Les nucléotides naturels sont les monomères constitutifs de l’ADN et de l’ARN, et sont nécessaires à la prolifération des cellules cancéreuses et des virus. L’utilisation d’analogues de nucléosides comme agents anti-cancéreux et/ou antiviraux a rapidement suscité un grand intérêt thérapeutique. Plusieurs analogues comportant un centre quaternaire carboné en position C3' ont été synthétisés par le laboratoire du Dr. Guindon et possèdent d’intéressantes activités biologiques. Une nouvelle approche acyclique a été développée afin d’accéder efficacement et sélectivement à une multitude de nouveaux analogues de nucléosides ciblés. Cette stratégie se distingue par l’élaboration d’une nouvelle réaction d’aldolisation de Mukaiyama énantiosélective à partir d’un alpha-alkoxy aldéhyde protégé et d’un complexe chiral. L’addition stéréosélective de la nucléobase sur un précurseur dithioacétal, suivi d’une cyclisation intramoléculaire de type « SN2-like », permet la synthèse directe des anomères alpha de la série (D)-1',2'-trans porteurs d’un atome de fluor en C2' et d’un centre quaternaire en C3'. La différenciation des deux alcools primaires rend possible la fonctionnalisation sélective sur la position C3' ou C5' en fin de synthèse pour potentiellement conférer une amélioration des propriétés biologiques sur de tels analogues. L’application de cette stratégie a également permis de synthétiser facilement et efficacement une nouvelle famille d’analogues de nucléosides C2'-désoxy porteurs d’un centre quaternaire en C3'. La différenciation des deux alcools primaires en C3' et C5' facilite la séparation des produits de glycosylation suite à la déprotection sélective d’une de ces deux positions. Il a été déterminé que lorsque le précurseur de glycosylation contient une acétylglycine sur la position C3', un effet bêta-directeur est induit. Finalement, de nouveaux analogues C2'-désoxy ont été préparés et sont présentement testés contre une série de virus et d’enzymes polymérases. / Natural nucleotides are the constituent monomers of DNA and RNA, and are necessary for the proliferation of cancer cells and viruses. The use of nucleoside analogues as anti-cancer and/or antiviral agents quickly aroused great therapeutic interest. Several analogues containing an all-carbon quaternary center in the C3' position have been synthesized by the Guindon laboratory and have interesting biological activities. A new acyclic approach has been developed in order to gain efficient and selective access to a multitude of these novel targeted nucleoside analogues. This strategy is distinguished by the development of a new enantioselective Mukaiyama aldol reaction starting from a protected alpha-alkoxy aldehyde and a chiral complex. The stereoselective addition of the nucleobase on an acyclic dithioacetal precursor, followed by an intramolecular SN2-like cyclization, allows the direct synthesis of alpha-anomers in the (D) -1',2'-trans series bearing a fluorine atom at the C2' position and a quaternary center at C3'. The differentiation of the two primary alcohols throughout the synthetic routes is necessary to selectively functionalize the C3' or C5' position at the end of the synthesis to potentially confer enhanced biological properties on such analogues. The application of this strategy has also made it possible to easily and efficiently synthesize a new family of C2'-deoxy analogues bearing a C3' quaternary center. The differentiation of the C3' and C5' primary alcohols facilitates the separation of the glycosylation products through the selective deprotection of one of these two positions. It has been determined that when the glycosylation precursor contains an acetylglycine at the C3' position, a bêta-directing effect is induced. Finally, new C2'-deoxy analogues have been prepared and are currently being tested against a series of viruses and polymerase enzymes.

[pt] O envolvimento de militares em operações de resposta a desastres, emergências e crises vem aumentando, pois além dessas situações apresentarem complexidades cujo enfrentamento faz parte de sua doutrina, os militares possuem infraestrutura e treinamento necessários à prestação de assistência humanitária. O Comando e Controle (C2) exercido nas operações militares é considerado essencial dada a complexidade para realização dessas operações. A literatura científica sobre C2 é, em sua maior parte, registrada como doutrina militar, baseada no empirismo. O presente estudo objetiva compreender como o C2 é realizado pelos militares em duas operações humanitárias acionadas pelo Ministério da Defesa. E com tal propósito, é realizada uma revisão da literatura sobre elementos essenciais do C2, como sua definição, ações, funções, níveis, meios e ativos para sua realização e agentes envolvidos. A partir de 22 documentos resultantes da revisão da literatura, são apresentados uma taxonomia, uma proposta de definição de C2 e um framework que visa auxiliar acadêmicos, profissionais da área e as Forças Armadas. Posteriormente, para verificar a factibilidade dos elementos identificados na literatura e sua aplicação nessas operações, são propostos dois estudos de caso: um sobre a Operação Acolhida, que oferece assistência emergencial aos imigrantes e refugiados venezuelanos, e outro sobre a Operação Carro-pipa, que contempla ações de distribuição de água potável às populações rurais atingidas pela estiagem e seca. Como resultado, essa pesquisa identifica que a forma como o C2 é realizada pelos militares depende do tipo de desastre e do nível em que o C2 está sendo exercido, além de contribuir academicamente pela proposição de uma definição de C2, uma taxonomia e um framework acerca do C2 exercido pelos militares em operações de resposta a desastres, emergências e crises. / [en] The involvement of the military in disaster, emergency, and crisis response operations has been increasing, as in addition to these situations presenting complexities similar to those faced on the battlefield, they have the infrastructure and training necessary to provide humanitarian assistance. The Command and Control (C2) exercised by the military is considered essential given the complexity of carrying out these operations. The scientific literature on C2 is, for the most part, registered as military doctrine, based on empiricism. This study aims to understand how C2 is performed by the military in two humanitarian operations triggered by the Ministry of Defense. And with this purpose, a literature review is carried out on essential elements of C2, such as its definition, actions, functions, levels, means, and assets for its realization and agents involved. From 22 documents resulting from the literature review, a taxonomy, a proposed definition of C2, and a framework that aims to support academics, professionals in the field, and the Armed Forces are presented. Subsequently, to verify the feasibility of the elements identified in the literature and their application in these operations, two case studies are proposed: one on Operação Acolhida, which offers emergency assistance to Venezuelan immigrants and refugees, and another on Operação Carro-pipa, which includes actions for the distribution of drinking water to rural populations affected by drought and dry season. As a result, this research identifies that the manner C2 is performed by the military depends on the type of disaster and the level at which C2 is being exercised, in addition to contributing academically by proposing a definition of C2, a taxonomy, and a framework about of the C2 exercised by the military in disaster, emergency, and crisis response operations.

No description available.

Some metals and metalloids make significant contributions to the harmful effects of tobacco consumption although understanding the mechanisms involved in toxicity is hampered by the lack of information on their chemical and valence species, both in tobacco and in smoke. This research addresses the speciation of the metals and metalloids most frequently implicated, particularly those elements that exist in nature in multiple valence states, namely arsenic (As) and chromium (Cr), there being considerable differences in toxicity with oxidation state. A strategy was devised to overcome some of the problems that have thwarted earlier attempts at speciation. Firstly tobacco plants were cultivated under controlled conditions in compost burdened with high levels of metals and metalloids resulting in leaf with up to 250 µg g⁻¹ As, although Cr uptake was less successful. Secondly valence speciation even at the exceptionally low concentrations of As and Cr in smoke from unburdened tobacco was achieved with XANES analysis using the exceptionally bright Diamond synchrotron source. This revealed that combustion of tobacco has a marked effect on valence speciation with As(III), the reduced form of As, dominating (and persisting) in condensate of tobacco smoke while ash is dominated by the oxidised form, As(V). Chromium also appears to be present in smoke mainly as reduced Cr(III) species. HPLC-ICPMS analysis of arsenic indicates the dominance of inorganic over organic species (~4:1). Other metals were investigated in less detail. These findings establish that arsenic is present in smoke in its most toxic form and represents a significant risk to health. Conversely smokers appear to be exposed to the less harmful species of chromium. These results support a recent WHO report that includes As but not Cr in a list of four metals and metalloids recommended for regulation in crops and commercial products in the interests of public health.

This paper analyses the sources of income measurement error in surveys with a unique dataset.We use the Austrian 2008-2011 waves of EU-SILC which provide individual information on wages,pensions and unemployment benefits from survey interviews and officially linked administrativerecords. Thus, we do not have to fall back on complex two-sample matching procedures likerelated studies. We empirically investigate four sources of measurement error, namely (i) socialdesirability, (ii) socio-demographic characteristics of the respondent, (iii) the survey design, and(iv) the presence of learning effects. We find strong evidence for a social desirability bias inincome reporting, while the presence of learning effects is mixed and depends on the income typeunder consideration. An Owen value decomposition reveals that social desirability is a majorexplanation of misreporting in wages and pensions, whereas socio-demographic characteristicsare most relevant for mismatches in unemployment benefits. / Series: INEQ Working Paper Series

La durabilité des composants mécaniques en général et leur résistance à la corrosion en particulier ont une importance primordiale dans l’industrie moderne, qu’elle concerne la production d’énergie, les produits chimiques, le transport, les machines, les matériels médicaux, ou même les composants électroniques. Pour des pièces obtenues par usinage, il est donc nécessaire d’améliorer leur durée de vie et de réduire le risque de défaillance prématurée en améliorant leur intégrité de surface. Ainsi, une compréhension de l’effet du procédé sur l’intégrité de surface induite par usinage et ses conséquences au niveau de sa résistance à la corrosion sont les clés pour relever ces défis.Cette thèse traite le cas particulier de l’usinage de finition du cuivre Cu-c2 et son impact sur la résistance à la corrosion. D’abord, une étude expérimentale comparative du tournage et de la coupe orthogonale est effectuée. Ensuite, vu sa simplicité, la coupe orthogonale fait l’objet de la suite de l’étude. Un modèle numérique est développé pour la prédiction de l’intégrité de surface induite par la coupe. Il utilise une nouvelle loi constitutive du Cu-c2 tenant en compte les transformations microstructurales et l’état des contraintes dans le matériau. Enfin, les résultats issus des études expérimentales ainsi que des simulations numériques concernant l’intégrité de surface sont statistiquement traités dans une analyse multi-physique, dans la perspective d’établir le lien entre la résistance à la corrosion, l’intégrité des surfaces et la physique de la coupe. / The functional performance and life of mechanical components in general and their corrosion resistance in particular are of prime importance in the modern industry, as far as energy production, transportation, machines, medical and even electronic components are concerned. In the case of machined components, it is essential to improve their life and to reduce the premature failure by improving their surface integrity. So, a comprehension of the effect of the machining process mechanics on surface integrity and its consequences on corrosion resistance are essential.This thesis deals with the particular case of finishing machining of oxygen free high conductivity copper (OFHC) and its impact on the surface integrity and corrosion resistance. Firstly, a comparative experimental study between turning and orthogonal cutting is performed. Then, due to its simplicity, orthogonal cutting makes the object of the pursuit of the study. A numerical model is developed to predict the surface integrity induced by the cutting process. It uses a new constitutive model for OFHC copper taking into account microstructural transformations and the state of stress in the work material. Finally, the results issued from experimental studies and the numerical simulations are statistically treated in a multi-physical analysis with the objective of establishing the relationship between corrosion resistance, surface integrity and cutting physics.

La levure Yarrowia lipolytica est une levure oléagineuse capable de croître sur les substrats hydrophobes et les composés en C2 comme seul source de carbonne. La première partie de notre étude a permis de déterminer la localisation des protéines Lro1p et Dga1p impliquées dans la dernière étape de la synthèse des triglycérides. Ces protéines sont localisées dans la membrane cytoplasmique et à la surface des corps lipidique pour Lro1p et à la surface des corps lipidique pour Lro1p et à la surface des corps lipidiques pour dga1p. La deuxième partie de cette étude a permis d'avoir une idée plus précise du fonctionnement du cycle du glyoxylate chez la levure Y. lipolytica. Le premier objectif de cette deuxième partie de notre étude était de comprendre le fonctionnement du gène de la malate déshydrogénase chez cette levure. Contrairement à la levure S. cerevisiae qui possède trois gènes codant pour une malate déshydrogénaze, Y. lipolytica ne possède que deux gènes. Le premier gène YALI0D16753g code une malate déshydrogénase mitochondriale et le second gène YALI0E14190g présente une particularité d'épissage alternatif. En effet, le gène YALI0E14190g, en fonction de l'épissage, code une malate déshydrogénase cytoplasmique (séquence C-terminale PAN) ou une malate déshydrogénase adressée aux peroxysomes (séquence C-terminale AKI). Dans une troisième partie, nous nous sommes intéressés aux autres gènes du cycle du glyoxylate. La disruption du gène ICL1 a entrainé une incapacité de croissance du mutant sur acide oléique et sur les composés en C2 (éthanol, acétate). Néanmoins la suppression MLS et CIT2 n'a pas eu d'impact lors de la croissance sur les milieux nécessitant l'implication cycle du glyoxylate.

<p>Cancer immunotherapy aims at reversing the immunosuppressive tumor environment and enhancing anti-tumor immunity. This thesis comprises studies on murine models for prostate (TRAMP-C2) and bladder (MB49) cancer with the aim to explore if the introduction of an adenoviral vector expressing CD40 ligand (AdCD40L) can induce anti-tumor immune responses.</p><p>We show in subcutaneous mouse models that AdCD40L treatment suppresses tumor growth. Bladder cancer is known to secrete immunosuppressive IL-10 which may inhibit T cell function. We show that introducing AdCD40L into mouse bladder tumors inhibits IL-10 production and reverses immunosuppression. AdCD40L-transduced mouse prostate cancer cells showed caspase activation and reduced cell viability. Vaccination with CD40L-modified prostate cancer cells induces anti-tumor responses and protects mice against rechallenge with native TRAMP-C2 cells. In order to enhance AdCD40L therapy, we explored the possibility of combining it with the histone deacetylase inhibitor FK228, also known as depsipeptide. We show that FK228 upregulates coxsackie and adenovirus receptor expression and thereby enhances adenoviral-mediated CD40L expression in both murine and human prostate cancer cells. Increasing amounts of FK228 or AdCD40L reduces prostate cancer cell viability, while the combined treatment gives at least an additive therapeutic effect. Moreover, we show that AdCD40L transduction of prostate cancer cells induces endogenous CD40 expression and sensitize them for CD40L-mediated therapy.</p><p>In order to conduct prostate-specific gene therapy, prostate-specific promoters can be used to drive transgene expression. However, there are no reports on prostate-specific promoters that are transcriptionally active in mouse cells. Here we show that by using the two-step transcription activation system (TSTA), we can enhance the activity of a recombinant human promoter sequence and obtain activity in mouse prostate cancer cells as well. This finding paves the way for future studies of prostate-specific gene therapy in immunocompetent mouse models.</p>

No description available.

Cancer immunotherapy aims at reversing the immunosuppressive tumor environment and enhancing anti-tumor immunity. This thesis comprises studies on murine models for prostate (TRAMP-C2) and bladder (MB49) cancer with the aim to explore if the introduction of an adenoviral vector expressing CD40 ligand (AdCD40L) can induce anti-tumor immune responses. We show in subcutaneous mouse models that AdCD40L treatment suppresses tumor growth. Bladder cancer is known to secrete immunosuppressive IL-10 which may inhibit T cell function. We show that introducing AdCD40L into mouse bladder tumors inhibits IL-10 production and reverses immunosuppression. AdCD40L-transduced mouse prostate cancer cells showed caspase activation and reduced cell viability. Vaccination with CD40L-modified prostate cancer cells induces anti-tumor responses and protects mice against rechallenge with native TRAMP-C2 cells. In order to enhance AdCD40L therapy, we explored the possibility of combining it with the histone deacetylase inhibitor FK228, also known as depsipeptide. We show that FK228 upregulates coxsackie and adenovirus receptor expression and thereby enhances adenoviral-mediated CD40L expression in both murine and human prostate cancer cells. Increasing amounts of FK228 or AdCD40L reduces prostate cancer cell viability, while the combined treatment gives at least an additive therapeutic effect. Moreover, we show that AdCD40L transduction of prostate cancer cells induces endogenous CD40 expression and sensitize them for CD40L-mediated therapy. In order to conduct prostate-specific gene therapy, prostate-specific promoters can be used to drive transgene expression. However, there are no reports on prostate-specific promoters that are transcriptionally active in mouse cells. Here we show that by using the two-step transcription activation system (TSTA), we can enhance the activity of a recombinant human promoter sequence and obtain activity in mouse prostate cancer cells as well. This finding paves the way for future studies of prostate-specific gene therapy in immunocompetent mouse models.