Le travail réalisé au cours de cette thèse concerne le développement du système de bobines de l'expérience n2EDM à l'Institut Paul Sherrer (PSI). Le but de cette expérience est de mettre en évidence de nouvelles sources de violation CP à travers la mesure du moment dipolaire électrique du neutron. L'actuelle limite supérieure sur la mesure de nEDM, $2.9 \cross 10^{-26}$ e.cm (90\% C.L.) à été obtenue par la collaboration RAL-Sussex-ILL en 2006.L'expérience n2EDM vise à améliorer d'un ordre de grandeur la sensibilité statistique en gardant sous contrôle les effets systématiques. Cela requiert la production d'un champ magnétique très uniforme. Les non-uniformités de ce dernier sont en effet responsable de la dépolarisation des neutrons et impliqués dans plusieurs effets systématiques.Dans le premier chapitre, les motivations physiques sont discutées.Le second chapitre décrit le principe de mesure de l'expérience n2EDM, ainsi que l'importance de l'uniformité du champ magnétique. Le chapitre s'achève par une présentation globale du dispositif expérimental.Le troisième chapitre présente le logiciel COMSOL et discute du design et des performances de la bobine B$_{0}$, en charge de la production du champ magnétique principal.Dans le quatrième chapitre, le système de bobines correctrices chargées de corriger les non-uniformités du champ magnétique et celles devant produire des gradients spécifiques sont présentées.Finalement, le cinquième et dernier chapitre présente l'étude des dipôles magnétiques localisés et de leur influence sur l'expérience. / This work presents the design of the coils system developed for the n2EDM experiment at the Paul Sherrer Institute (PSI). The goal of this experiment is to reveal new sources of CP violation through the measurement of the neutron electric dipole moment. The current upper limit of the nEDM measurement, $2.9 \cross 10^{-26}$ e.cm (90\% C.L.) was achieved by the RAL-Sussex-ILL collaboration in 2006.The n2EDM experiment aims at improving by one order of magnitude the statistical sensitivity while keeping under control the systematics effects. It requires to produce a very uniform field, its non-uniformities being responsible of the neutron's depolarization and of severals systematic effects.In the first chapter, the theoretical motivation are discussed.The second chapter describes the measurement principle of the n2EDM experiment, as well as the importance of the magnetic field uniformity. This chapter ends by an overview of the apparatus.The third chapter introduces the COMSOL software and discuss the design and the performances of the B0 coil, in charge of the production of the main magnetic field.In the fourth chapter, the correcting coils used to suppress the non-uniformities of the magnetic field and the ones which produce specific gradients are presented.Finally, the fifth and last chapter talks about the study of localised magnetic dipoles and their influence on the experiment.

Sous réserve d’une énergie cinétique suffisamment faible, un neutron libre peut être piégé matériellement ou magnétiquement de sorte à garantir son confinement au sein d’un volume défini. Cette caractéristique permet l’étude de plusieurs paramètres, notamment de son temps de vie moyen. L’expérience HOPE, piège magnétique de neutrons ultra-froids mis en œuvre à l’Institut Laue Langevin à Grenoble, vise à fournir une valeur précise de ce temps de vie au travers de différentes méthodes. L’une d’entre elles consiste à observer les électrons émis par la décroissance bêta du neutron. Le détecteur SECOND a été spécifiquement conçu pour permettre le comptage de ces électrons au sein de l’expérience HOPE. La grande difficulté de ce projet réside dans le faible taux de comptage des électrons attendu, qui nécessite la discrimination des rayonnements parasites. Dans ce but, SECOND est constitué de deux étages de détection, dont le principal, un phoswich de scintillateurs plastiques, a donné des résultats probants lors de premiers tests fonctionnels à basse température ; la différenciation des événements induits par des muons cosmiques est efficace dans 98 % des cas, et tout porte à croire qu’elle sera considérablement améliorée par l’utilisation d’un système d’acquisition adapté à l’application souhaitée. / Considering a low enough kinetic energy, a free neutron can be materially or magnetically trapped in a defined volume. This trapping allows experimenters to study the neutron and its characteristics, and in this case, to measure its mean lifetime. The HOPE experiment commissioned at Laue Langevin Institute in Grenoble is aimed at providing a 1 %- accuracy value. One way to measure lifetime is to record every single neutron beta decay occurring in the trap by counting the emitted electrons. The detector SECOND has been specifically designed to fulfill this goal within HOPE but also to discriminate other types of particles that induce false events. The latter argument is the reason for the two detection stages SECOND is composed of. The plastic scintillators phoswich constitutes the main part of the detector and has been successfully operated during preliminary tests at low temperature. The rejection rate of cosmic muons events is about 98 %, and this value can be drastically enhanced using a more suitable data acquisition system.

The goal of this study is to determine whether SKI-606, a Src/abl inhibitor, potentiates chk1 inhibitor UCN-01 to induce apoptosis in multiple myeloma cells, and what mechanism maybe involved. We found that the co-exposure of human myeloma cells (e.g., U266, RPMI8226, MM.1S and its dexamethasone-resistant counterparts MM.1R) to minimally toxic concentration of SKI-606 (e.g., 1-2 ƒÝM) and UCN-01 (e.g., 100-150 nM) resulted in dramatic increase in mitochondrial damage and apoptosis. In our previous reports, it has been well demonstrated that activation of Ras/Raf/MEK/ERK pathway represents a critical cytoprotective response in cells exposed to UCN-01. Moreover, Src is required to activate this pathway by growth factors and cytokines. To this end, we examined whether the Src inhibitor enhances UCN-01 lethality through interruption of Ras/Raf/MEK/ERK signaling cascade. Firstly, it was found that co-adminstration of SKI-606 markedly diminished ERK phosphorylation/activation induced by UCN-01, accompanied by an increase in cdc2 activation. Furthermore, myeloma cells with ecpotic expression of either active mutant Ras (Q61L) or constitutive active MEK1 were significantly resistant to combined treatment with SKI-606 and UCN-01, indicating Src inhibition acts upstream of Ras/Raf/MEK to potentiate UCN-01 lethality. Conversely, stable expression of dominant-negative mutant Ras (S17N) markedly sensitized myeloma cells to this combination regimen. Lastly, ectopic expression of kinase inactive (K297R) or dominant-negative (K296R/Y528F) mutant Src blocked ERK activation by UCN-01 and thereby sensitized myeloma cells to UCN-01. Together, these findings indicate that Src inhibitors act through a Ras/Raf/MEK-dependent mechanism to prevent ERK activation in UCN-01-treated cells, resulting in the synergistic induction of cell death.

O CRF é um regulador do eixo HPA, gerando respostas neuroendócrinas, autônomicas, comportamentais ao estresse, assim como a Ucn-I. Os benzodiazepínicos agem por um efeito inibitório sobre o CRF e um efeito ainda discutido sobre a Ucn-I.Para análise das áreas relacionadas à resposta ao estresse pela imunorreatividade da proteína Fos, da expressão do mRNA do CRF e da Ucn-I, e dos efeitos do alprazolam, ratos foram submetidos aos estresses de restrição e eletrochoque, e ao alprazolam. No estresse de restrição as áreas com maior imunorreatividade da proteína Fos foram PVH e AMIme, e no estresse de eletrochoque foram AMIme e PAGdl. Com o alprazolam houve uma baixa imunorreatividade nas áreas PVH, PAGlat e CC no grupo restrição e, PVH, LSV e PAGlat no grupo choque, com alta imunorreatividade nas áreas EW e LSV no grupo restrição e PAGdl no grupo choque. O fármaco gerou uma diminuição da expressão do mRNA do CRF no PVH no grupo restrição e um aumento no grupo choque, e um aumento da expressão do mRNA da Ucn-I no EW no grupo restrição e uma diminuição no grupo choque. / The CRF is a regulator of the HPA axis, with neuroendocrine, autonomic and behavioral responses to the stress, such as the Ucn-I. The benzodiazepines performing an inhibitory effect on the CRF and a possibly effect on the Ucn-I. It was analyzed the stress related areas by Fos protein and the expression of the CRF and Ucn- I mRNA. Rats were submitted to the restraint and electroshock stress, and to the alprazolan. The restraint stress showed greater Fos-ir in the following areas PVH and AMIme and AMIme and PAGdl in the the electroshock stress. The alprazolam had an inhibition effect in the following areas PVH, PAGlat and CC in the restraint group, and PVH, LSV and PAGlat in the electroshock group. The alprazolan had an excitatory effect in the following areas EW and LSV in the restraint group, and PAGdl in the electroshock group. The alprazolan caused reduction of CRF mRNA in the PVH in the restraint group and increase in the electroshock group, and increase of Ucn-I mRNA in the EW in the restraint group, with reduction in the electroshock group.

O CRF é um regulador do eixo HPA, gerando respostas neuroendócrinas, autônomicas, comportamentais ao estresse, assim como a Ucn-I. Os benzodiazepínicos agem por um efeito inibitório sobre o CRF e um efeito ainda discutido sobre a Ucn-I.Para análise das áreas relacionadas à resposta ao estresse pela imunorreatividade da proteína Fos, da expressão do mRNA do CRF e da Ucn-I, e dos efeitos do alprazolam, ratos foram submetidos aos estresses de restrição e eletrochoque, e ao alprazolam. No estresse de restrição as áreas com maior imunorreatividade da proteína Fos foram PVH e AMIme, e no estresse de eletrochoque foram AMIme e PAGdl. Com o alprazolam houve uma baixa imunorreatividade nas áreas PVH, PAGlat e CC no grupo restrição e, PVH, LSV e PAGlat no grupo choque, com alta imunorreatividade nas áreas EW e LSV no grupo restrição e PAGdl no grupo choque. O fármaco gerou uma diminuição da expressão do mRNA do CRF no PVH no grupo restrição e um aumento no grupo choque, e um aumento da expressão do mRNA da Ucn-I no EW no grupo restrição e uma diminuição no grupo choque. / The CRF is a regulator of the HPA axis, with neuroendocrine, autonomic and behavioral responses to the stress, such as the Ucn-I. The benzodiazepines performing an inhibitory effect on the CRF and a possibly effect on the Ucn-I. It was analyzed the stress related areas by Fos protein and the expression of the CRF and Ucn- I mRNA. Rats were submitted to the restraint and electroshock stress, and to the alprazolan. The restraint stress showed greater Fos-ir in the following areas PVH and AMIme and AMIme and PAGdl in the the electroshock stress. The alprazolam had an inhibition effect in the following areas PVH, PAGlat and CC in the restraint group, and PVH, LSV and PAGlat in the electroshock group. The alprazolan had an excitatory effect in the following areas EW and LSV in the restraint group, and PAGdl in the electroshock group. The alprazolan caused reduction of CRF mRNA in the PVH in the restraint group and increase in the electroshock group, and increase of Ucn-I mRNA in the EW in the restraint group, with reduction in the electroshock group.

The primary objective of this study is to elucidate the mechanism by which the reagent UCN-01 induces apoptosis when administered to leukemia cells along with HmG-CoA reductase inhibitors, mainly the statins. In this study, we demonstrated that exposure of leukemia cell lines to lovastatin (20 uM, 18 hours) and UCN-01 (100 nM, 18 hours) resulted in mitochondria dysfunction, procaspase 3 and 9 cleavage, and PAW degradation along with marked cytochrome C release and apoptosis. Although similar molecular mechanisms have not yet been confirmed in other cancers, our hypothesis holds that enhanced apoptotic effects of UCN-01 are due in part to lovastatin's ability to block formation of geranylgeranylpyrophosphate and farnesylpyrophosphate by interfering with the rate-limiting step of the mevalonate pathway. Geranylgeranylpyrophosphate and farnesylpyrophosphate induce post-translational modifications in RAS that anchor the protein to the cell membrane so that it acts as a signal transducer to the nucleus, promoting cell proliferation.

The UCNA Experiment at the Los Alamos Neutron Science Center (LANSCE) is the first measurement of the β-decay asymmetry parameter A0 using polarized ultracold neutrons (UCN). A0 , which represents the parity-violating angular correlation between the direction of the initial neutron spin and the emitted decay electron’s momentum, determines λ = gA /gV , the ratio of the weak axial-vector and vector coupling constants. A high-precision determination of λ is important for weak interaction physics, and when combined with the neutron lifetime it permits an extraction of the CKM matrix element Vud solely from neutron decay. At LANSCE, UCN are produced in a pulsed, spallation driven solid deuterium source and then polarized via transport through a 7 T magnetic field. Their spins can then be flipped via transport through an Adiabatic Fast Passage spin flipper located in a low-field-gradient 1 T field region prior to transport to a decay storage volume situated within a 1 T solenoidal spectrometer. Electron detector packages located at each end of the spectrometer provide for the measurement of decay electrons. Previous UCNA results (based on data collected in 2010 and earlier) were limited by systematic uncertainties, in particular those from the UCN polarization, calibration of the electron energy, electron backscattering, and angular acceptance of events. This dissertation will present a background of neutron decay, an overview of the UCNA Experiment, followed by a detailed report on the entire analysis process for data acquired during run periods in 2011-2012 and 2012-2013.

No description available.

Our laboratory is primarily interested in novel pharmacological intervention of cell proliferation and survival pathways expressed in various types of cancer. These cyto-protective pathways can be activated in response to growth factor stimulation, toxic insult and radiation. In our studies, we utilized novel drug combinations with and without radiation to enhance breast & prostate tumor cell death both in vitro and in vivo. Previous studies from our group have shown that UCN-01 and MEK1/2 inhibitors interact to cause tumor cell death in transformed cell lines in vitro. We extended this observation to an in vivo animal model system using the estrogen dependent breast cell carcinoma line MCF-7 and the estrogen independent breast cell carcinoma line MDA-MB-231. This drug combination was shown to profoundly reduce tumor cell proliferation in vivo and also exhibited the ability to significantly reduce ex-vivo tumor cell colony formation 30 days after cessation of the combination drug treatment. In addition, tumor cell death coincided with decreased ERK112 phosphorylation, reduced immunoreactivity of Ki67 and CD31. Overall, these studies demonstrate that UCN-01 and MEK112 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase-3 levels or oncogenic K-RAS expression. In our LnCap prostate carcinoma cell studies we demonstrated the impact of hCG and lovastatin in combination with ionizing radiation to radiosensitize and enhance tumor cell lethality. This enhancement was attributed to the hCG-induced activation of ERBB1 via a GPCR, MEK112 and metalloprotease dependent paracrine mechanism which was further enhanced by radiation. This enhanced cell killing effect was shown to involve prolonged activation of PARP1 which could be suppressed by inhibition of ERBB1, MEKl , PI3 kinase or PARP1. Therefore, the combination of hCG, lovastatin and radiation may represent a novel approach to kill prostate cancer cells and potential new therapy.

A new measurement of the neutron electric dipole moment (nEDM) is being developed at TRIUMF, where a high density source of ultra cold neutrons (UCN) is currently under construction. A fast, high-efficiency UCN detector is needed for the experiment, and a 6-Li doped glass scintillation detector is being explored for this purpose. In this work, simulations and test measurements were carried out to optimize the light guide design for the new UCN detector. Acrylic and air-core light guides, the latter with two different reflecting surfaces, were considered. Three prototype light guides were constructed and tested, and results were compared with simulations. The best solution was found to be an acrylic guide, wrapped with mylar foil. For a guide 12 cm in length as required by the experimental layout, a lower limit of approximately 25 photoelectrons per neutron capture was established for the proposed geometry and photomultiplier configuration. / May 2016