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Outcomes after Postoperative ICU Admission in the Elderly in France: A Population-Based Cohort StudySaadat, Pakeezah January 2019 (has links)
Postoperative ICU admission is afforded to patients with high clinical severity, but the benefits and harms of such an endeavour are debateable. The purpose of my thesis was to further understand a) the type of patients being admitted to ICU, b) the role of age in ICU admission, and c) the association (if any) between ICU admission and subsequent mortality and complications.
The thesis consists of 4 chapters. Chapter I provides a brief introduction of the topic and the rationale behind the researched questions. Chapter II examines the association between chronological age and ICU admission in postoperative patients. This analysis sheds light on one of the 17 variables included in the score (i.e. age), which drives the clinical severity score in parts of the population. Chapter III uses a propensity score model to match patients that were admitted to ICU and those that were not based on several pretreatment variables, to assess the impact ICU admission has on postoperative mortality and complications. Finally, Chapter IV reflects the conclusions of the thesis and suggests further research agendas.
Overall, these three thesis components will illustrate the role of ICU admission in an adult postoperative population as well as its consequences in comparison to those not admitted to an ICU. / Thesis / Master of Science (MSc)
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The synthesis and characterization of Rh₂(II,II) templated photoactive assembliesCooke, Michael January 2007 (has links)
Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.
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Structural Study of 4-(2-Pyridylmethylaminomethyl)- imidazolyl and 4-(2-Pyridylmethyliminomethyl)- imidazolyl Metal (Zn, Cu, Ni) ComplexesWang, Hsiao-Ting 04 August 2006 (has links)
Late transition metal complexes bearing nitrogen-containing ligands may act as catalyst in biotechnology or industrial catalysis. Imidazole is one of the most common biofunctional ligands that play critical roles in meta1loenzymes, since the imidazole moiety of the histidyl residues often constitutes all or part of the binding sites of various transition metal centers.
In this work, some new zinc(II), copper(II) and nickel(II) complexes containing the imidazolate and pyridyl moieties incorporated in the imine (ImPyI) and amine (ImPyA) ligands were obtained. Different methods of crystallization yield crystals of complexes (2), (6), (8), (9), (10), (17) and (18). Subsequent structural analyses revealed their interesting structures. In zinc(II) and nickel(II) complexes, facial isomers were isolated while none of the meridional isomers were observed. Particularly interesting is the zinc(II) complexes where two facial complexes with different geometries were identified. The mixture of the different nitrogen donor groups in the same ligand provides handy comparison of these structural variations due to the different nature of these donor groups. One tridentate ligand with bromide substitution on the imidazolate and a tetradentate ligand with an additional pyridyl group were synthesized as an extension of this work. One crystal structure of each of the corresponding metal complex bearing these ligands is also discussed here. Most metal complexes are consolidated by extensive weak hydrogen bonds among them in the crystal lattices.
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Avaliação das dimensões e relacionamentos dos arcos dentários no tratamento da má-oclusão classe II, divisão 1 de Angle com aparelho bionator de BaltersJacob, Helder Baldi [UNESP] 31 July 2006 (has links) (PDF)
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jacob_hb_me_arafo.pdf: 541294 bytes, checksum: 3439beb03630dce20425833af9507d49 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A deficiência de dados na literatura nos levou a avaliar o efeito do tratamento com o aparelho Bionator de Balters nas alterações das dimensões e relacionamento dos arcos dentários em crianças com má-oclusão Classe II, divisão 1 de Angle. O grupo experimental foi consistituido de 36 pares de modelos de pacientes leucodermas com idades entre 7 anos e 10 meses e 11 anos e 8 meses sendo 10 do gênero feminino e 8 do gênero masculino. A seleção da amostra teve como critérios de inclusão a presença dos incisivos centrais e laterais erupcionados, ausência de apinhamento dentário e relação transversal dos arcos normais. Um grupo controle (pseudo-amostra controle) foi simulado a partir de uma amostra obtida por Moyers com idade e gêneros aproximadamente iguais ao grupo experimental. A análise dos modelos constou de 24 medidas das quais 18 puderam ser comparadas com a pseudo-amostra. A aplicação do teste de Levene mostrou evidências estatísticas de semelhança entre os grupos. Procedeu-se então a análise estatística que mostrou alterações significantes (p<0,005) nas variáveis indicativas de distância intermolares superiores, sobressaliência horizontal, comprimento total do arco superior, comprimento anterior do arco superior, comprimento posterior do arco superior, relação molar direita, relação molar esquerda, relação canino direita e relação canino esquerda. Por outro lado não houve alteração significante em relação as medidas do arco inferior e distancia intercaninos do arco superior. Pode ser concluído com base nos resultados encontrados que o uso do aparelho Bionator de Balters teve efeito favorável na melhora da correção da má-oclusão de Classe II (diminuição das relações molares e caninos) e um aumento transversal do arco superior, principalmente na região posterior do arco. / The deficiency of data in the literature took us to evaluate the Bionator of Balters appliance in the alterations of the dimensions and relationship of the dental archs in children with malocclusion Class II, Division 1 of Angle. The experimental group was constituted of 36 pairs of cast of leucodermas patients between the age of 7 years and 10 months and 11 years and 8 months, being 10 females and 8 males. The sample selection had as criterion of inclusion the presence of the central and lateral incisor erupted, absence of crowded teeth and normal transversal relationship. A control group (pseudo-sample group) was simulated beginning from a sample obtained by Moyers with approximately the same age and gender to the experimental group. The analysis of the casts consisted of 24 measures and 18 of them could be compared with the pseudo-sample. The Leveneþs test showed statistical evidences of likeness among the groups. Statistical analysis was proceeded with showed significant alterations (p<0,005) in the variable indicatives of distance of maxillary first molars, over jet, total length of upper arch, anterior length of the upper arch, right molar relationship, left molar relationship, right canine relationship and left canine relationship. On the other hand, there wasn't significant alteration related to the lower arch and maxillary intercanines distance. It be concluded with the use of the Bionator of Balters appliance that it had a favorable effect in the improvement of the correction of the malocclusion in Class II (decrease of the molars and canines relationship) and transversal increase of the upper arch, mainly in the posterior area of arch.
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Interactions with topoisomerase IIa enhance the unwinding activity of the BLM helicase on recombination substrates and are necessary for preventing chromosome breakageRussell, Beatriz January 2009 (has links)
No description available.
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[en] NEW DINUCLEAR ZN(II), CU(II) AND NI(II) COMPLEXES OF THE LIT LIGAND: POTENTIAL ANTINEOPLASTIC AGENTS / [pt] NOVOS COMPLEXOS BINUCLEARES DE ZN(II), CU(II) E NI(II) DO LIGANTE LIT: POTENCIAIS AGENTES ANTINEOPLÁSICOS21 December 2021 (has links)
[pt] Câncer é o nome dado a um conjunto de mais de 100 doenças e entre as
possibilidades de tratamento está a quimioterapia. Após a descoberta das
propriedades antitumorais do complexo de coordenação comumente chamado
cisplatina, um dos compostos mais utilizados em neoplasias malignas, o estudo
dos complexos metálicos teve um grande impulso e alguns compostos
promissores de cobre(II) já foram desenvolvidos. Por outro lado, bases de Schiff
derivadas de aminas e aldeídos aromáticos têm apresentado uma ampla aplicação
em muitas áreas de pesquisa, sendo que algumas são farmacologicamente
utilizadas na terapia anti-hipertensiva, hipnótica e antineoplásica. Neste contexto,
no presente trabalho, foi sintetizado e caracterizado um ligante imínico
binucleante sulfonado derivado da taurina, já conhecido na literatura: (LIT) e, a partir deste, seus complexos inéditos de Zn(II),
Cu(II) e Ni(II), que foram caracterizados pelas seguintes técnicas: espectroscopia
vibracional e eletrônica, análise elementar de CHNS, análise termogravimétrica,
espectroscopia de ressonância paramagnética eletrônica (EPR) e modelagem
molecular computacional. Os novos compostos obtidos neste trabalho são, a
saber: composto (1), composto (2)
e composto (3), em que LIT representa uma forma parcialmente
hidrolisada de LIT. Os complexos 1 e 2 são os primeiros compostos binucleares
do ligante LIT descritos. Neles, os centros metálicos são tetracoordenados e
apresentam uma ponte exógena acetato coordenada nas formas bidentada, para o
composto 1, e monodentada, para 2. Esta diferença na coordenação da ponte se dá,
provavelmente, devido aos distintos arranjos geométricos em torno dos metais:
enquanto o zinco apresenta um arranjo tetraédrico, o cobre mostra um do tipo
quadrático. O complexo 3 é binuclear, composto por um dímero altamente
simétrico envolvendo, como dito acima, uma forma parcialmente hidrolisada de
LIT. Os centros metálicos são hexacoordenados, ligados por pontes endógenas
fenólicas. Tanto 2 quanto 3 são silenciosos ao EPR. Foi realizado também um
ensaio de toxicidade aguda em Artemia salina para as espécies hidrossolúveis LIT
e complexo 1. Este ensaio mostra boa correlação com a atividade citotóxica para
alguns tumores sólidos humanos. / [en] Cancer is a name given to a set of more than 100 diseases and among the
possibilities of treatment is chemotherapy. After the discovery of the antitumor
properties of the coordination complex commonly called cisplatin, it is one of
the compounds most used in malignancies. The study of metal complexes had a
big boost and some promising copper(II) compounds have been developed.
Furthermore, the Schiff bases derived from aromatic aldehydes and amines
present a wide range of applications in many areas of research, some of which are
pharmacologically used in antihypertensive, hypnotic, and antineoplastic therapy.
In this context, in the present study, we synthesized and characterized a
binucleating imine ligand, derivative of taurine, already known in the literature:
(LIT). New dinuclear Zn(II), Cu(II) and Ni(II)
complexes of this ligand were synthesized, and were characterized by the
following techniques: vibrational and electronic spectroscopies, CHNS elemental
analysis, thermogravimetric analysis, electron paramagnetic resonance (EPR) and
computational molecular modeling. The new compounds obtained in this work
are: composite (1), composite (2)
composite (3), where LIT represents a LIT partially
hydrolyzed form. Complexes 1 and 2 are the first dinuclear compounds of the LIT
ligand described. In these, metal centers are tetracoordinated, with the presence of
an exogenous acetate bridge, which shows a bidentate coordination mode for
compound 1 and a monodentate coordination pattern for 2. This difference occurs
probably due to different geometrical arrangements around the metal centers:
while zinc has a tetrahedral coordination geometry, copper shows one of the
square planar type. On the other hand, compound 3 a dinuclear complex, which is
composed of a highly symmetric dimer involving, as mentioned above, a partially
hydrolyzed form of LIT. The hexacoordinated metal centers are connected by two
endogenous phenolic bridges. Both 2 and 3 are EPR silent. An acute toxicity test
on Artemia salina shrimp was also carried out for the hydro-soluble species LIT
and 1. This assay shows good correlation with cytotoxic activity for some human
solid tumors.
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Régulation des chaperons de la présentation antigénique par ubiquitinationLadouceur, Annie 05 1900 (has links)
La chaîne invariante forme un complexe nonamérique avec les molécules classiques du CMH de classe II. HLA-DM et HLA-DO, des molécules non-classiques de classe II, sont aussi impliquées dans la présentation des peptides antigéniques aux lymphocytes T. Ces molécules chaperones de la présentation antigénique modulent la capacité d’une cellule à présenter des antigènes par les moloécules classiques du CMH de classe II. La régulation transcriptionnelle des molécules chaperones, tout comme celle des autres molécules du CMH de classe II, est assurée par le transactivateur CIITA. La molécule HLA-DR peut être régulée négativement de manière post-traductionnelle par ubiquitination grâce à l’enzyme E3 ubiquitine ligase MARCH1. Celle-ci est induite par l’interleukine-10 dans les monocytes. L’objectif de ce projet était de déterminer si l’ubiquitination par MARCH1 peut aussi réguler l’expression des molécules chaperones de la présentation antigénique. Les expériences furent réalisées dans le contexte de co-transfections en cellules HEK293T. L’expression des molécules fut évaluée par immunomarquages et cytométrie de flux. Il a été montré que l’isoforme p33 de la chaîne invariante est régulé négativement en présence de MARCH1 à partir de la surface cellulaire, causant ainsi sa dégradation. Tel que démontré par l’utilisation d’un mutant dépourvu de queue cytoplasmique, cette dernière région n’est pas indispensable à ce phénomène. Une hypothèse est qu’une molécule non-identifiée, associée à Ii, serait ubiquitinée par MARCH1, l’entraînant dans sa régulation négative. Il fut déterminer que cette molécule n’était pas CXCR2, un récepteur pouvant être impliqué, avec la chaîne invariante et CD44, en tant que récepteur de MIF (Macrophage Inhibitory Factor). Il fut aussi montré que HLA-DO peut être ciblé par MARCH1 mais ceci ne semble pas être un phénomène dominant; l’expression des complexes DO/DM n’étant pas affectée bien qu’ils entrent en interaction avec MARCH1. L’expression de HLA-DM n’est pas affectée par MARCH1. Il n’a toutefois pas été déterminé hors de tout doute si MARCH1 peut modifier DM; des résultats obtenus avec une queue cytoplasmique de DM possédant une lysine laissant suggérer qu’il est possible que MARCH1 interagisse avec DM. Dans l’ensemble, les travaux démontrent que l’ubiquitination par MARCH1 joue un rôle dans la régulation post-transcriptionnelle de la chaîne invariante p33 mais pas HLA-DO et HLA-DM. / The invariant chain, which form a nonameric complex with the classical MHC class II molecules. HLA-DM and HLA-DO (non-classical class II molecules) are involved in the presentation of antigens to T lymphocytes. The chaperons molecules of the antigenic presentation can modulate the capacity of the cells to present antigens. The transcriptional regulation of the chaperons and all of the other molecules linked to the MHC is assured by the CIITA transactivator. Little is know of the post-transcriptional mechanisms, other than the fact that HLA-DR molecule can be down-regulated by ubiquitination due to E3 ubiquitin ligase MARCH1. MARCH1 is induce by interleukin-10 in monocytes. The goal of this project is to figure out if ubiquitination by MARCH1 can also regulate the expression of the antigenic presentation chaperons. The experiences were performed in the context of co-transfections in HEK293T cells and the expression of the diverses molecules was evaluated by cell stainings and FACS analysis. The p33 isoform of the invariant chain was found to be down-regulated and degraded in the presence of MARCH1. The invariant chain cytoplasmic tail is not completely essential to this phenomenon; a non-identified molecule, associated with Ii, is probably ubiquitinated by MARCH1 and is then down-regulated, together with Ii. It was shown tha CXCR2, a reeptor involved with the invariant chain and CD44 in the reception of the MIF signal, is not that molecule. HLA-DO can ben targetd by MARCH1 but this does not seem to be a general phenomenon; the expression of the DO/DM complexes remaning unaffected even with the interaction of those complexes with MARCH1. Therefore, a certain protection seem to be provided by HLA-DM to HLA-DO. The expression of HLA-DM itself is not affected by the presence of MARCH1. However, it was not cleary demonstrated if MARCH1 can modify DM. Some results obtained with a cytoplasmic tail of DM comprising an additional lysine suggest that there is a possibility that MARCH1 interact with DM. Generally, the work presented here show that ubiquitination by MARCH1 is involved in post-transcriptionnal regulation of the p33 isoform of the invariant chain but not in the regulation of HLA-DO and HLA-DM.
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Estudo da autoxidação dos complexos de Cu(II), Ni(II) e Co(II)/tetraglicina induzida por S(IV) / Study of the autoxidation of the complexes of Cu (II), Ni (II) and Co (II)/tetraglycine induced by S(IV)Sebastian, Maria Vespertina Alipazaga 19 September 2003 (has links)
O presente trabalho apresenta estudos espectrofotométricos relacionados à autoxidação dos complexos de Cu(II), Ni(II) e Co(II)/tetraglicina induzida por sulfito. Nossos estudos verificaram que a autoxidação de Cu(II)/tetraglicina (1,0x10-3 mol L-1) em pH = 9,0 (tampão borato) é afetada pela presença de traços de Ni(II) ou Co(II). Na ausência de Ni(II) ou Co(II), a reação é muito ineficiente e lenta com períodos de indução longos (aproximadamente 4 h). Ni(II) ou Co( II) em concentrações baixas ( 10-5 - 10-6 mol L-1) afetam significativamente a cinética: o período de indução diminui drasticamente (a menos de 2 s) e a formação de Cu(III) é fortemente acelerada com simultâneo aumento da eficiência da reação. A atividade catalítica e o sinergismo positivo de Co(II) e Ni(II) podem ser explicados pela oxidação mais rápida de Co(II) ou Ni(II)/tetraglicina pelo oxigênio dissolvido. O processo eletroquímico relacionado aos sistemas Cu(II)/Cu(III)/tetraglicina e Ni(II)/Ni(III)/tetraglicina são reversíveis, possibilitando monitorá-los adequadamente mediante o uso da técnica de eletrodo rotativo disco-anel. Entretanto, o sistema Co(II)/Co(III)/tetraglicina é irreversível. Esses estudos mostraram que as espécies de Cu(III) e Ni(III) geradas no eletrodo disco são instáveis nas condições experimentais empregadas. O efeito sinérgico positivo na presença de Ni(II) (que permitiu aumentar a sensibilidade) foi aproveitado para desenvolvimento de método espectrofotométrico e amperométrico simples e sensível para a determinação indireta de sulfito em meio aquoso. O método espectrofotométrico está baseado na medida de absorbância do complexo de Cu(III)/tetraglicina (gerado na presença de sulfito e traços de Ni(II)) em 365 nm. O método amperométrico em análise por injeção em fluxo baseia-se na medida de corrente (0,1 V vs Ag/AgCl) em função da concentração de Cu(III)/tetraglicina gerado quimicamente, na presença de sulfito e traços de Ni(II). Os métodos desenvolvidos foram empregados para a determinação de S(IV), em vinhos e sucos, após a sua extração da amostra acidificada, os resultados obtidos concordaram com aqueles obtidos pelo método iodométrico. / The present work presents spectrophotometric studies related to the sulfite induced autoxidation of Cu(II), Ni(II) and Co(II)/tetraglycine complexes. The sulfite induced autoxidação of Cu(II)/tetraglycine (1.0x10-3 mol L-1) at pH = 9.0 (borate buffer) is affected by the presence of small quantities of the Ni(II) or Co(II). In the absence of added nickel (II) or cobalt (II), the reaction is very inefficient and slow with one large induction period (about 4 h). Trace amounts of Ni(II) or Co(II) (10-5 - 10-6 M) affect the kinetic significantly: the induction period drastically decreases (less than 2 s) and the formation of Cu(III) is strongly accelerated. The effectiveness of Cu(III) formation becomes much higher. The catalytic activity and the positive synergism of Co(II) and Ni(II) may be explained by the faster oxidation of Co(II) or Ni(II)/tetraglycine complexes by dissolved oxygen. The electrochemistry of Cu(II)/Cu(III)/tetraglycine and Ni(II)/Ni(III)/tetraglycine systems are reversible, such as it was possible to monitor them by using the rotating ring-disk electrode technique. However, the Co(II)/Co(III)/tetraglycine system is irreversible. Those studies showed that the Cu(III) and Ni(III) species generated on the disk electrode are unstable in the employed experimental conditions. The positive sinergistic effect in the presence of Ni(II) (which allowed to increase the sensibility) was taken in advantage for development of one simple and sensitive spectrophotometric and amperometric method for indirect determination of sulfite in aqueous medium. The spectrophotometric method is based on the absorbance measurement of the Cu(III)/tetraglicyne complex (generated in the presence of sulfite and small quantities of Ni(II)) at 365 nm. The amperometric method by flow injection analysis is based on the current measurement (0.1 V vs Ag/AgCl) as function of Cu(III)/tetraglycine concentration chemically generated, in the presence of sulfite and Ni(II). The methods were employed for the determination of S(IV), in wines and juices, after its extraction from acidified samples and the results were in agreement with those obtained by the iodometric procedure.
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Étude du modèle d’arthrose par rupture du ligament croisé crânial chez le lapin : suivi biologique et évaluation histologique / Histological and biological analysis of anterior cruciate ligament transection experimental model in young and adult rabbitsDuclos, Marie-Ève 12 February 2010 (has links)
Les objectifs de ce travail étaient l’évaluation de stades précoces et tardifs de l’arthrose grâce à une étude histologique et biologique de l’arthrose sur un modèle de rupture de ligament croisé crânial chez le lapin (RLCC) et l’évaluation de l’effet de l’âge sur l’évolution de la maladie. L’étude biologique a été réalisée par le dosage sérique d’un marqueur de la dégradation du collagène de type II, le CTX-II, jusqu’à 20 semaines post-chirurgie. Chez les animaux adultes, les concentrations du CTX-II étaient influencées par la chirurgie et par le développement de la pathologie. Chez les jeunes animaux, les niveaux de CTX-II étaient plus élevés en début d’étude et diminuaient au cours du temps. Chez ce groupe d'animaux, les taux de CTX-II n’étaient pas modifiés par l’intervention chirurgicale. L’étude histologique a été réalisée avec une analyse histomorphologique du cartilage et des analyses histomorphométriques du cartilage et de l’os sous-chondral. L’évaluation histologique a permis d’observer des changements liés à l’arthrose chez tous les animaux opérés. Les altérations au niveau du cartilage étaient plus sévères chez les animaux adultes que chez les jeunes, ces derniers présentant une meilleure capacité de compensation à l’instabilité articulaire. Il a été démontré que l’analyse de la plaque osseuse sous-chondrale a permis de distinguer les animaux opérés des animaux non-opérés dans les 2 groupes d’âge, mais les surfaces articulaires affectées n’étaient pas toujours les mêmes. En conclusion, ce travail suggère l’intérêt du CTX-II dans l’évaluation de l’arthrose, mais aussi la pertinence d’effectuer plusieurs temps d’analyse pour mieux connaître l’évolution de la maladie. Les analyses histologiques ont permis de mettre en évidence des changements au niveau du cartilage et de l’os sous-chondral. Les différences observées entre les lapins adultes et les jeunes remettent en question l'utilisation d’animaux trop jeunes dans les études portant sur l’arthrose / The goals of this work were the evaluation of early and late stages of osteoarthritis through a histological and biological study of osteoarthritis using a rabbit model of the anterior cruciate ligament transaction (ACLT) and the evaluation of the effect of age on the evolution of the disease. Biological study was performed with longitudinal analysis of serum level of CTX-II, a marker a type II collagen degradation. In adult animals, serum concentration of CTX-II was influenced by the ACLT surgery and varied with time. In the young rabbits, the serum levels of CTX-II were more elevated at the beginning of study and decrease after. In this animal group, the rates of CTX-II were not influenced by surgical operation. Histological study was accomplished with both histomorphological analysis of the cartilage and with histomorphometric study of both cartilage and sub-chondral bone. Histological evaluation showed osteoarthritis changes in all operated animals. Changes of the cartilage appeared more severe in the adult group compared to the young rabbits, suggesting that these last have a better compensation capacity during articular instability. Bony changes allowed to differentiate operated animals from the unoperated, but the affected articular surfaces were not always the same. In conclusion, this study suggest the interest of the CTX-II biomarker in the evaluation of osteoarthritis, but also the pertinence to perform several time points of analysis to know better the disease evolution. The histological analysis allowed to put in an obvious place changes at the levels of the cartilage and of the sub-chondral bone. Difference noticed between the adult animals and the young rabbits offers a new look for the use of too young animals in osteoarthritis studies
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Régulation des chaperons de la présentation antigénique par ubiquitinationLadouceur, Annie 05 1900 (has links)
La chaîne invariante forme un complexe nonamérique avec les molécules classiques du CMH de classe II. HLA-DM et HLA-DO, des molécules non-classiques de classe II, sont aussi impliquées dans la présentation des peptides antigéniques aux lymphocytes T. Ces molécules chaperones de la présentation antigénique modulent la capacité d’une cellule à présenter des antigènes par les moloécules classiques du CMH de classe II. La régulation transcriptionnelle des molécules chaperones, tout comme celle des autres molécules du CMH de classe II, est assurée par le transactivateur CIITA. La molécule HLA-DR peut être régulée négativement de manière post-traductionnelle par ubiquitination grâce à l’enzyme E3 ubiquitine ligase MARCH1. Celle-ci est induite par l’interleukine-10 dans les monocytes. L’objectif de ce projet était de déterminer si l’ubiquitination par MARCH1 peut aussi réguler l’expression des molécules chaperones de la présentation antigénique. Les expériences furent réalisées dans le contexte de co-transfections en cellules HEK293T. L’expression des molécules fut évaluée par immunomarquages et cytométrie de flux. Il a été montré que l’isoforme p33 de la chaîne invariante est régulé négativement en présence de MARCH1 à partir de la surface cellulaire, causant ainsi sa dégradation. Tel que démontré par l’utilisation d’un mutant dépourvu de queue cytoplasmique, cette dernière région n’est pas indispensable à ce phénomène. Une hypothèse est qu’une molécule non-identifiée, associée à Ii, serait ubiquitinée par MARCH1, l’entraînant dans sa régulation négative. Il fut déterminer que cette molécule n’était pas CXCR2, un récepteur pouvant être impliqué, avec la chaîne invariante et CD44, en tant que récepteur de MIF (Macrophage Inhibitory Factor). Il fut aussi montré que HLA-DO peut être ciblé par MARCH1 mais ceci ne semble pas être un phénomène dominant; l’expression des complexes DO/DM n’étant pas affectée bien qu’ils entrent en interaction avec MARCH1. L’expression de HLA-DM n’est pas affectée par MARCH1. Il n’a toutefois pas été déterminé hors de tout doute si MARCH1 peut modifier DM; des résultats obtenus avec une queue cytoplasmique de DM possédant une lysine laissant suggérer qu’il est possible que MARCH1 interagisse avec DM. Dans l’ensemble, les travaux démontrent que l’ubiquitination par MARCH1 joue un rôle dans la régulation post-transcriptionnelle de la chaîne invariante p33 mais pas HLA-DO et HLA-DM. / The invariant chain, which form a nonameric complex with the classical MHC class II molecules. HLA-DM and HLA-DO (non-classical class II molecules) are involved in the presentation of antigens to T lymphocytes. The chaperons molecules of the antigenic presentation can modulate the capacity of the cells to present antigens. The transcriptional regulation of the chaperons and all of the other molecules linked to the MHC is assured by the CIITA transactivator. Little is know of the post-transcriptional mechanisms, other than the fact that HLA-DR molecule can be down-regulated by ubiquitination due to E3 ubiquitin ligase MARCH1. MARCH1 is induce by interleukin-10 in monocytes. The goal of this project is to figure out if ubiquitination by MARCH1 can also regulate the expression of the antigenic presentation chaperons. The experiences were performed in the context of co-transfections in HEK293T cells and the expression of the diverses molecules was evaluated by cell stainings and FACS analysis. The p33 isoform of the invariant chain was found to be down-regulated and degraded in the presence of MARCH1. The invariant chain cytoplasmic tail is not completely essential to this phenomenon; a non-identified molecule, associated with Ii, is probably ubiquitinated by MARCH1 and is then down-regulated, together with Ii. It was shown tha CXCR2, a reeptor involved with the invariant chain and CD44 in the reception of the MIF signal, is not that molecule. HLA-DO can ben targetd by MARCH1 but this does not seem to be a general phenomenon; the expression of the DO/DM complexes remaning unaffected even with the interaction of those complexes with MARCH1. Therefore, a certain protection seem to be provided by HLA-DM to HLA-DO. The expression of HLA-DM itself is not affected by the presence of MARCH1. However, it was not cleary demonstrated if MARCH1 can modify DM. Some results obtained with a cytoplasmic tail of DM comprising an additional lysine suggest that there is a possibility that MARCH1 interact with DM. Generally, the work presented here show that ubiquitination by MARCH1 is involved in post-transcriptionnal regulation of the p33 isoform of the invariant chain but not in the regulation of HLA-DO and HLA-DM.
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