe contenant des particules d’oxyde bien dispersées et l’autre est unréseau de particules d’oxyde connectées entre elles, liées par le carbone amorphe. En raison de la différence dedilatation entre le carbone amorphe et les particules d’oxyde, des microfissures se sont développées dans lamicrostructure soit au niveau des interfaces carbone/oxyde, soit au sein de la matrice carbonée elle-même. Les résultatsprésentés sur ces matériaux modèles ont révélés que les propriétés thermomécaniques de ces matériaux peuvent êtreconçues en adaptant la microstructure

The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

<div><p>Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. <i>Chop</i>-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. <i>Chop</i>-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.</p></div

CHOP is induced by fibrotic insult and promotes fibrosis.

<p>(A) CCl₄ injection promotes collagen deposition. Masson's trichrome staining was used to assess collagen deposition (blue) in formalin-fixed paraffin-embedded liver sections of mice injected i.p. with 10% CCl₄ twice a week for 12 weeks, or with mineral oil as a control. (B–C) CHOP expression is associated with CCl₄-challenged livers. (B) CHOP was detected by IHC in mouse livers from (A) and samples were counterstained with hematoxylin as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#pgen-1003937-g001" target="_blank">Figure 1C</a>. Representative data are shown. (C) The number of CHOP-positive nuclei per microscopic field from (B) was quantitated in multiple fields from 3 mice per group, and is expressed here as mean +/− S.E.M. per field. (D–E) <i>Chop</i> deletion attenuates DEN-induced fibrosis. Mild-to-moderate fibrosis is seen in wild-type but not <i>Chop</i>−/− livers by trichrome staining after DEN treatment as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#pgen-1003937-g002" target="_blank">Figure 2</a>. Sections from two separate DEN-treated animals of each genotype are shown. (E) A METAVIR score was blindly determined from trichrome stains as described in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#s4" target="_blank">Materials and Methods</a>, and the p-value was calculated by Asymptotic Wilcoxon Rank Sum Test. 0 = no fibrosis; 1 = portal fibrosis lacking septa; 2 = portal fibrosis with some septa; 3 = abundant septa; 4 = cirrhosis.</p

CHOP promotes hepatocellular apoptosis and proliferation.

<p>(A) <i>Chop</i>−/− mice show reduced cell death upon DEN challenge. Apoptosis in vehicle- or DEN-treated livers of wild-type or <i>Chop</i>−/− mice was detected by IHC staining for the cleaved form of Caspase-3. Liver nodule borders are indicated by a dashed outline. Hematoxylin counterstain is not shown because it interfered with Caspase-3 staining. In (A–C), representative images are shown. (B–D) Reduced proliferation in <i>Chop</i>−/− DEN-challenged animals. Hepatocellular proliferation was detected by IHC staining for PCNA (B) or Ki-67 (C). (D) The extent of PCNA and Ki-67 staining was quantitated blindly as described in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#s4" target="_blank">Materials and Methods</a>. P-values were determined by Asymptotic Wilcoxon Rank Sum Test.</p

CHOP is expressed in human HCC tumors.

<p>(A) Histology of tumor-proximal liver (uninvolved HCC) and tumor (two regions) tissue from the same patient. H&E images are representative of 28 tumor samples and 5 uninvolved matched controls. For (A) only, scale bar = 100 µm (B–C) CHOP immunostaining is associated with human HCC but not uninvolved regions. (B) Samples from uninvolved tumor-proximal tissue and HCC tumors were probed for CHOP expression by immunohistochemistry. CHOP-positive nuclei are indicated by arrowheads. Cellular and nuclear architecture in some HCC samples was distorted as seen in the non-counterstained image, accounting for the large nuclei. Scale bar = 50 µm. (C) The average number of CHOP-positive nuclei per microscopic field per patient was quantitated blindly from 5 HCC tumors and their uninvolved matched controls, as well as from 4 non-HCC specimens, and these were aggregated by Boxplot. P-values were calculated by Asymptotic Wilcoxon Rank Sum Test. (D) HCC-associated CHOP is expressed in hepatocytes. Expression of CHOP (brown) and cell type-specific markers (blue) for hepatocytes (cytokeratin-18), macrophages (CD68), bile ducts (cytokeratin-7), or activated stellate cells (smooth muscle actin) is shown by immunohistochemistry, with a hematoxylin counterstain applied. Representative data are shown. Note that only hepatocytes show CHOP-positive nuclei; arrowheads are used to show CHOP-positive cells in other samples. Scale bar = 50 µm. Insets show 25 µm×25 µm regions with distinct CHOP-positive nuclei.</p

Microarray profiling reveals CHOP-dependent differences in inflammation and ribosomal biogenesis genes.

<p>(A) Basal expression differences in <i>Chop</i>−/− mice. 18,138 significantly expressed genes were analyzed using Illumina MouseRef-8 v2.0 BeadChips, with total RNA from 9 month old mouse liver homogenate as input. The number and percentage of genes upregulated (upper left) and downregulated (lower right) in wild-type versus <i>Chop</i>−/− tissue is shown, showing only genes differing by 1.5-fold or more, p<0.05. Expression is given on a log₂ scale. In (A), (D), and (E), the position of <i>Chop</i> is shown as a yellow-filled circle. (B–C) Suppressed basal expression of genes involved in immune and inflammatory pathways in <i>Chop</i>−/− mice. (B, top) GO pathways enriched among all regulated genes in PBS-treated wild-type versus <i>Chop</i>−/− animals were determined using DAVID, with all pathways that were significantly enriched after Bonferroni correction shown. (B, bottom) Same as (top), but considering only genes downregulated in <i>Chop</i>−/− animals. (C) Average array-determined expression of genotype-dependent immune- and inflammation-related genes from PBS-treated animals is shown on a log₂ scale +/− S.D.M. All genes shown are differentially expressed >1.5-fold (i.e., >0.585 on the y-axis), p<0.05. (D) DEN treatment alters gene expression in wild-type mice. Scatter plot of all genes differentially expressed (>1.5-fold; p<0.05) in tumors from 9 month-old DEN-treated wild-type animals versus normal liver tissue in age-matched PBS-treated wild-type animals. The positions of <i>Nfe2</i>, <i>Cyclin D1</i> (<i>Ccnd1</i>), and <i>β-catenin</i> are indicated by red diamonds. (E–F) Uniform upregulation of genes involved in ribosome biogenesis in tumors from <i>Chop</i>−/− mice. (E) Scatter plot of gene expression from tumor tissue of DEN-treated wild-type animals compared to <i>Chop</i>−/− animals is presented, showing all genes differing by >1.5-fold, p<0.05. (F) Average expression of all ribosomal subunit genes that were significantly different (p<0.05, fold-change >1.5) in <i>Chop</i>−/− versus wild-type large tumors is shown on a log₂ scale +/− S.D.M. as in (C).</p

CHOP is upregulated in a genetic mouse model of HCC.

<p>(A) eIF2α-dependent genes are upregulated in tumors induced by <i>SB</i> mutagenesis. Relative expression of the indicated UPR genes in tumors versus normal mouse liver tissue, as quantified by transcriptome sequencing. Sequencing was performed on total RNA from mouse liver tumors generated by T2/Onc3 transposition into the <i>Rtl1</i> locus (n = 8) and age-matched normal liver tissue (n = 7). The branch of UPR signaling to which each gene is most responsive is indicated. Here and in (B), error bars represent means +/− S.D.M. Here and elsewhere: *, p<0.05; **, p<0.01; ***, p<0.001. (B) qRT-PCR of <i>SB</i>-induced tumors confirms upregulation of <i>Chop</i>. Relative expression of the indicated genes quantitated by qRT-PCR from tumors arising from T2/Onc3 <i>Rtl1</i> locus integrants (n = 7), compared to expression in normal tissue (n = 5). Relative expression of total (tot) and spliced (spl) <i>Xbp1</i> mRNA is also shown. mRNA levels were normalized against average expression of 2 housekeeping genes (<i>Btf3</i> and <i>Ppia</i>). (C and D) CHOP and BiP expression, respectively, in tumors from <i>Rtl1</i> locus integrants and normal liver tissue from age-matched control animals using IHC. Also shown for CHOP staining are hematoxylin-counterstained samples, with exemplar CHOP-positive nuclei indicated by arrowheads. All scale bars throughout this work represent 50 µm unless indicated otherwise. The same anti-mouse immunoglobulin secondary antibody was used for both CHOP and BiP immunostains.</p

Model for the role of CHOP in HCC.

<p>The simplest interpretation of the data presented is a linear pathway whereby CHOP promotes apoptosis, which in turn activates inflammatory signaling, leading to fibrosis, compensatory proliferation, and ultimately tumorigenesis. Fibrosis and cellular transformation might in turn exacerbate cellular stress and CHOP expression, amplifying the tumor-promoting function of CHOP.</p