Thesis (M.S.)--University of Michigan, 1976.

Thesis (Ph. D.)--Northeastern University, 2008. / Bouvé College of Health Sciences, School of Pharmacy. Includes bibliographical references (p. 181-188).

Thesis (Ph.D.)--Northeastern University, 2008. / Bouvé College of Health Sciences, School of Pharmacy. Includes bibliographical references (p. 181-188).

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 143-181).

Thesis (doctoral)--University of Copenhagen, 1981. / Bibliography: p. 47-64.

Thesis (doctoral)--Lund University, 1998. / Thesis statement on t.p. verso. Includes bibliographical references.

A partir du constat que les discours scientifiques se prononcent souvent en faveur de l'intégration du numérique à l’école, allant dans le sens des instructions officielles, nous nous demandons alors pourquoi les différents rapports et enquêtes sur le sujet montrent que les enseignants en ont un usage limité. Nous analysons le décalage observé à partir de deux corpus. Le premier, constitué d'écrits de recherche, nous amène à questionner l'objectivité de ces dernier et à mieux cerner les fondements des périmètres de la recherche en sciences humaines sur le thème du numérique à l'école. Le deuxième corpus s'appuie sur des entretiens effectués avec des enseignants de collège. Loin de résister volontairement à l'usage des TIC en classe, ils expriment d'autres façons de comprendre, percevoir et s'approprier ces supports. Le dispositif ainsi forme autour des TIC révèle une situation plus complexe qu une simple opposition entre une institution coercitive et des enseignants résistants. / Based on the observation that scientific discourses are often in favour of digital technologies at school, following the line of official instructions, we wonder why different reports and inquiries show that teachers have limited uses. We analyse this discrepancy from two bodies of discourses. The first one, made of scientific writings, drives us to examine their objectivity and also to identify the theoretical bases and background in human sciences research about digital technologies at school. The second one relies on interviews made with teachers. Far from resisting on purpose to the uses of ICT, they express other ways to understand, perceive and appropriate these technologies. The so-formed dispositif reveals a much more complex situation than a mere opposition in-between a coercive institution and resistant teachers.

In this dissertation, the extraordinary magnetoresistance (EMR) effect in semiconductor/metal hybrid structures is studied to improve the performance in sensing applications. Using two-dimensional finite element simulations, the geometric dependence of the output sensitivity, which is a more relevant parameter for EMR sensors than the magnetoresistance (MR), is studied. The results show that the optimal geometry in this case is different from the geometry reported before, where the MR ratio was optimized. A device consisting of a semiconductor bar with length/width ratio of 5~10 and having only 2 contacts is found to exhibit the highest sensitivity. A newly developed three-dimensional finite element model is employed to investigate parameters that have been neglected with the two dimensional simulations utilized so far, i.e., thickness of metal shunt and arbitrary semiconductor/metal interface. The simulations show the influence of those parameters on the sensitivity is up to 10 %. The model also enables exploring the EMR effect in planar magnetic fields. In case of a bar device, the sensitivity to planar fields is about 15 % to 20 % of the one to perpendicular fields. 5 A “top-contacted” structure is proposed to reduce the complexity of fabrication, where neither patterning of the semiconductor nor precise alignment is required. A comparison of the new structure with a conventionally fabricated device shows that a similar magnetic field resolution of 24 nT/√Hz is obtained. A new 3-contact device is developed improving the poor low-field sensitivity observed in conventional EMR devices, resulting from its parabolic magnetoresistance response. The 3-contact device provides a considerable boost of the low field response by combining the Hall effect with the EMR effect, resulting in an increase of the output sensitivity by 5 times at 0.01 T compared to a 2-contact device. The results of this dissertation provide new insights into the optimization of EMR devices for sensor applications. Two novel concepts are presented, which are promising for realizing EMR devices with high spatial resolution and for opening new applications for EMR sensors in the low-field regime.

Obesity can lead to Type 2 Diabetes, both conditions increase in association with physical inactivity and high-energy diets, resulting in elevated blood glucose, decreased insulin sensitivity and increased insulin resistance. Sutherlandia frutescens (S.frutescens), an anti-diabetic plant, reverses and prevents insulin resistance in a rat model and human cell culture model. Gene expression analysis in hepatocyte cultures, identified genes down regulated in insulin resistance and up regulated by S.frutescens. These included genes encoding vesicle transporter proteins, hypothesised to be linked to hepatic lipid accumulation and lipid droplet formation during insulin resistance. The aim of this study was to investigate critical genes involved in lipid droplet formation, vesicle assembly and transport in high fat diet (HFD)-induced insulin resistant rat liver tissue during the development of insulin resistance and the reversal of these changes by S.frutescens. Rats were fed a low fat diet (LFD) or HFD supplemented with S.frutescens for 2, 4 and 8 weeks. Rats fed a HFD for 12 weeks developed insulin resistance, confirmed by plasma glucose and insulin levels (compared to normal controls). Groups of these rats were gavaged with S. frutescens (50mg/kg BW), Metformin (13mg/kg BW) or water for a further 4 weeks and starved for 12 hours, anaesthetized and blood removed by heart puncture. Liver was stored in RNA-Later™ for qRT-PCR and snap-frozen in liquid nitrogen for western blotting and confocal microscopy analysis. Changes in expression of vesicle transporter genes VAMP3 and NSF were analysed by qRT-PCR and changes in the protein expression by western blotting analysis. Proteins were localised within the liver by confocal immunohistochemistry using ZEN lite™ software. Statistical analysis was performed using One-Way ANOVA and unpaired t-test. mRNA gene expression of vesicle transport components VAMP3, NSF and SNAP25 showed relatively moderate changes with considerable individual variation within control or experimental groups. Uncorrelated changes in mRNA and protein products were found and may be due to differential regulation by siRNA. Proteins also showed altered staining patterns in high fat diet rats that reverted towards normal on S. frutescens treatment, potentially reflecting functional changes associated with transport of lipid-filled vesicles.

Les gliomes sont des tumeurs du système nerveux central. Leur plus haut degré de malignité est le glioblastome (GBM), le plus fréquent des cancers du cerveau. Les patients atteints de GBM sont d’abord opérés (si possible) puis traités par la radiothérapie avec témozolomide concomitant et adjuvant. Ce traitement n’est cependant pas curatif, en partie en raison d’une radiorésistance primaire élevée des cellules de GBM. La voie de signalisation JAK/STAT3 (Janus Kinase/Signal Transducer and Activator of Transcription 3) semble contribuer à la gravité des GBM. STAT3 est une protéine intracellulaire de transduction du signal. Elle est activée par phosphorylation de ses résidus tyrosine 705 (pSTAT3-Y705) et sérine 727 (pSTAT3-S727). L’activation de la tyrosine 705 se produit en aval du signal induit par la liaison de la cytokine interleukine 6 (IL-6) à son complexe récepteur transmembranaire gp130-IL-6Rα. Les mécanismes d’activation de la sérine 727 sont moins bien caractérisés. Le rôle de l’activation de STAT3 dans la radiorésistance des GBM a été ici étudié. Une évaluation du niveau basal de pSTAT3-Y705, pSTAT3-S727 et de la radiorésistance intrinsèque a été faite sur un panel de 15 lignées de GBM humain. L’activation de STAT3 dans les lignées cellulaires de gliomes a été évaluée par western blot et la radiorésistance par la survie cellulaire à l’irradiation. En plus de la description de l’état basal d’activation de STAT3 dans les lignées cellulaires de gliomes, cette étude a mis en évidence pour la première fois, une corrélation de pSTAT3-S727 avec la radiorésistance intrinsèque des GBM. Une stratégie de blocage pharmacologique de STAT3 nous a permis d’identifier le Gö6976 comme inhibant la phosphorylation Y705 de STAT3 dans les cellules de GBM. Celui-ci s’est avéré inhiber aussi la phosphorylation S727 mais seulement dans les lignées de GBM pSTAT3-Y705 négatives. Le traitement par le Gö6976 ralentit la croissance des cellules de GBM, indépendamment du statut d’activation de STAT3. De façon intéressante, le Gö6976 a montré un pouvoir radiosensibilisant très significatif sur les lignées pSTAT3-Y705 négatives, ce qui est concordant avec la baisse du niveau de pSTAT3-S727. La pertinence de ces résultats est confortée par un marquage immunohistochimique sur des échantillons cliniques de GBM, montrant la présence à des degrés variables de pSTAT3-S727 dans toutes les cellules cancéreuses de tous les patients. En parallèle, une étude in vitro des fonctions de pSTAT3-S727 utilisant des dominants positif et négatif est en cours. En somme, nous avons démontré que pSTAT3-S727 participe à la radiorésistance intrinsèque et que pSTAT3-Y705 est un marqueur prédictif négatif de la réponse des cellules de GBM au Gö6976 à la fois comme inhibiteur de pSTAT3-S727 et radiosensibilisant. L’ensemble de nos résultats conforte l’intérêt d’une inhibition spécifique de pSTAT3-S727 pour radiosensibiliser les GBM et ainsi améliorer le traitement des patients. / Gliomas are tumors of the central nervous system. The highest degree in glioma malignancy is Glioblastoma (GBM) that is the most frequent of the brain cancers. GBM patients are treated by surgery at first (if it is possible), followed by radiotherapy and concomitant and adjuvant temozolomide. However, this treatment is not curative in part because GBM cells display an outstanding primary radioresistance. The JAK/STAT3 (Janus Kinase/Signal Transducer and Activator of Transcription 3) signaling pathway seems to be involved in the GBM aggressiveness. STAT3 is an intracellular signal transducer protein. It is activated by phosphorylation on its tyrosine 705 (pSTAT3-Y705) and serine 727 (pSTAT3-S727) residues. The tyrosine 705 activation is produced downstream the signal induced by the binding of interleukine-6 (IL-6) cytokine to its gp130-IL-6Rα transmembrane receptor complex. The mechanisms of the serine 727 phosphorylation are less characterized. The role of STAT3 activation in the radioresistance of GBM was studied here. Basal levels of pSTAT3-Y705, pSTAT3-S727 and intrinsic radioresistance were evaluateded in a panel of 15 GBM cel lines. Activation of STAT3 in the glioma cell lines was assessed by western blotting and radioresistance through cell surviving fraction to irradiation. In addition to the description of the basal activation of STAT3 in the glioma cell lines, this study evidenced, for the first time, a correlation between pSTAT3-S727 and GBM intrinsic radioresistance. Using a pharmacological inhibition strategy, we identified Gö6976 as a chemical blocking Y705 phosphorylation of STAT3 in GBM cells. Gö6976 also inhibited pSTAT3-S727 but only in the pSTAT3-Y705-negative cell lines. Treating GBM cell with Gö6976 slowed their growth regardless of STAT3 activation status. Interestingly, Gö6976 showed a highly significant radiosensitizing effect on pSTAT3-Y705-negative cell lines that was consistent with the down-modulation of pSTAT3-S727. The relevance of these results is strengthened by immunohistochemical assay performed of GBM clinical samples that showed a variable level of pSTAT3-S727 positive staining in all tumor cells of all the patients. Furthermore, we are currently running on an in vitro study of the pSTAT3-S727 biological function by the mean of STAT3 dominant positive and dominant negative proteins. In summary, we showed that pSTAT3-S727 is involved in the intrinsic radioresistance and that pSTAT3-Y705 is a negative predicting marker of GBM cell response to Gö6976 as both a pSTAT3-S727 inhibitor and a radiosensitizer. Altogether, our results strengthen the clinical relevance of a specific inhibition of pSTAT3-S727 to radiosensitize GBM and then improve the patient treatment.