Background Evaluating potential genotoxicity of pharmaceutical drug candidates is important during drug development. A method that can be used for this purpose is the micronucleus assay (MN- assay) which can identify agents that induce chromosomal damage. One of the most commonly used cell lines in an in vitro MN-assay is Chinese Hamster Ovarian K1 (CHO-K1) cells. Propolis, a natural substance produced by honeybees from exudates of different types of plant, is used in folk medicine to improve health and prevent diseases and was the evaluated substance in this study. Aim The major aim of this thesis project was to evaluate the potential cytotoxic and genotoxic effects of propolis in CHO-K1 cells by in vitro MN-assay. Method Two solutions of propolis were prepared in different ways and CHO-K1 cells were cultured. The two different ethanolic extracts of propolis were evaluated with the cytochalasin B protocol of the MN-assay, using mitomycin C as a positive control. Results Ethanolic extract number 1 had a statistically significant increase of genotoxicity at 50 μg/ml and 100 μg/ml. It was also found to induce a statistically significant increase of cytotoxicity at all concentrations tested (5-100 μg/ml). Ethanolic extract number 2 had a statistically significant increase of genotoxicity at 50 μg/ml but no statistically significant increase of cytotoxicity. General conclusion Rather surprisingly, the present study showed that propolis induced chromosomal damage in CHO-K1 cells, and one of the extracts tested was also found to be cytotoxic using the cytochalasin B version of the in vitro MN-assay.

Uses rule based AI (forward and backward chaining) to model legal decision making by judges. / AI to model legal decision making (c) Eric Engle

Les quantum dots (QDs) sont des cristaux semi-conducteurs de dimensions nanométriques. Ils peuvent être employés comme des marqueurs photosensibles du métabolisme cellulaire et peuvent être utiles dans différents domaines notamment en médecine mais il s’est rapidement avéré nécessaire de démontrer leur innocuité avant leur utilisation à grande échelle et leur diffusion dans l’environnement. Nous proposons un projet de thèse de doctorat sur le thème : La génotoxicité des quantum dots et le rôle du stress oxydant, implications sur l’environnement et la santé humaine. Il s’organise suivant trois axes: L’étude in vitro des propriétés génotoxiques et mutagènes des QDs Les QDs induisent des lésions primaires de l’ADN sur cellules CHO-K1 par le test des comètes qui sont associées à un stress oxydant. Ils sont plus actifs après irradiation par le spectre solaire. Ils induisent des mutations chromosomiques. L’étude in vivo des propriétés génotoxiques et mutagènes des QDs Les QDs induisent une augmentation significative des lésions de l'ADN chez le rat qui varie selon l’organe considéré (foie, rein, poumon, cerveau et testicule). Ils induisent une augmentation significative et une réponse dose-dépendante des micronoyaux indiquant nettement leur pouvoir clastogène/aneugène. Aucune variation significative des variables biochimiques mesurées n’est apparue. La mise en évidence de leurs effets sur l’environnement L'exposition aux QDs et au CdCl2 a entraîné une augmentation significative des lésions de l'ADN chez E. fetida et N. diversicolor. / Quantum dots (QDs) are semiconductor nanocrystals which can be employed as sensitive biomarkers of cellular metabolism and thus show their usefulness in various fields, including medicine and it soon became necessary to prove their safety before their widespread use and their distribution in the environment. The thesis project targeted on: Genotoxicity of quantum dots and the role of oxidative stress implications for the environment and human health. This study was organized in three main parts The in vitro study of the genotoxic and mutagenic properties of QDs QDs induced primary DNA lesions in CHO-K1 cells using the comet assay and were associated with oxidative stress. We demonstrated that the QDs were more active after irradiation by the solar spectrum. We showed the ability of QDs to induce chromosomal mutations. The main mechanism was probably that of the production of free radicals. The in vivo study of the genotoxic and mutagenic properties of QDs The comet assay shows that QDs induced an overall significant increase in DNA lesions of different organs (liver, kidneys, lungs, brain and testes). However, each organ had a specific susceptibility. QDs induced a significant increase in a dose-dependent manner of micronuclei. These results clearly indicated the in vivo clastogenic / aneugenic properties of QDs. No significant variation in the measured biochemical variables. The evidence of their effects on the environment Evaluation of genotoxicity was performed on coelomocytes of E. fetida and N. diversicolor resulting in a significant increase in DNA damage.

La apoA-I cumple un rol muy importante en el transporte reverso del colesterol (TRC), es el componente mayoritario de las lipoproteínas de alta densidad (HDL) que desempeñan diversas funciones en las distintas etapas del TRC. Resultados previos de este laboratorio permiten postular la hipótesis de que la región central de la apoA-I, formada por el par de hélices tipo Y, estaría involucrada en la interacción con la membrana celular, que sería importante para el eflujo de lípidos y la movilización de depósitos intracelulares de colesterol (como el disponible a ser esterificado por ACAT) hacia la membrana plasmática. Como la conformación del dominio central es influenciada por el tamaño y composición lipídica (contenido de colesterol) de las HDL, también se postula que esto podría modular la capacidad de interacción con la membrana celular y el consecuente eflujo lipídico. El objetivo general de este trabajo fue someter a prueba esta hipótesis y aportar información relevante para entender los mecanismos implicados en las etapas iniciales del TRC, como en la interacción de las HDL con membranas celulares y el eflujo celular de lípidos. Como objetivos específicos, nos propusimos: 1) Reconstituir partículas discoidales HDL similares a las pre-β-HDL del plasma, de diferente composición y tamaño, mediante la técnica de diálisis con el detergente colato. Estas fueron comparadas en cuanto a su capacidad de unirse a la membrana celular, y de promover el eflujo de colesterol y fosfolípidos de dos líneas celulares diferentes: CHO-K1 (células de ovario de hámster chino) y RAW 264.7 (macrófagos murinos). 2) Estudiar en comparación con apoA-I salvaje, la funcionalidad y las respuestas celulares a dos mutantes de deleción de un residuo de lisina en las regiones de hélices tipo Y: una con la deleción en la región central de la hélice 4 (ΔK107) y la segunda con la deleción en la posición homóloga de la hélice 10 (ΔK226). La primera de estas mutantes es una variante natural cuyos portadores presentan un metabolismo alterado de las HDL e incrementado riesgo aterogénico, por lo que los resultados de estos estudios también podrían ayudar a la comprensión de los síntomas presentados por estos pacientes. Es de esperar que estas mutaciones desplacen en ~100º la orientación relativa entre las caras hidrofílica e hidrofóbica de la hélice anfipática a ambos lados de la mutación, lo que puede afectar tanto la interacción con lípidos como con los receptores celulares.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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The purpose of this study was to evaluate the stability of vitamin K1 oral liquids in Sterile Water for Injection when stored in amber glass bottles and amber plastic syringes under refrigerated conditions. Four 100-mL batches of vitamin K1 in Sterile Water for Injection were prepared in amber glass bottles to protect from light. One of the batches was divided into 1-mL aliquots, using amber plastic oral syringes, and capped. The prepared bottles and syringes were stored in a laboratory refrigerator. On each day of sampling, 1-mL aliquots were removed from each bottle and mixed with an equal volume of ethanol. Likewise, the contents of sample syringes were mixed with ethanol to achieve an assay concentration of 0.5 mg/mL. Recovery of vitamin K1 in the compounded samples was quantified against a United States Pharmacopeia reference standard. Quantification was achieved using a stability-indicating high-performance liquid chromatography with ultraviolent light detection method. Product stability is defined as 90% to 110% of the initial concentration. The percent recovery in the Sterile Water for Injection preparations in glass bottles remained above 90% for the 105-day duration of the study, but some samples stored in amber plastic syringes fell below 90% on day 21. Furthermore, a statistically significant difference (2-way ANOVA, P < 0.0001) emerged between syringes at day 0 and day 30, and this trend continued through the day 60, 90, and 105 samples. The only statistically significant difference found within the bottle-stored samples occurred on day 105 (versus zero, P = 0.0465), but the recovery on day 105 still exceeded 90%. Vitamin K1 in Sterile Water for Injection, stored in a refrigerated amber glass bottle, is stable for 105 days. This preparation can also be stored in amber plastic syringes, but this decreases the beyond-use date to 14 days.

La désintégration radiative du méson B en méson étrange axiale, B--> K1(1270) gamma, a été observée récemment avec un rapport d'embranchement assez grand que B--> K* gamma. Ce processus est particulièrement intéressant car la désintégration du K1 dans un état final à trois corps nous permet de déterminer la polarisation du photon, qui est surtout gauche (droit) pour Bbar(B) dans le Modèle Standard tandis que des modèles divers de nouvelle physique prédisent une composante droite (gauche) supplémentaire. Dans cette thèse, une nouvelle méthode est proposée pour déterminer la polarisation, en exploitant la distribution totale du Dalitz plot, qui semble réduire considérablement les erreurs statistiques de la mesure du paramètre de la polarisation lambda_gamma.Cependant, cette mesure de la polarisation nécessite une connaissance détaillée de la désintégration forte K1--> K pi pi : c'est-à-dire l'ensemble complexe des différentes amplitudes d'ondes partielles en plusieurs canaux en quasi-deux-corps ainsi que leurs phases relatives. Un certain nombre d'expériences ont été faites pour extraire ces informations bien qu'il reste divers problèmes dans ces études. Dans cette thèse, nous étudions en détail ces problèmes en nous aidant d'un modèle théorique. Nous utilisons ainsi le modèle 3P0 de création d'une paire de quarks pour améliorer notre compréhension des désintégrations fortes du K1.A partir de ce modèle nous estimons les incertitudes théoriques : en particulier, celle venant de l'incertitude de l'angle de mélange du K1, et celle due à l'effet d'une phase ``off-set'' dans les désintégrations fortes en ondes-S. Selon nos estimations, les erreurs systématiques se trouvent être de l'ordre de sigma(lambda_gamma)^th<20%. D'autre part nous discutons de la sensibilité des expériences futures, notamment les usines SuperB et LHCb, pour lambda_gamma. En estimant naïvement les taux annuels d'évènements, nous trouvons que l'erreur statistique de la nouvelle méthode est sigma(lambda_gamma)^stat<10%, ce qui est deux fois plus petit qu'en utilisant seulement les distributions angulaires simples.Nous discutons également de la comparaison avec les autres méthodes de mesure de la polarisation en utilisant les processus tels que B--> K* e^+ e^-, Bd--> K* gamma et Bs--> phi gamma, pour la détermination du rapport des coefficients de Wilson C7gamma^‘eff/C7gamma^eff. Nous montrons un exemple de contraintes possibles sur C7gamma^‘eff/C7gamma^eff dans plusieurs scénarios de modèles supersymétriques. / Recently the radiative B-decay to strange axial-vector mesons, B--> K1(1270) gamma, was observed with a rather large branching ratio. This process is particularly interesting as the subsequent K1-decay into its three-body final state allows us to determine the polarization of the photon, which is mostly left(right)-handed for Bbar(B) in the Standard Model while various new physics models predict additional right(left)-handed components. In this thesis, a new method is proposed to determine the polarization, exploiting the full Dalitz plot distribution, which seems to reduce significantly the statistical errors on the polarization parameter lambda_gamma measurement.This polarization measurement requires, however a detailed knowledge of the K1--> K pi pi strong interaction decays, namely, the complex pattern of the various partial wave amplitudes into several possible quasi-two-body channels as well as their relative phases. A number of experiments have been done to extract all these information while there remain various problems in the previous studies. In this thesis, we investigate the details of these problems. As a theoretical tool, we use the 3P0 quark-pair-creation model in order to improve our understanding of strong K1 decays.Finally we try to estimate some theoretical uncertainties: in particular, the one coming from the uncertainty on the K1 mixing angle, and the effect of a possible ``off-set'' phase in strong decay S-waves. According to our estimations, the systematic errors are found to be of the order of sigma(lambda_gamma)^th<20%. On the other hand, we discuss the sensitivity of the future experiments, namely the SuperB factories and LHCb, to lambda_gamma. Naively estimating the annual signal yields, we found the statistical error of the new method to be sigma(lambda_gamma)^stat<10% which turns out to be reduced by a factor 2 with respect to using the simple angular distribution.We also discuss a comparison to the other methods of the polarization measurement using processes, such as B--> K* e^+ e^-, Bd--> K* gamma and Bs--> phi gamma, for the determination of the ratio of the Wilson coefficients C7gamma^‘eff/C7gamma^eff. We show an example of the potential constraints on C7gamma^‘eff/C7gamma^eff. in several scenarios of supersymmetric models.

Recently the radiative B-decay to strange axial-vector mesons, B--> K1(1270) gamma, was observed with a rather large branching ratio. This process is particularly interesting as the subsequent K1-decay into its three-body final state allows us to determine the polarization of the photon, which is mostly left(right)-handed for Bbar(B) in the Standard Model while various new physics models predict additional right(left)-handed components. In this thesis, a new method is proposed to determine the polarization, exploiting the full Dalitz plot distribution, which seems to reduce significantly the statistical errors on the polarization parameter lambda_gamma measurement.This polarization measurement requires, however a detailed knowledge of the K1--> K pi pi strong interaction decays, namely, the complex pattern of the various partial wave amplitudes into several possible quasi-two-body channels as well as their relative phases. A number of experiments have been done to extract all these information while there remain various problems in the previous studies. In this thesis, we investigate the details of these problems. As a theoretical tool, we use the 3P0 quark-pair-creation model in order to improve our understanding of strong K1 decays.Finally we try to estimate some theoretical uncertainties: in particular, the one coming from the uncertainty on the K1 mixing angle, and the effect of a possible ''off-set'' phase in strong decay S-waves. According to our estimations, the systematic errors are found to be of the order of sigma(lambda_gamma)^th<20%. On the other hand, we discuss the sensitivity of the future experiments, namely the SuperB factories and LHCb, to lambda_gamma. Naively estimating the annual signal yields, we found the statistical error of the new method to be sigma(lambda_gamma)^stat<10% which turns out to be reduced by a factor 2 with respect to using the simple angular distribution.We also discuss a comparison to the other methods of the polarization measurement using processes, such as B--> K* e^+ e^-, Bd--> K* gamma and Bs--> phi gamma, for the determination of the ratio of the Wilson coefficients C7gamma^'eff/C7gamma^eff. We show an example of the potential constraints on C7gamma^'eff/C7gamma^eff. in several scenarios of supersymmetric models.