Este estudo tem como objetivo central avaliar a influência da secagem por aspersão de nanocápsulas de núcleo lipídico contendo tretinoína nos perfis in vitro de liberação e de penetração cutânea deste fármaco a partir de hidrogéis. Esses experimentos foram conduzidos empregando-se células de difusão de Franz, pele de abdome de porcos (fêmeas), regime de aplicação de doses infinitas e meio receptor composto por tampão fosfato pH 7,4 e etanol (70:30). A secagem por aspersão das suspensões de nanocápsulas, utilizando PVP e lactose (1:1, m/m) a 10% como adjuvantes, forneceu produtos com bons perfis de dispersão em água, bons rendimentos (próximos a 70%), baixos teores de substâncias voláteis, e teores do fármaco acima de 92%. O tipo de produto intermediário, suspensão aquosa ou respectivo pó, utilizado na produção de hidrogéis (G-LNC-TTN e G-LNC-TTN-SD, respectivamente) não influenciou no perfil de liberação in vitro da tretinoína, que se ajustou ao modelo de Higuchi. No estrato córneo houve diferenças nas quantidades de tretinoína penetradas a partir das duas formulações. O G-LNC-TTN levou a uma retenção exponencial do fármaco nessa camada, enquanto para o G-LNC-TTN-SD isso não ocorreu. Essa diferença foi associada à forma de organização das nanocápsulas na matriz do gel. Na epiderme e na derme, ambas as formulações permitiram a chegada de pequenas e constantes quantidades de tretinoína. No compartimento receptor da célula de Franz o fármaco não foi detectado. A pequena permeação da tretinoína para as camadas mais profundas da pele e para o meio receptor são indicativos de baixa absorção sistêmica, e também podem contribuir para a diminuição dos efeitos adversos associados à terapia tópica com essa substância. A secagem das suspensões de nanocápsulas de núcleo lipídico, nas condições utilizadas, forneceu um intermediário em potencial para a produção de formas farmacêuticas semissólidas contendo tretinoína. / This study’s central goal is to assess the influence of spray-drying lipid core nanocapsules on tretinoin in vitro release profiles as well as skin penetration/permeation from hydrogels. These experiments were conducted employing Franz diffusion cells, pig abdominal skin (female), infinite doses regimen and receptor medium composed of phosphate buffer pH 7.4 and ethanol (70:30). Spray-drying of the nanocapsules suspensions, using PVP and lactose (1:1, m/m) at 10% (m/v) as drying adjuvant provided powders with good water dispersion profiles, good yields (around 70%), low volatile substances contents, in addition to drug contents above 92%. Interchanging intermediate products, aqueous suspension or respective powder, used in hydrogel formulation (G-LNC-TTN and G-LNC-TTN-SD, respectively) caused no influence on tretinoin in vitro release profile which was adjusted by Higuchi model. In corneum stratum there were differences in tretinoin quantities which penetrated from those formulations. The G-LNC-TTN provided an exponential retention of the drug on this skin’s layer, although G-LNC-TTN-SD did not. This difference was associated with the nanocapsules organization form in hydrogel matrix. In epidermis and dermis both formulations allowed permeation of constant and low tretinoin quantities. Moreover, at receptor fluid the drug was not detected. The low tretinoin permeation for deeper skin layers and for receptor fluid is low systemic absorption indicative, furthermore, may contribute in reducing adverse effects associated with tretinoin topical therapy. In given conditions, spray-drying of lipid core nanocapsules provided a potential intermediate for production of semi solids pharmaceutical forms containing tretinoin.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The contamination by toxic metals has been a serious environmental problem. Many researches have been developed with the objective the environmental remediation. The adsorption has been one of the most used process by researchers to remove metals in recent years. In this work, it was studied the use of natural clays of the state of Sergipe, with high levels of kaolinite and montmorillonite as adsorbent materials to remove Pb (II), Cd (II) and Cu (II) in aqueous solution. It was investigated the adsorption conditions including contact time, pH and adsorption isotherms. Using kaolinite equilibrium of adsorption for the three metals was reached at about 30 min, and a contact time of 60 min was chosen. In the beginning of study was conducted at pH of metal nitrate solutions (pH 5.2 ± 0.2) resulting in a maximum removal of 86.0 %, 43.2 % and 34.3 % for Pb (II), Cd (II) and Cu (II) respectively. The pH 7.0 was determined to be the most efficient for the removal of Pb (II) ( 99.9 %), Cd (II) (82.9 %) and Cu (II) (97.9 %). The Langmuir isotherm was the model with the best fit to the adsorption data obtained for the three metals, with Qo of 1.511 mg g-1 for Pb (II); 0.853 mg g-1 for Cd (II) and 0.417 mg g-1 for Cu (II). In the application of natural clay containing montmorillonite, it was obtained; high removal percentages for Pb (II), Cd (II) and Cu (II). The adsorption equilibrium was reached in the first minutes and the contact time of 30 min was selected, with maximum adsorption of 99.54 %; 93.37 %; 99.48 % for Pb(II), Cd (II) and Cu (II) in natural pH of metal in the pH (pH 5.2 ± 2). In pH study, it was observed that the pH variations did not alter significantly the adsorption of metals. Among the models applied, Langmuir was the best fitted one for the three adsorbents applied in this work with Qo of 6.98 mg g-1 1.48 mg g-1 and 2.07 mg g-1 for Pb (II), Cd (II) and Cu (II) respectively. The results show clays that have high levels either kaolinite or montmorillonite show appropriate features for application in the process of adsorption of Pb (II), Cd (II) and Cu (II). / A contaminação por metais tóxicos representa um sério problema ambiental. Inúmeras pesquisas têm sido desenvolvidas tendo como objetivo a remediação ambiental. A adsorção tem sido um dos processos mais utilizados por pesquisadores nos últimos anos para remover metais. No presente trabalho, foi estudada a utilização das argilas naturais do estado de Sergipe, contendo alto teor de caulinita e montmorilonita como materiais adsorventes para remoção do Pb (II), Cd (II) e Cu (II) em solução aquosa. Foram investigadas as condições de adsorção incluindo tempo de contato, pH e isotermas de adsorção. Na utilização da argila caulinita natural, o equilíbrio de adsorção para os três metais foi alcançado em torno de 30 min, sendo utilizado nos experimentos o tempo de contato de 60 min. Inicialmente, o estudo foi desenvolvido no pH das soluções dos nitratos dos metais (pH 5,2 ± 0,2), obtendo-se uma remoção máxima de 86,0 % para o Pb (II), 43,2 % para Cd (II) e 34,3 % para Cu (II). A avaliação do efeito do pH sobre a adsorção mostrou que o aumento do pH favorece a remoção até certo valor, acima do qual os íons metálicos são precipitados como hidróxidos insolúveis. O pH 7,0 foi determinado como sendo o mais adequado para a remoção do Pb (II) ( 99,9 %), Cd (II) (82,9 %) e Cu (II) (97,9 %). A isoterma de Langmuir foi a que melhor se ajustou aos dados de adsorção obtidos para os três metais, com Qo de 1,51 mg g-1 para o Pb (II); 0,85 mg g-1 para o Cd (II) e 0,42 mg g-1 para o Cu (II). Na aplicação da argila natural contendo montmorilonita, obtiveram-se altas percentagens de remoção para o Pb (II), Cd (II) e Cu (II). O equilíbrio de adsorção foi alcançado nos primeiros minutos, sendo otimizado o tempo de contato de 30 min, com máxima adsorção de 99,54 %, 93,37 %, 99,48 % para o Pb (II), Cd (II) e Cu (II) em pH natural das soluções dos respectivos metais (pH 5,2 ± 0,2). No estudo de pH observou-se que a variação deste mesmo não alterou significativamente a adsorção dos metais. Entre os modelos aplicados, o de Langmuir mostrou-se mais adequado para os três adsorvatos estudados neste trabalho, com Qo de 6,98 mg g-1 para o Pb (II); 1,48 mg g-1 para o Cd (II) e 2,07 mg g-1 para o Cu (II). Os resultados apresentados mostram que as argilas contendo alto teor de caulinita ou montmorilonita apresentam características apropriadas para sua aplicação no processo de adsorção do Pb (II), Cd (II) e Cu (II).

Le cancer colorectal est la première pathologie cancéreuse de la sphère digestive, tant en terme de fréquence que de mortalité par an. Chaque année, 41 000 nouveaux cas sont diagnostiqués et 17 000 décès sont dus à ce cancer en France. Deux paramètres cliniques expliquent la mortalité de ce cancer; d'une part le fait qu'un patient sur deux est diagnostiqué au stade métastatique ou va présenter des lésions métastatiques durant l'histoire de sa pathologie, d'autre part le fait que les patients après traitement vont fréquemment présenter une récidive de leur pathologie. L'utilisation de régimes de chimiothérapies avant et après résection métastatique améliore la survie sans récidive à court terme, mais à 2 ans post chirurgie l'avantage apporté est perdu. Ainsi, la compréhension des mécanismes d'échappement à la chimiothérapie et régissant la croissance tumorale est d'intérêt pour tenter de limiter la récidive tumorale. L'objectif de ce travail de thèse a consisté en l'analyse de sous-populations obtenues sous pression de chimiothérapie au 5-Fluorouracile (5FU) dérivées de la lignée cancéreuse colique HT29, ainsi que les mécanismes moléculaires associés. Notre clone le plus chimiorésistant isolé, le modèle cellulaire 5F31, quitte le compartiment prolifératif sous traitement à fortes doses de 5FU, ceci étant associé à une perturbation de la voie de signalisation de la Src kinase c-Yes et de son partenaire, le co-activateur transcriptionnel YAP. Sous traitement, les cellules chimiorésistantes entrent en quiescence, le complexe protéique entre c-Yes et YAP est perdu et la quantité totale et nucléaire de YAP diminue de manière significative (Igoudjil, Touil, Corvaisier et al. 2014 Clinical Cancer Research). Dès lors, la suite des travaux a consisté en l'étude du rôle potentiel de YAP sur la balance quiescence/prolifération sous 5FU. L'inhibition pharmacologique ou l'inhibition transitoire de l'expression de YAP et de son paralogue, la protéine TAZ, dans plusieurs lignées cancéreuses coliques induit l'augmentation de la fraction de cellules quiescentes, associée au ralentissement significatif de la croissance tumorale. A l'inverse, la surexpression d'une forme constitutivement active de YAP demeurant nucléaire sous 5FU maintient les cellules 5F31 en prolifération et sensibilise les cellules à la chimiothérapie. Au niveau des effecteurs protéiques, l'induction de quiescence (par traitement à la chimiothérapie ou inhibition de YAP/TAZ) est associée à la perte d'expression de la Cycline E1 et du facteur de transcription c-Myc. A l'inverse, la surexpression du dominant constitutivement actif de YAP dans les cellules 5F31 conduit à l'expression soutenue de la Cycline E1 sous 5FU, expression nécessitant l'activation du facteur de transcription CREB. L'inhibition de la Cycline E1 permet d'induire la quiescence cellulaire, proposant cette protéine comme l'un des effecteurs des protéines YAP/TAZ dans la régulation entre la quiescence et la prolifération cellulaire (Corvaisier et al, Oncotarget, 2016). En conclusion, nos données montrent l'importance du rôle des protéines YAP/TAZ dans le maintien des cellules en prolifération via l'expression notamment de la Cycline E1. Nos résultats sur cohorte de patients atteints de métastases hépatiques de cancers colorectaux montrent que l'expression des co-activateurs YAP/TAZ est liée à un index prolifératif plus important, confortant nos données sur le rôle de ces protéines dans la croissance tumorale. De plus, l'expression élevée de YAP et TAZ est associée en analyses multivariées à une récidive plus précoce et à une survie globale plus faible. Ainsi, l'étude de l'expression et du niveau d'activation de ces acteurs serait un marqueur pronostic intéressant dans l'anticipation de la récidive métastatique ; ainsi que des cibles thérapeutiques intéressantes pour tenter de limiter la rechute tumorale. / Colorectal cancer is the most frequent and lethal cancerous pathology from the digestive system. Each year in France, 41 000 new cases are diagnosed and 17 000 patients die due to this pathology. This high mortality is mainly due to the rate of patients with liver metastatic lesions and the early relapse of those metastases after treatment. The use of chemotherapy prior to surgery induces a decrease of early relapse, however 2 years after resection this advantage is lost. Thus, understanding the mechanisms underlying escape to treatment is required to try to delay or prevent tumor recurrence.The aim of this doctoral work was to analyze clonal chemoresistant subpopulations derived from the colorectal cancer cell line HT29 after chronic exposure to 5-Fluorouracil (5FU) and molecular mechanisms associated with chemoresistance. The most chemoresistant clonal subpopulation, 5F31, stops its proliferation after treatment with high dose of 5FU, this behavior being associated with the modulation of the c-Yes/YAP axis. After treatment, 5F31 cells enter quiescence, interaction between c-Yes and YAP is lost and total and nuclear YAP protein expression reduces significantly (Igoudjil, Touil, Corvaisier et al. 2014, Clinical Cancer Research). The next step was to study functions of YAP protein in this chemotherapy- induced quiescence.Pharmacological or transient inhibition of YAP and its homolog TAZ, induces quiescence and reduces cellular growth in several colorectal cancer cell lines. On the other hand, overexpression of a constitutively active form of YAP in 5F31 cells forces cells to remain proliferative under 5FU treatment, enhancing 5F31 cell chemosensitivity to 5FU.Regarding proteic effectors, quiescence (either induced by 5FU or YAP/TAZ inhibition) is associated with loss of expression of the transcription factor c-Myc and Cyclin E1. In 5F31 cells expressing the active mutant form of YAP, Cyclin E1 expression is sustained after 5FU treatment through the activation of the transcription factor CREB. Cyclin E1 inhibition is sufficient to induce quiescence, therefore introducing this protein as one of the final effectors of YAP/TAZ co-activators in the regulation of the proliferation/quiescence switch in colorectal cancer cells (Corvaisier et al. 2016, Oncotarget).To conclude, our work reveals the importance of YAP/TAZ proteins for the maintenance of colorectal cancer cells proliferation through Cyclin E1 expression. Our work on liver metastases from patients with colorectal cancer shows that high expression of YAP/TAZ is connected to a higher proliferative index in metastatic lesions. Moreover, high YAP/TAZ expression is associated with shorter patient progression-free survival and shorter overall survival. Studying the expression and level of YAP/TAZ activation could be an interesting prognosis marker to anticipate metastatic relapse and potent druggable target to delay tumoral recurrence.

Orientador: Fernando Aparecido Sigoli / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T05:08:39Z (GMT). No. of bitstreams: 1 Bosshard_GabrielaZanotto_M.pdf: 4132378 bytes, checksum: abfa0f7115fb10b1aa31e7b1e9367ef8 (MD5) Previous issue date: 2012 / Resumo: O objetivo deste projeto foi investigar a síntese de óxido de zinco contendo enxofre obtido a partir de sulfeto de zinco nas fases wurtzita (hexagonal) e blenda de zinco (cúbica), assim como fazer a caracterização e estudar as alterações estruturais e ópticas dos materiais sintetizados e compará-las às propriedades do óxido de zinco sintetizado a partir de hidroxicarbonato de zinco. O método de síntese utilizado permite a obtenção de sulfeto de zinco hexagonal ou cúbico a baixa temperatura, permitindo um estudo comparativo da influência da estrutura cristalina do sulfeto de zinco na formação do óxido de zinco. Os estudos por difração de raios X mostram que há leve variação nos parâmetros de rede do material obtido, principalmente quando a síntese parte da fase hexagonal do ZnS. Somado a isso, a análise da luminescência dos materiais obtidos mostra emissão em torno de 520 nm, que pode ser atribuída a transição eletrônica entre defeitos de Frenkel (Zni e VZn") que foram formados a temperaturas inferiores à requerida para a formação deste tipo de defeito, indicando, portanto alterações na rede do óxido de zinco contendo enxofre. / Abstract: This project aimed to investigate the synthesis of sulfur-containing zinc oxide obtained from zinc sulfide in the wurtzite (hexagonal) or zinc blende (cubic) phases, in order to study possible changes in the structural and optical properties of the obtained, material which were compared to the properties of zinc oxide synthesized from zinc hydroxicarbonate. The used method of synthesis allowed obtaining zinc sulfide hexagonal or cubic at low temperature and therefore comparative studies of the influence of crystalline structure of zinc sulfide in the formation of zinc oxide was possible. X-ray diffraction data show that there is a slight variation in the lattice parameters of the obtained material, especially in the material synthesized from hexagonal ZnS. In addition to that, luminescence emission around 520 nm, assigned to the electronic transition among Frenkel defects (Zni and VZn"), indicate changes in the network of the sulfur-containing zinc oxide, since this type of defect is expected to be formed at temperatures above the ones used in the present work. / Mestrado / Quimica Inorganica / Mestra em Química

Orientadores: Celso Aparecido Bertran, Italo Odone Mazali / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T18:05:40Z (GMT). No. of bitstreams: 1 Lopes_JoaoHenrique_D.pdf: 497901561 bytes, checksum: bc2ebe969caf9d4e0bc28574f75fae56 (MD5) Previous issue date: 2015 / Resumo: Esta tese está dividida em quatro capítulos. O capítulo I apresenta os fundamentos sobre biomateriais e biovidros. O capítulo II é dedicado a investigar os efeitos da adição de óxido de nióbio (Nb2O5) sobre as propriedades físicas, a estrutura do vidro e a bioatividade de duas séries vítreas derivadas do 45S5 Bioglass® (BG45S5). A composição química do BG45S5 foi modificada pela substituição de 1,3 e 2,6% de P2O5 por Nb2O5 e 1, 2 e 5% do SiO2 pelo Nb2O5, gerando as séries (I) e (II), respectivamente (BGNs). A introdução do Nb2O5 aumenta significativamente a densidade e a estabilidade contra a desvitrificação, como evidenciado pelo parâmetro ?Txg = (Tx - Tg). Os espectros de ressonância magnética nuclear no estado sólido MAS NMR para os núcleos 29Si, 31P e 23Na, espectroscopia Raman e a determinação de algumas propriedades físicas permitiu um entendimento detalhado da estrutura dos vidros BGNs. Para os vidros da série I, o octaedro de NbO6 entra na rede silicato, partilhando os seus vértices com os tetraedros de silício para formar cadeias O-Si-O-Nb-O-Si-O, enquanto que para os vidros da série II, os octaedros NbO6 atuam como agente de reticulação para as cadeias de silicatos. A viabilidade celular e a atividade metabólica foram determinadas utilizando o ensaio de MTT. Os resultados dos estudos in vitro com os vidros BGNs sobre a viabilidade dos osteoblastos e proliferação não mostram diferenças significativas entre BGNs e BG45S5. Os resultados da experimentação in vivo em ratos Wistar sugerem que a presença de Nb2O5 pode efetivamente promover um aumento na bioatividade de BGNs, observado pelo aumento da quantidade formada de osso cortical e trabecular. O capítulo III abrange a investigação da modificação da superfície do biovidro BG45S5 pelo enriquecimento com cálcio, por imersão em banho de sal fundido contendo cálcio (BG45Cas) e o seu efeito sobre a estrutura da superfície, a velocidade de dissolução e também a cinética da formação do fosfato de cálcio. A combinação da microscopia de força atômica e espectroscopia Raman (AFM) permitiu o acompanhamento das mudanças estruturais do BG45S5 submetido a diversos tempos de imersão no banho de sal fundido a 480 °C, enquanto que a fluorescência de raios X (XRF) foi empregada para monitorar a evolução temporal do processo de troca iônica entre Ca2+ e Na+. Os rearranjos estruturais, como resultado da troca iônica, foram sistematicamente investigados no BG45Ca30 pelas espectroscopias FTIR e 29Si e 31P MAS NMR. Os resultados mostram que a quantidade de íons cálcio que entram na estrutura do vidro é maior do que a quantidade de íons sódio que deixa a rede, de modo que, para preservar a eletroneutralidade na rede, ocorrem alterações locais na estrutura que conduzem a uma depolimerização da rede de silicato. A formação da fase de fosfato de cálcio quimicamente equivalente à hidroxiapatita (HA) na superfície do biovidro foi estudada por imersão dos biovidros em HEPES 50,69 mmol L-1 e fluido corpóreo simulado (SBF) durante 2 dias. A camada de apatita formada foi caracterizada pela espectroscopia 31P MAS NMR. A cinética de crescimento da camada de apatita sobre a superfície do BG45Ca30 sugere que a modificação da superfície do vidro não só promove uma redução no tempo para a formação de HA, mas também a formação de hidroxiapatita com maior grau de cristalinidade. Finalmente, o capítulo IV descreve as nossas contribuições, observações finais e sugestões para futuros trabalhos / Abstract: This thesis is divided into four chapters. Chapter I presents background information on the biomaterial and bioglasses. Chapter II is devoted to investigate the effects of adding niobium oxide (Nb2O5) on the physical properties, glass structure and bioactivity of two glasses series derived from the 45S5 Bioglass® (BG45S5). The chemical composition of BG45S5 was modified by replacing 1.3 and 2.6% of P2O5 with Nb2O5 and 1, 2.5, and 5% of SiO2 with Nb2O5, generating series (I) and (II), respectively (BGNs). Adding Nb2O5 significantly increases the density and the stability against devitrification as indicated by ?Txg = (Tx - Tg). The multinuclear 29Si, 31P, and 23Na solid-state MAS NMR spectra of the glasses, Raman spectroscopy, and the determination of some physical properties have generated insight into the structure of the glasses. For the series I glasses, the octahedral niobium take part in glasses network, sharing its corners with silicon tetrahedra forming O-Si-O-Nb-O-Si-O chains, whereas for the series II, NbO6 octahedra act as crosslinker for the silicates chains. Cell viability and metabolic activity were determined using the MTT assay. We investigated the in vitro effect of BGNs glasses on osteoblast viability and proliferation. No significant differences were found between BGNs and BG45S5. Furthermore, in vivo tests in Wistar rats have suggested that the presence of Nb2O5 might actually promote an increase in bioactivity of BGNs, increasing formation of cortical and cancellous bones. The chapter III covers research related to of the surface modification of BG45S5 bioglass (BG45Cas) and its effect on the surface structure, dissolution rate and calcium phosphate formation. BG45Cas were obtained by ion exchange method by immersion in molten salt bath containing calcium. The combination of Raman spectroscopy and atomic force microscopy (AFM) allowed the monitoring of the structural changes of BG45S5 bioglass submitted to increasing durations of immersion in the molten salt bath at 480 °C, whereas X-ray Fluorescence (XRF) was employed to derive the time evolution of Ca2+-Na+ ion exchange process. Structural rearrangements as a result of Ca2+-Na+ ion exchange have been investigated systematically on 45S5 bioglasses by FTIR and 29Si and 31P MAS NMR spectroscopies. Results show that the insertion of calcium ions in the glass structure is higher than the departure of sodium ions. The electroneutrality of the glass structure is preserved with local alterations, which lead to a higher degree of depolymerization of the silicate network. The formation of calcium phosphate layer chemically equivalent to hydroxyapatite (HA) on the bioglass surface was evaluated by immersing the bioglasses in the HEPES 50,69 mmol L-1 and simulated body fluid (SBF) for up to 2 days. This apatite layer was characterized by 31P MAS NMR spectroscopy. The growth kinetics of the apatite layer on the surface of the bioglasses demonstrated that modification of the glass surface (BG45Ca30) cause not only a reduction in time of the formation of HA, but also induced hydroxyapatite phase formation with a higher degree of crystallinity. Finally, chapter IV describes our contributions, final remarks and suggests some ideas for future works / Doutorado / Físico-Química / Doutor em Ciências

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23085号 / 医博第4712号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 安達 泰治, 教授 戸口田 淳也, 教授 別所 和久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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<p> The automotive industry is using advanced high strength steels (AHSS) to improve the fuel efficiency of passenger vehicles by lightweighting strategy. The higher strength of AHSS allows vehicle manufacturers to implement thinner and lighter components while still meet the safety requirements. Press hardened steels (PHS) exhibit the highest tensile strength among AHSS and are widely used for manufacturing crash relevant automotive parts. Boron-containing steel with enhanced hardenability is the most commonly used grade of steel for press hardening. The addition of a small amount of boron, 0.002 – 0.005 wt.%, can effectively increase hardenability. However, the boron addition also causes problems in commercially production of steel slabs by continuous casting. Defects including transverse corner cracks, surface cracks, and internal halfway cracks are sometimes found in continuously-cast boron steel slabs during or after the final cooling process. These problems can arise during the post-casting cooling process because boron addition changes the phase transformation behavior of steel.</p> <p>The cooling of slabs during and after continuous casting is a multiphysics process including coupled heat transfer, solidification, solid-solid phase transformations, and deformation. Numerical models are helpful for a better understanding of the cooling process and the interaction of different physical phenomena in it. In this work, a 3-D thermomechanical finite volume model (FVM) with coupled heat transfer, stress, and phase transformation calculations is developed to investigate the temperature history, phase evolution, and stress development during cooling.</p> <p>The model is used to simulate the cooling process of continuous cast steel slabs at different post-casting stages. The effect of boron addition on stress development and phase evolution during cooling of a single slab is investigated via simulation of both boron-containing and non-boron steels. The results show the slab with boron consists of mostly bainite, in contrast to the non-boron grade which is mostly ferrite and pearlite after cooling. Higher tensile stresses, both peak and residual, and plastic strains, which could lead to cracking, are observed at the edge of slab in the boron-containing grade. The effect of slowing the cooling rate by using a radiation shield is studied for the boron-containing steel. The reduced thermal gradient and the increased ferrite formation reduce the stresses in the slab. The cooling process of a stack of multiple slabs is also simulated to study the influence of slabs stacking on cooling rate and slab deformation. A slower cooling rate can be achieved in stacked slabs and the compressive load provided by slabs above the slab can prevent large deformation and flatten the slab during cooling. The combination of slab stacking and radiation shield is modeled to study the stress development under a slow cooling rate that is feasible in practice. Boron addition also affects the water quenching process of steel strips on the runout table after hot rolling. Simulations of strips with and without boron show different cooling curves, residual stress and phase distributions as austenite decomposition does not occur for boron-containing steel due to the fast cooling rate. Therefore, the cooling strategy on the runout table should be adjusted accordingly to control the coiling temperature and improve strip quality.</p>

Aluminium is usually added to the continuous hot-dip galvanizing bath to improve coating ductility and adhesion through the rapid formation of a thin Fe-Al intermetallic layer at the substrate-liquid interface, thereby inhibiting the formation of brittle Fe-Zn intermetallic compounds. On the other hand, Mn is essential for obtaining the desired microstructure and mechanical properties in advanced high strength steels, but is selectively oxidized in conventional continuous galvanizing line annealing atmospheres. This can deteriorate reactive wetting by the liquid Zn(Al,Fe) alloy during galvanizing and prevent the formation of a well developed Fe-Al interfacial layer at the coating/substrate interface, resulting in poor zinc coating adherence and formability. However, despite Mn selective oxidation and the presence of surface MnO, complete reactive wetting and a well developed Fe-Al interfacial layer have been observed for Mn-containing steels. These observations have been attributed to the aluminothermic reduction of surface MnO in the galvanizing bath. According to this reaction, MnO is reduced by the bath dissolved Al, so the bath can have contact with the substrate and form the desired interfacial layer. Heat treatments compatible with continuous hot-dip galvanizing were performed on four different Mn-containing steels whose compositions contained 0.2-3.0 wt% Mn. It was determined that substrate Mn selectively oxidized to MnO for all alloys and process atmospheres. Little Mn surface segregation was observed for the 0.2Mn steel, as would be expected because of its relatively low Mn content, whereas the 1.4Mn through 3.0Mn steels showed considerable Mn-oxide surface enrichment. In addition, the proportion of the substrate surface covered with MnO and its thickness increased with increasing steel Mn content.A galvanizing simulator equipped with a He jet spot cooler was used to arrest the reaction between the substrate and liquid zinc coating to obtain well-characterized reaction times characteristic of the timescales encountered while the strip is resident in the industrial continuous galvanizing bath and short times after in which the Zn-alloy layer continues to be liquid (i.e. before coating solidification). Two different bath dissolved Al contents (0.20 and 0.30 wt%) were chosen for this study. The 0.20 wt% Al bath was chosen as it is widely used in industrial continuous galvanizing lines. The 0.30 wt% Al bath was chosen to (partially) compensate for any dissolved Al consumption arising from MnO reduction in the galvanizing bath.The Al uptake increased with increasing reaction time following non-parabolic growth kinetics for all experimental steels and dissolved Al baths. For the 0.20 wt% dissolved Al bath, the interfacial layer on the 1.4Mn steel showed the highest Al uptake, with the 0.2Mn, 2.5Mn and 3.0Mn substrates showing significantly lower Al uptake. However, increasing the dissolved bath Al to 0.30 wt% Al resulted in a significantly increased Al uptake being observed for the 2.5Mn and 3.0Mn steels for all reaction times. These observations were explained by the combined effects of the open microstructures associated with the multi-phase nature of an oxide-containing interfacial layer and additional Al consumption through MnO reduction. For instance, in the case of the 1.4Mn steel, the more open interfacial layer structure accelerated Fe diffusion through the interfacial layer and increased Al uptake versus the 0.2Mn substrate for the same bath Al. However, in the case of the 2.5Mn and 3.0Mn substrates and 0.20 wt% Al bath, additional Al consumption through MnO reduction caused the interfacial layer growth to become Al limited, whereas the very open structure dominated growth in the case of the 0.30 wt% Al bath and resulted in the changing the growth kinetics from mixed diffusion-controlled to a more interface controlled growth mode. A kinetic model based on oxide film growth (Smeltzer et al. 1961, Perrow et al. 1968) was developed to describe the Fe-Al interfacial layer growth kinetics within the context of the microstructural evolution of the Fe-Al interfacial layer for Mn-containing steels reacted in 0.20 wt% and 0.30 wt% dissolved Al baths. It indicated that the interfacial layer microstructure development and the presence of MnO at the interfacial layer had significant influence on the effective diffusion coefficient and interfacial layer growth rate. However, in the cases of the 2.5Mn and 3.0Mn steels in 0.20 wt% Al bath, the kinetic model could not predict the interfacial layer Al uptake, since the Fe-Al growth was Al limited. In fact, in these cases, additional Al was consumed for reducing their thicker surface MnO layer, resulted in limiting the dissolved Al available for Fe-Al growth. / Dissertation / Doctor of Science (PhD)

Phosducin-like protein (PhLP) binds G-protein beta gamma subunits and is thought to assist in assembly of the G-protein beta gamma dimer. Phosphorylation of PhLP at serine residues 18-20 by the casein kinase 2 (CK2) appears to play an essential role in this process. PhLP has also been shown to interact with the chaperonin containing TCP-1 (CCT) atop its apical domain, not entering the substrate folding cavity. However, the physiological role of the PhLP-CCT interaction in G-protein beta gamma dimer formation remains unclear. This study addresses the mechanism of G-protein beta gamma assembly by exploring the specific roles of CCT and CK2 phosphorylation of PhLP in the assembly process. Both overexpressed and endogenous Gbeta were shown to co-immunoprecipitate with CCT to a similar extent as PhLP, indicating that CCT may be involved in the folding of Gbeta. In addition, Ggamma overexpression enhanced the binding of PhLP to CCT, suggesting the formation of a ternary PhLP-Gbeta-CCT complex. In contrast, overexpression of PhLP caused the release of G-beta from CCT. This release was blocked by a PhLP S18-20A variant that lacks the S18-20 CK2 phosphorylation site. PhLP S18-20A has been previously shown to negatively affect the G-protein beta gamma dimer formation, suggesting a correlation between PhLP-mediated release of Gbeta from CCT and G protein beta gamma assembly. Experiments investigating the role of Ggamma in this process show that Ggamma does not interact with CCT nor is it the essential factor in the release of Gbeta from CCT. A new model is therefore proposed for the G-protein beta gamma subunits' assembly involving the formation of a PhLP-Gbeta-CCT ternary complex followed by the release of a phosphorylated PhLP-Gbeta complex from CCT. In the PhLP-Gbeta complex, the Ggamma binding face of Gbeta is exposed, allowing for the formation of the G-protein beta gamma dimer.