The research presented in this dissertation involves the development of chiral and achiral analysis using capillary electrochromatography (CEC) and CEC coupled to mass spectrometry (CEC-MS). Chapter 1 briefly reviews CEC fundamentals and latest development on chiral CEC and CEC-MS. The CEC-UV enantioseparations for several acidic compounds are described in Chapter 2. The optimum resolutions for these acidic enantiomers are achieved in ion-suppression mode, i.e. with an acidic mobile phase. One of major drawback in coupling CEC with MS is the bubble formation at the column outlet end, resulting in irreproducible retention time and erratic baseline, or even current breakdown. By introducing internal tapered columns, the aforementioned limitations of CEC-MS are successfully overcome in Chapter 3. The CEC-MS enantioseparation of warfarin and coumachlor is carefully investigated and applied to quantify R- and S-warfarin in human plasma. For individual enantiomers, a concentration of 25 ng/mL is detectable. To further improve the robustness of CEC-MS column, a new procedure of fabricating internal tapered columns is reported in Chapter 4. These internal tapered columns demonstrate excellent ruggedness, low background noise, and good compatibility in reversed-phase and polar organic modes of CEC-MS. In chapter 5, the feasibility of using internal tapered columns packed with vancomycin chiral stationary phase (CSP) is explored for simultaneous enantioseparation of eight â-blockers using CEC-MS. After a careful optimization of the mobile phase composition, sheath liquid and spray chamber parameter, 15 out of 16 enantiomers could be simultaneously resolved with excellent efficiency and detection sensitivity. The synthesis and characterization of sulfated and sulfonated cellulose phenylcarbamate CSPs is described in Chapter 6. The use of these CSPs, especially the sulfonated one, significantly enhances the EOF profile and sample throughput but maintain high enantiomeric resolving power under various modes of CEC and CEC-MS. By combining CEC and atmospheric pressure photo-ionization (APPI) MS, Chapter 7 demonstrates the separation and detection of mono-methylated benzo[a]pyrene (MBAP) isomers with ~100 times enhancement on detection sensitivity than CEC-UV. In Appedix 2, monolithic columns are synthesized through photopolymerized sol-gel approach and utilized for CEC and CEC-APPI-MS of polyaromatic hydrocarbons, and alkyl phenyl ketones.

This dissertation contains a Hebrew edition and annotated Catalan translation of Isaac the Blind's (1165-1235) Commentary on the Book of Creation. The introduction introduces the historical context in which the author lived as well as some biographical data and the intellectual influence from Jewish Andalusian culture in the text. It further analyzes the relationship of the author's philosophy with other schools of thought, as the ones in Troyes and Paris, as well as his neoplatonic influences. It proceeds to a detailed analysis of the author's views on epistemology, cosmology and anthropology which, while act as breaking points with previous mystical views, at the same time they set the platform for the development of medieval kabbalah. / Aquesta tesi presenta el text en hebreu, i una traducció anotada al català del comentari escrit per Isaac el cec (1165-1235). L'estudi previ que acompanya la traducció introdueix el context històric en què va viure l'autor així com la seva biografia i les relacions que l'autor va tenir amb els corrents intel•lectuals provinents de l'Al-Andalus. Analitzem els referents culturals del mon cristià en l’obra, especialment les escoles de Troyes i París, així com la influència del neoplatonisme. La tesi estudia amb detall els aspectes epistemològic, cosmològic i antropològic del pensament de rabí Isaac, novedós perqué trenca amb concepcions precedents pel que fa a la divinitat, el cosmos, l’ésser humá i la seva relació amb la natura, establint així les bases pel desenvolupament del que serà la cabalà medieval.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20693号 / 工博第4390号 / 新制||工||1682(附属図書館) / 京都大学大学院工学研究科都市環境工学専攻 / (主査)教授 米田 稔, 教授 伊藤 禎彦, 准教授 松井 康人 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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No / The interleukin-2-deficient (IL-2¿/¿) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2¿/¿ mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2¿/¿ mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-B (p65) activation with the inhibitory p50 form of NF-B predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.

The explosive 2,4,6-trinitrotoluene (TNT) is currently a main ingredient in munitions; however the compound has failed to meet the new sensitivity requirements. The replacement compound being tested is 2,4-dinitroanisole (DNAN). DNAN is less sensitive to shock, high temperatures, and has good detonation characteristics. However, DNAN is more soluble than TNT, which can influence transport and fate behavior and thus bio-availability and human exposure potential. The objective of this study was to investigate the environmental fate and transport of DNAN in soil, with specific focus on sorption processes. Batch and column experiments were conducted using soils collected from military installations located across the United States. The soils were characterized for pH, electrical conductivity, specific surface area, cation exchange capacity, and organic carbon content. In the batch rate studies, change in DNAN concentration with time was evaluated using the first order equation, while adsorption isotherms were fitted using linear and Freundlich equations. Solution mass-loss rate coefficients ranged between 0.0002 h(-1) and 0.0068 h(-1). DNAN was strongly adsorbed by soils with linear adsorption coefficients ranging between 0.6 and 6.3 L g(-1), and Freundlich coefficients between 1.3 and 34 mg(1-n) L-n kg(-1). Both linear and Freundlich adsorption coefficients were positively correlated with the amount of organic carbon and cation exchange capacity of the soil, indicating that similar to TNT, organic matter and clay minerals may influence adsorption of DNAN. The results of the miscible-displacement column experiments confirmed the impact of sorption on retardation of DNAN during transport. It was also shown that under flow conditions DNAN transforms readily with formation of amino transformation products, 2-ANAN and 4-ANAN. The magnitudes of retardation and transformation observed in this study result in significant attenuation potential for DNAN, which would be anticipated to contribute to a reduced risk for contamination of ground water from soil residues.

INTRODUCTION : L’utilisation de la circulation extracorporelle durant la chirurgie cardiaque est associée à des problèmes pulmonaires chez certains patients. L’utilisation d’une pression pulsatile induite par un ballon intra-aortique (BIA) pourrait diminuer la dysfonction endothéliale et la survenue de tels événements. MATÉRIEL ET MÉTHODE : 12 porcs Landrace-Yorkshire ont subi une circulation extracorporelle et ont été divisés en deux groupes et 4 porcs ont servi de contrôles sans CEC. Le premier groupe (n=6) a bénéficié d’un flot pulsatile créé par un BIA en mode interne à 80 battements par minute durant les 90 minutes de l’opération alors que le second groupe (n=6) a subi une CEC standard. Après 60 minutes de reperfusion suivant la CEC, les valeurs hémodynamiques ont été évaluées dont les pressions artérielles, les pressions pulmonaires, l’index cardiaque et la concentration de glucose et de lactate. Les artères pulmonaires sont ensuite montées en chambre d’organe pour évaluer la fonction endothéliale. RÉSULTATS : Les porcs avec pression pulsatile ont tendance à produire moins de lactate sanguin après 60 minutes de reperfusion. Les autres valeurs hémodynamiques sont semblables. Finalement, la relaxation à la bradykinine est significativement meilleure dans le groupe pression pulsatile alors que la relaxation à l’acétylcholine n’est pas significativement différente. CONCLUSION : Ces résultats démontrent que la perfusion pulsatile produite par un BIA protège l’endothélium pulmonaire lors d'une CEC. Cet effet pourrait être dû à une augmentation du flot bronchique qui diminuerait l’ischémie pulmonaire ou à une diminution de la libération de cytokines et de bradykinine qui réduirait les dommages de reperfusion. / INTRODUCTION : Cardiopulmonary bypass (CPB) during cardiac surgery leads to postoperative pulmonary complications. The use of pulsatile pressure with an intra-aortic balloon pump (IABP) could preserve the endothelial function and decrease the occurence of pulmonary problems. MATERIAL AND METHODS : Twelve Landrace-Yorkshire swine were divided into two groups, one group (n=6) received pulsatile perfusion under CPB from an IABP in an internal mode at 80 beats per minute (bpm) and the other (n=6) had a standard CPB of 90 minutes. A third group (n=4) has been used as controls without CPB. The two first groups underwent aortic clamping for 80 minutes with administration of intermittent blood cardioplegia. After 60 minutes of reperfusion following of bypass, swine were sacrificed and pulmonary arteries were harvested. Haemodynamic values were calculated including pulmonary arterial pressures (PAP), mean arterial pressures (mAP), lactate production, blood glucose and cardiac index. Pulmonary arteries were placed in organ chambers and vascular reactivity studies were performed. RESULTS : There was a trend towards lower lactate production with use of pulsatile perfusion after 60 minutes of reperfusion. All other hemodynamics were not significally different in both groups. Relaxation to bradykinin was greater in pulsatile group while relaxation to acetylcholine did not differ. CONCLUSION : IABP induced pulsatile pressure protect the pulmonary endothelium during CPB. This could be explained by an increase in blood flow through the bronchial arteries or by a decreased release of cytokines or bradykinin which could reduce reperfusion damage.

Orientador: Regina Paolucci El Dib / Resumo: Cirurgias cardíacas são procedimentos muito eficientes para tratar os sintomas do infarto miocárdico, e para realizar trocas e plastias valvares. Contudo, problemas clínicos ocorrem ao realizar-se tais procedimentos em razão da lesão de isquemia-reperfusão e estresse oxidativo. Ambos, a cirurgia e a circulação extracorpórea (CEC) causam liberação de citocinas inflamatórias (TNF-α, IL-6, IL-10) e ativação de espécies reativas de oxigênio (O2-, H2O2-). Glutationa peroxidase (GPO) é uma enzima antioxidante que exerce papel importante no equilíbrio oxidativo e tem sua atividade limitada pela depleção das reservas de glutationa (GSH). N-acetilcisteína (NAC) é um resíduo acetilado do composto cisteína, e é necessária à ressíntese da glutationa (GSH). Estudos têm demonstrado a ação antioxidante da NAC, e seus efeitos na proteção da função dos pulmões, rins e coração, com resultados conflitantes. Sendo assim, este estudo avaliou o papel da n-acetilcisteína na redução da morbimortalidade de pacientes submetidos a cirurgias cardíacas. Foi realizada uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) e quase-ECRs, sem restrições quanto a línguas. ECRs foram pesquisadas nas seguintes bases de dados: MEDLINE, EMBASE, CENTRAL e LILACS, e a última busca ocorreu em 10 de outubro de 2018. Dois revisores independentes (JEGP, RED) selecionaram e extraíram os dados dos estudos, e a abordagem GRADE foi utilizada para classificar a certeza das evidências para os desfechos ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Cardiac surgeries are very efficient procedures to treat acute myocardial infarction symptoms, and to perform heart valve repair or replacement. Nervertheless, clinical issues arise upon performing such procedures, like isquemia-reperfusion injury and oxidative stress. Both, surgery and the cardiopulmonary by-pass (CPB) cause liberation of inflammatory cytokines (TNF-α, IL-6, IL-10) and activation of reactive oxygen species (O2-, H2O2-). Glutathione peroxidase (GPO) is an enzymatic antioxidant and plays a major role on the oxidative balance, and its activity is limited due to glutathione (GSH) reserve depletion. N-acetylcysteine (NAC) is an acetylated residue of the cysteine compound, and is necessary for glutathione (GSH) resynthesis. Studies have demonstrated the antioxidant action of NAC, and its effects on the protection of lung, kidney and heart functions, although with conflicting results. Therefore, this study evaluated the role of NAC on the reduction of morbimortality of the patients submitted to cardiac surgeries. A Systematic review and metanalysis of randomized controlled trials (RCTs) and Quasi-RCTs, with no restrictions to languages, was performed. RCTs were searched from the following databases: MEDLINE, EMBASE, CENTRAL and LILACS, and the last search date was October 10th, 2018. Two independent reviewers have selected and extracted the data from the studies, and the GRADE approach was utilized to classify the certainty of the evidences for the outcomes assesse... (Complete abstract click electronic access below) / Doutor

Os carcinomas de cabeça e pescoço correspondem a 10% de todos dos tumores malignos, destes aproximadamente 40% se manifestam na boca e 90% correspondem ao carcinoma espinocelular. Os principais agentes carcinogênicos relacionados ao câncer bucal são o tabaco e o álcool. A cirurgia é o tratamento de eleição para o carcinoma de boca seguido dos tratamentos quimio e radioterápicos. O uso de lipossomas como vetor de quimioterápicos abre grandes perspectivas para o tratamento do câncer, pois possibilitam maior eficácia, reduzindo a toxicidade e a dosagem do fármaco. Neste projeto foram avaliados os efeitos pró apoptóticos \"in vitro\" da fosfoetanolamina sintética (FOS) e da sua formulação lipossomal DODAC/FOS em duas linhagens celulares de carcinoma espinocelular de língua humano, SCC-9 e SCC-25. A FOS, a formulação lipossomal DODAC/FOS e o carreador DODAC vazio apresentam diferentes significados em seu potencial citotóxico. A FOS aumentou significativamente a formação de lipoperóxidos pela membrana celular nas maiores concentrações estudadas. A análise das fases do ciclo celular mostrou aumento significativo da população de células com DNA fragmentado em ambas as linhagens celulares induzindo a morte celular por apoptose com aumento da expressão de Bad, Bax, citocromo c e diminuição de Bcl-2, como também alterou o potencial elétrico mitocondrial promovendo a ativação da caspase-3. A FOS e a formulação lipossomal DODAC/FOS induziram retração dos filamentos de actina e fragmentação do DNA. O conjunto de resultados mostra que o composto FOS e a sua formulação lipossomal DODAC/FOS atuam nos efeitos citotóxicos e antitumoral promovidos por estes alquilfosfoésteres, sendo capazes de induzir a morte celular por apoptose em diferentes apresentações / Head and neck carcinomas account for 10% of all malignant tumors, approximately 40% of these tumors manifest in the mouth and 90% correspond to squamous cell carcinoma. The main carcinogenic agents related to oral cancer are tobacco and alcohol. Surgery is the treatment of choice for oral carcinoma followed by chemo and radiotherapeutic treatments. The use of liposomes as a vector of chemotherapy offers great prospects for treatment of cancer, as they allow greater efficacy, reducing the toxicity and the dosage of drug. In this project, in vitro pro apoptotic effects of synthetic phosphoethanolamine (Pho-S) and DODAC/Pho-S liposomal formulation were evaluated in two human tongue squamous cell carcinoma cell lines, SCC-9 and SCC-25. Pho-S, DODAC/Pho-S liposomal formulation and the empty DODAC carrier have different meanings in their cytotoxic potential. Pho-S significantly increased the formation of lipoperoxides by cell membrane in higher concentrations studied. Analysis of the cell cycle phases showed a significant increase in the cell population with fragmented DNA in both cell lines inducing apoptosis cell death with increase expression of Bad, Bax, cytochrome c and decrease of Bcl-2, as well as altered the potential mitochondrial activation promoting caspase-3 activation. Pho-S and the DODAC/Pho-S liposomal formulation induced retraction of the actin filaments and DNA fragmentation. The set of results shows that the Pho-S compound and its liposomal formulation DODAC/Pho-S act on the cytotoxic and antitumor effects promoted by these alkylphosphoesters, being able to induce cell death by apoptosis in different presentations

Ce travail de thèse est une étude des relations entre les fluides et les déformations dans le prisme d'accrétion de Nankai. Ce travail s'appuie entre autres sur les résultats des deux campagnes de forage récentes Leg Ocean Drilling Program 190 et 196. L'étude des relations entre la mise en place de déformations et les circulations de fluides est plus particulièrement centrée sur le décollement, au front du prisme. Nous présentons d'abord une estimation de la surpression de fluides dans les formations sédimentaires autour du décollement à partir de l'étude des profils de porosité. Ceci nous permet de montrer que le décollement n'est pas une barrière pour les surpressions de fluides et de proposer que le saut de porosité au niveau du décollement résulte d'une discontinuité de l'état de contrainte au travers du décollement. Nous étudions ensuite l'anomalie de chlorinité présente dans les fluides interstitiels de la formation dans laquelle se développe le décollement. Nous montrons que l'on peut rendre compte de cette anomalie en ne considérant que les processus de compaction des argiles et de transformation des smectites en illites. Par ailleurs, nous avons mesuré la perméabilité d'échantillons du prisme sous contraintes avec une presse triaxiale, nécessaire pour la réalisation de simulations numériques de circulation de fluides dans le prisme. Les perméabilités mesurées sont comprises entre 10-18 et 10-19 m2. La rupture des échantillons entraîne une augmentation de la perméabilité à faible pression de confinement mais pas de modification de la perméabilité à une pression de confinement correspondant à la contrainte verticale de l'échantillon en place. Dans une autre partie, nous comparons les mesures de porosité des échantillons et la porosité calculée dans la formation in situ à partir d'un log de résistivité. Cela nous permet de montrer que la zone de décollement présente à la fois des déformations compactantes et dilatantes. Nous estimons la dilatance de fracture du décollement entre 2 et 8 %, et nous proposons un modèle incrémentiel de propagation du décollement par couplage entre des transferts transitoires de surpression de fluides et la déformation mécanique en tête de décollement. Enfin, nous présentons une étude numérique en 2D de la propagation d'ondes de surpression de fluide le long du décollement en supposant que la perméabilité dépend de la pression effective. Les ondes peuvent se propager rapidement le long du décollement. Le couplage hydromécanique entre l'état de contrainte dans la séquence subduite et la pression de fluide dans le décollement est proposés comme un mécanisme possible d'initiation et d'entretien de l'onde de pression.