Production d'IgG sialylées en CHO et impact sur leurs fonctions effectrices

La sialylation des N-glycanes du fragment Fc des immunogobulines G (IgG) est une modification peu fréquente des IgG humaines. Pourtant, elle est l’objet de beaucoup d’attention depuis que deux articles fondateurs ont été publiés, qui montrent l’un que la sialylation des IgG diminue leur capacité à déclencher la cytotoxicité cellulaire dépendant de l’anticorps (ADCC), et l’autre que les IgG sialylées en α2,6 seraient la fraction efficace des IgG intraveineuses (IgIV) anti-inflammatoires. Les anticorps monoclonaux thérapeutiques, qui sont le plus souvent des IgG recombinantes produites en culture de cellules de mammifère, connaissent depuis la fin des années 90 un succès et une croissance phénoménaux sur le marché pharmaceutique. La maîtrise de la N-glycosylation du Fc des IgG est une clé de l’efficacité des anticorps monoclonaux. Si les IgG sialylées sont des molécules peu fréquentes in vivo, elles sont très rares en culture cellulaire. Dans cette étude, nous avons développé une méthode de production d’IgG avec une sialylation de type humain en cellules CHO. Nous avons travaillé principalement sur la mise au point d’une stratégie de production d’IgG sialylées par co-expression transitoire d’une IgG1 avec la β1,4-galactosyltransférase I (β4GTI) et la β-galactoside-α2,6-sialyltransférase I (ST6GalI). Nous avons montré que cette méthode permettait d’enrichir l’IgG1 en glycane fucosylé di-galactosylé mono-α2,6-sialylé G2FS(6)1, qui est le glycane sialylé présent sur les IgG humaines. Nous avons ensuite adapté cette méthode à la production d’IgG présentant des profils de glycosylation riches en acides sialiques, riches en galactose terminal, et/ou appauvris en fucosylation. L’analyse des profils de glycosylation obtenus par la co-expression de diverses combinaisons enzymatiques avec l’IgG1 native ou une version mutante de l’IgG1 (F243A), a permis de discuter des influences respectives de la sous-galactosylation des IgG1 en CHO et des contraintes structurales du Fc dans la limitation de la sialylation des IgG en CHO. Nous avons ensuite utilisé les IgG1 produites avec différents profils de glycosylation afin d’évaluer l’impact de la sialylation α2,6 sur l’interaction de l’IgG avec le récepteur FcγRIIIa, principal récepteur impliqué dans la réponse ADCC. Nous avons montré que la sialylation α2,6 augmentait la stabilité du complexe formé par l’IgG avec le FcγRIIIa, mais que ce bénéfice n’était pas directement traduit par une augmentation de l’efficacité ADCC de l’anticorps. Enfin, nous avons débuté le développement d’une plateforme d’expression stable d’IgG sialylées compatible avec une production à l’échelle industrielle. Nous avons obtenu une lignée capable de produire des IgG enrichies en G2FS(6)1 à hauteur de 400 mg/L. Cette étude a contribué à une meilleure compréhension de l’impact de la sialylation sur les fonctions effectrices des IgG, et a permis d’augmenter la maîtrise des techniques de modulation du profil de glycosylation des IgG en culture cellulaire.

Modos de intervención criminal punible en crímenes de atrocidad: un análisis jurídico-penal a partir de los aportes de la criminología

790 p.

Absolute Inequality and Violent Property Crime

Rational choice models argue that income inequality leads to a higher expected utility of crime and thus generates incentives to engage in illegal activities. Yet, the results of empirical studies do not provide strong support for this theory; in fact, Neumayer provides apparently strong evidence that income inequality is not a significant determinant of violent property crime rates when a representative sample is used and country specific fixed effects are controlled for. An important limitation of this and other empirical studies on the subject is that they only consider proportional income differences, even though in rational choice models absolute difference in legal and illegal incomes determine the expected utility of crime. Using the same methodology and data as Neumayer, but using absolute inequality measures rather than proportional ones, this paper finds that absolute income inequality is a statistically significant determinant of robbery and violent theft rates. This result is robust to changes in sample size and to different absolute inequality measures, which not only implies that inequality is an important correlate of violent property crime rates but also suggests that absolute measures are preferable when the impact of inequality on property crime is studied.

Processo de implantação de um sistema integrado de gestão em uma organização pública à luz da teoria da hospitalidade :um estudo de caso

In the present time, public organizations are employing more and more solutions that uses information technology in order to ofer more transparency and better services for all citizens. Integrated Systems are IT which carry in their kernel features of integration and the use of a unique database. These systems bring several benefits and face some obstacles that make their adoption difficult. The conversion to a integrated system may take years and, thus, the study of the adoption of this IT in public sector organizations become very stimulant due to some peculiarities of this sector and the features of this technology. First of all, information about the particular integrated system in study and about its process of conversion are offered. Then, the researcher designs the configuration of the conversion process aim of this study the agents envolved and the moments and the tools used to support the process in order to elaborate the methodology of the conversion process understood as the set of procedures and tools used during all the conversion process. After this, the researcher points out, together with all the members of the conversion team, the negative and positive factors during the project. Finally, these factors were analysed through the Hospitality Theory lens which, in the researcher opinion, was very useful to understand the elements, events and moments that interfered in the project. The results consolidated empirically the Hospitality Theory presumptions, showing yet a limitation of this theory in the case in study

Cuidados paliativo em crianças portadoras de malformações cerebrais

Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Bioética, 2016.

Current Legal Rules Benefit Spray Applicators When It Comes to Pesticide Drift

Homeowners, landowners, pesticide applicators, and farmers are concerned about pesticide drift. It may injure a homeowner’s garden or flowers or ruin a neighboring farmer’s crop. While no Maryland court has considered the issue of liability from pesticide drift, courts in other states have. These decisions provide some guidance on how a Maryland court might handle the issue. Depending on the facts of the drift case, pesticide applicators and farmers could owe damages for nuisance or trespass case, or for uses inconsistent with the pesticide label.

A cartola mágica : um instrumento de intervenção em perturbações da linguagem

"As perturbações da linguagem apresentam um elevado risco para dificuldades de aprendizagem e podem comprometer a inserção escolar e social das crianças afetadas. Quando a fala não se constitui como um meio de linguagem expressiva, torna-se muito importante proporcionar à criança uma intervenção terapêutica precoce.Com este propósito foi criado um instrumento lúdico-pedagógico para a terapia de fala, capaz de dar suporte conjunto aos cinco domínios linguísticos e que é facilmente apreendido pela criança, favorecendo a sua aprendizagem. O instrumento de intervenção designado por “A Cartola Mágica” é personificado num gato com uma cartola anatomicamente compartimentada em forma de gavetas, simbolizando os cinco domínios da linguagem, destinado a crianças com idades compreendidas entre os 5 e os 8 anos. O instrumento pode ser utilizado em várias vertentes linguísticas, de acordo com os objetivos terapêuticos pretendidos. O instrumento apresenta como limite a portabilidade do modelo criado e, como alcance empírico, o fato de incluir todos os domínios da linguagem e ser de fácil aplicação em settings terapêuticos restritos."

História de aprendizagem e seus contextos : uma análise comportamental das aquisições corporativas

Tese (doutorado)—Universidade de Brasília, Faculdade de Economia, Administração e Contabilidade, Programa de Pós-Graduação em Administração, 2016.

O Emprego Operacional das Unidades de Reconhecimento Blindado na Guerra de África (1961-1975)

Com esta investigação pretende-se avaliar se as missões, a organização, os sistemas de armas, a instrução ou o treino das Unidades de reconhecimento, originalmente vocacionadas para atuar em operações convencionais, se constituíram como fatores limitadores do seu emprego na Guerra de África. Na realização desta investigação foi feito um estudo pormenorizado dos fatores em cima referidos. Quanto às missões, organização, instrução e treino foi realizado um estudo comparativo entre aquilo que existia, e que era praticado, com aquilo que foi executado e utilizado na guerra de África. Este estudo pretendia perceber as diferenças que existiram, e se estas foram de facto uma influência limitadora ao emprego destas unidades. Quanto aos sistemas de armas, foram analisados aqueles que foram empregues em África, pretendendo-se assim perceber quais é que foram as restrições destes sistemas. Para a realização desta investigação utilizamos o procedimento histórico e comparativo para realizarmos à comparação entre aquilo que existia e o que se executou no terreno, nos fatores missões, organização e instrução e treino. Na análise dos sistemas de armas utilizámos o procedimento histórico para a enumeração dos sistemas empregues e suas limitações. No final do estudo de cada fator deduzimos mediante os dados que foram sendo apresentados, se estes foram limitadores ao emprego destas unidades. Na recolha de dados utilizámos a pesquisa documental para a consulta de Quadros Orgânicos (QO), relatórios das unidades, relatórios das regiões militares, bem como manuais doutrinários das unidades de reconhecimento blindado. Utilizámos também a pesquisa bibliográfica para a consulta de teses sobre o reconhecimento blindado, artigos da Revista da Cavalaria, resenhas das campanhas de África, bem como livros alusivos à subversão e às campanhas de África. No final deste trabalho verificámos que os sistemas de armas foram a maior limitação destas unidades, pelo simples facto de terem influenciado todos os outros fatores em análise. Contudo vemos que as razões desta influência sobre os outros fatores poderiam verificar-se em qualquer tipo de conflito, visto serem derivadas dos problemas de sustentação das viaturas. Realmente existiram pequenas limitações em todos os fatores de análise neste conflito, em relação ao convencional, sendo que nos parece que foram contornadas com dedicação, e capacidade de improvisação das forças Portuguesas, para as ultrapassar.

Natural plant polyphenols for alleviating oxidative damage in man: Current status and future perspectives

The balance between oxidation and reduction is important for maintaining a healthy biological system. Oxidative stress results from an imbalance between excessive formation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) and limited endogenous defense systems, and this imbalance can adversely alter lipids, proteins and DNA, causing a number of human diseases. Thus, exogenous antioxidants that can neutralize the effect of free radicals are needed to diminish the cumulative effects of oxidative damage over human life span. Current research reveals that phenolic compounds in plants possess high antioxidant activity and free radical scavenging capacity and can prevent the body from oxidative damage over human life span. This review focuses on the present understanding of free radicals and antioxidants and their importance in human health and disease. Information about the chemical features of free radicals as well as their deleterious effects on cell structures is reviewed. The chemical structure and anti-oxidative mechanisms of essential polyphenols and their potential health benefits are presented. In addition, the limitation of natural antioxidants and a perspective on likely future trends in this field are also discussed.

Efficient Hill Climber for Constrained Pseudo-Boolean Optimization Problems

Efficient hill climbers have been recently proposed for single- and multi-objective pseudo-Boolean optimization problems. For $k$-bounded pseudo-Boolean functions where each variable appears in at most a constant number of subfunctions, it has been theoretically proven that the neighborhood of a solution can be explored in constant time. These hill climbers, combined with a high-level exploration strategy, have shown to improve state of the art methods in experimental studies and open the door to the so-called Gray Box Optimization, where part, but not all, of the details of the objective functions are used to better explore the search space. One important limitation of all the previous proposals is that they can only be applied to unconstrained pseudo-Boolean optimization problems. In this work, we address the constrained case for multi-objective $k$-bounded pseudo-Boolean optimization problems. We find that adding constraints to the pseudo-Boolean problem has a linear computational cost in the hill climber.

La responsabilité civile dans les cas de dommages causés par les robots d’assistance au Québec

Le développement exponentiel de la technologie et le vieillissement de la population permettent d’introduire dans notre quotidien les robots d’assistance. La coexistence de l’homme avec ces robots intelligents et autonomes soulève une question fondamentale: dans l’éventualité où un robot provoquerait un accident causant un dommage à une personne ou à un bien qui serait le responsable? Aucune loi ne réglemente les activités de la robotique d’assistance dans le monde. Cette étude vise l’analyse de l’applicabilité des régimes de responsabilité du Code Civil du Québec aux cas de dommages causés par le robot d’assistance. L’analyse des régimes de responsabilité du Code civil du Québec permet de constater que deux régimes de responsabilité sont susceptibles d’être appliqués aux cas spécifiques de dommages causés par le robot d’assistance: le régime de responsabilité du fait des biens, énoncé à l’article 1465 C.c.Q., et le régime de responsabilité du fait des fabricants et vendeurs spécialisés, énoncé à l’article 1468 C.c.Q. Cela s’explique par la présence de critères et de conditions de mise en œuvre des régimes qui sont transposables aux différents aspects concernant la fabrication et l’utilisation du robot d’assistance.

Fibre Bragg gratings fabrication in four core fibres

Due to the limitation of the lens effect of the optical fibre and the inhomogeneity of the laser fluence on different cores, it is still challenging to controllably inscribe different fibre Bragg gratings (FBGs) in multicore fibres. In this article, we reported the FBG inscription in four core fibres (FCFs), whose cores are arranged in the corners of a square lattice. By investigating the influence of different inscription conditions during inscription, different results, such as simultaneous inscription of all cores, selectively inscription of individual or two cores, and even double scanning in perpendicular core couples by diagonal, are achieved. The phase mask scanning method, consisting of a 244nm Argon-ion frequencydoubled laser, air-bearing linear transfer stage and cylindrical lens and mirror setup, is used to precisely control the grating inscription in FCFs. The influence of three factors is systematically investigated to overcome the limitations, and they are the defocusing length between the cylindrical lens and the bare fibre, the rotation geometry of the fibre to the irritation beam, and the relative position of the fibre in the vertical direction of the laser beam.

La responsabilité civile dans les cas de dommages causés par les robots d’assistance au Québec

Le développement exponentiel de la technologie et le vieillissement de la population permettent d’introduire dans notre quotidien les robots d’assistance. La coexistence de l’homme avec ces robots intelligents et autonomes soulève une question fondamentale: dans l’éventualité où un robot provoquerait un accident causant un dommage à une personne ou à un bien qui serait le responsable? Aucune loi ne réglemente les activités de la robotique d’assistance dans le monde. Cette étude vise l’analyse de l’applicabilité des régimes de responsabilité du Code Civil du Québec aux cas de dommages causés par le robot d’assistance. L’analyse des régimes de responsabilité du Code civil du Québec permet de constater que deux régimes de responsabilité sont susceptibles d’être appliqués aux cas spécifiques de dommages causés par le robot d’assistance: le régime de responsabilité du fait des biens, énoncé à l’article 1465 C.c.Q., et le régime de responsabilité du fait des fabricants et vendeurs spécialisés, énoncé à l’article 1468 C.c.Q. Cela s’explique par la présence de critères et de conditions de mise en œuvre des régimes qui sont transposables aux différents aspects concernant la fabrication et l’utilisation du robot d’assistance.

TAKING ORGANIZATIONS SERIOUSLY: RESPONSIBLE AGENCY, ORGANIZATIONS AND THE CRIMINAL LAW

In the post-Enlightenment period, Anglo-American criminal law has been applied with increased force, and an ever expanding scope, to collective actors like corporations and other organizations. Recent scholarship has focused on developing “truly organizational” bases of liability that break with the conventional approach of imputing individual conduct to an organization and instead analyze culpable conduct and intent in a way that reflects the distinct and independent capacity of organizations to pursue their interests or goals collaboratively. In 2004, Canada enacted amendments inspired by these ideas in the hope they would lead to more effective criminal enforcement against organizations. Twelve years later, however, the promise of Bill C-45 is largely unfulfilled. In this thesis, I explore how much of this failure of law reform to deliver transformational change is attributable to an individualist bias that permeates how we think about what it means to be responsible and how this then shapes the responsibility ascription process. Using an analytical framework that combines criminal law theory with selected aspects of rational-structural theory and organization culture, I suggest that a promising way forward may lie in reframing the essential qualities required to be a subject of the criminal law in a way that captures the unique attributes that make organizations different from individuals. The resulting organizational concept of responsible agency allows for an integration of organizational reality into how we assess organizational culpability while keeping the ambit of criminal liability within the limits of what is practicable and fair. This better aligns with the spirit of Bill C-45: to impose criminal liability in a way that takes organizations – and their crimes – seriously.