De nos jours, l'apport de polyphénols s'avère être bénéfique dans la lutte contre les dommages oxydatifs liés au stress oxydant. Cependant, leur biodisponibilité est limitée par leur polarité. Pour contourner ce problème, une des stratégies consiste à ajuster la lipophilie de l'antioxydant par des réactions de lipophilisation mettant en jeu un vecteur lipidique. Ainsi, des précédentes études ont montré que l'activité antioxydante était directement liée à la longueur de la chaîne alkyle greffée et ont également révélé un effet non linéaire dit effet « cut-off ». L'objectif de notre étude a donc été de comprendre l'effet non linéaire de la lipophilisation sur l'activité antioxydante de l'acide rosmarinique. Ainsi, des rosmarinates d'alkyle et de diacylglycérol ont été synthétisés, et leurs propriétés antioxydantes évaluées sur des fibroblastes surexprimant une quantité d'EROs. L'effet « cut-off » a été à nouveau observé avec ces phénolipides. En effet, le rosmarinate de décyle et le 1-rosmarinoyl-2,3-dilauroyl glycérol sont les antioxydants les plus actifs. Cependant, la série des rosmarinates d'alkyle étant la plus efficace, l'influence du vecteur lipidique a été étudié uniquement sur cette dernière. Il a été ainsi constaté que la lipophilisation de l'acide rosmarinique avec une chaîne alkyle de 4 à 10 atomes de carbone améliore son transport au sein de la cellule, alors que les esters à 16 et 18 atomes de carbone s'organisent sous forme d'agrégats extracellulaires limitant ainsi leur internalisation. De plus, alors qu'une partie de ces esters est localisée dans le cytoplasme, tout comme l'acide rosmarinique et le rosmarinate de butyle, le rosmarinate de décyle est en revanche situé dans la mitochondrie. Cette propriété en fait donc une molécule très prometteuse pour la conception de nouveaux antioxydants à activité mitochondriale ciblée. Néanmoins, sa cytotoxicité joue un rôle majeur dans son mécanisme d'action. A fortes concentrations, il affecte la viabilité cellulaire, tandis qu'à faibles concentrations, aucun effet cytotoxique notable n'est mis en évidence. / Nowadays, polyphenols supply has proved to be beneficial against oxidative damages linked to oxidative stress. However, their bioavaibility is limited by their polarity. To solve the issue, one strategy consists in adjusting the antioxidant hydrophobicity by lipophilization reactions with lipidic carriers. Indeed, previous studies showed that antioxidant activity was directly linked to the alkyl chain length grafted and also revealed a “cut-off” effect. The objective of this study is to understand this nonlinear effect of the lipophilization of rosmarinic acid on antioxidant activity. Thus, alkyl rosmarinate and diacylglycerol rosmarinate were synthesized and their antioxidant activity was evaluated into fibroblasts cells overexpressing radical oxygen species. The “cut-off” effect was again observed with these phenolipids. In fact, decyl rosmarinate and dilauroyl rosmarinate were shown to the best antioxydants. The lipophilization of rosmarinic acid with an alkyl chain from 4 to 10 carbon atoms improve its cell uptake whereas esters of 16 and 18 carbon atoms assemble in extracellular aggregate limiting their cell uptake. Furthermore, one part of these esters is located into cytoplasm like rosmarinic acid and butyl rosmarinate. On the contrary, the decyl rosmarinate (R10) is located into mitochondria. This property allows targeting mitochondria. Nevertheless, its cytotoxicity is involved in mechanism. At high concentration, R10 affects cell viability, while at low concentration, no cytotoxic effect is observed.

Les facteurs de croissance endothéliaux (VEGFs) sont produits par les tumeurs qui sont hypoxiques. Principaux responsables de la néo-vascularisation pathologique, ils régulent le stroma tumoral. Les nouvelles stratégies qui ciblent et inhibent le VEGF ouvrent vers la thérapie anti-cancéreuse moderne. Elles ont pour but de contrôler l’angiogenèse tumorale plutôt que la détruire. Le défi est donc de piéger sélectivement le VEGF produit en excès, dans le microenvironnement tumoral, sous l’effet de l’hypoxie. La thèse présentée dans ce manuscrit est consacrée à la réalisation d’une nouvelle stratégie ciblante par l’intermédiaire de cellules, aussi appelée « Cheval de Troie ». Elle combine dans la même entité, une unité de ciblage et un système de délivrance spécifique d’un gène/molécule thérapeutique. Dans le but d’adresser la thérapie aux cellules cancéreuses sans affecter les cellules saines, un modèle de cellules endothéliales de type précurseur (CEPs) a été utilisé comme cellules ciblantes capables d’atteindre spécifiquement le site tumoral. Les CEPs ont été « armées » pour exprimer un gène thérapeutique chargé d’inhiber le VEGF. La neutralisation a été obtenue par la production d’une forme soluble du récepteur-2 du VEGF (VEGFR2 soluble), agissant comme inhibiteur. Caractéristique des tumeurs solides se développant, l’hypoxie a été choisie pour déclencher/éteindre l’expression et la sécrétion du VEGFR2 soluble, en introduisant, en amont du gène thérapeutique, une séquence régulatrice : HRE. Adressé au site tumoral par les CEPs, le régulateur de l’angiogenèse qu’est la forme soluble du VEGFR2, est exprimé de manière conditionnée et réversible, à l’hypoxie. Ceci ouvre à de nouvelles stratégies de normalisation contrôlée et stable des vaisseaux tumoraux en vue de l’utilisation de thérapies combinées. / Vascular endothelial growth factors (VEGFs) are over-expressed upon hypoxia in solid tumors. Major actors directing pathologic neo-vascularisation, they regulate the stromal reaction. Novel strategies that target and inhibit VEGF bring promise to modern anti-cancer therapies. They aim to control rather than destroy tumor angiogenesis. Consequently, the challenge is to selectively trap VEGFs, over-produced upon hypoxia, in the tumor microenvironment. The thesis presented in this manuscript focuses on the design of a novel cell-based targeting strategy, so-called “Trojan Horse”, combining in the same engineered entity, a targeting unit and a specific drug/gene delivery system. Aiming to address the therapy to cancer cells without affecting healthy cells, a model of endothelial precursor cell (EPCs) was used as targeting cell able to reach specifically the tumor site. EPCs were “armed” to express a therapeutic gene to inhibit VEGF. Trapping was attempted based on the production of a soluble form of the VEGF receptor-2 (sVEGFR2) as a candidate inhibitor. Hypoxia, a hallmark of developing solid tumors, was chosen to turn on/off the sVEGFR2 expression and secretion by introducing, upstream of the therapeutic gene, a hypoxia response element (HRE) regulating sequence. Properly addressed by the EPCs to the tumor site, such angiogenesis regulator as the soluble form of VEGFR2 is, was chosen to be expressed in a hypoxia-conditioned and reversible manner. This opens new strategies for a stably controlled normalization of tumor vessels in view of adjuvant design for combined therapies.

This thesis compares monetary policies, institutional status and different approaches to the selection of monetary policy and setting goals of central banks in the case of Czech National Bank, the European Central Bank and the Federal Reserve System. The first chapter deals with the characteristics of the central bank, legislative regulation of the Czech National Bank is analysed there and it mentions the Czech peculiarities in the adjustment of the central bank. In addition, this chapter deals with the possibilities for the name of the central bank and there are examples of different solutions from the world. The second chapter focuses on the analysis of the central bank's position in the state. It emphasise independence as it is the core value for the central bank. This chapter also describes the regulatory and supervisory powers of the central bank and briefly discuss the composition of assets and financing of the central bank and its basic financial statements. The third chapter deals with the theory of monetary policy. Particular attention is paid to the monetary policy of inflation targeting. Furthermore, this chapter provides an overview of transmission mechanisms and describes various monetary policy instruments which central banks have. At the end of this part of the thesis there is a...

Le ciblage de l’inflation est le cadre le plus récent de la politique monétaire dans le monde. Il est désormais largement choisi par les pays avancés ainsi que par les pays émergents. Cependant, deux questions principales sont encore en débat particulièrement dans les pays émergent et en développement. Ils s’agissent des avantages du ciblage d’inflation et du respect de conditions préalables afin d’assurer le succès de ce régime. Empiriquement, on conclut que le ciblage d’inflation est un cadre de politique monétaire réussie pour les pays émergents. En plus, il n'est pas nécessaire pour ces pays de satisfaire toutes les conditions préalables strictes avant de réussir à l'adopter. La situation budgétaire et l'indépendance de la banque centrale jouent un rôle plus important que les autres conditions et doivent être préparées en premier lieu. Concernant le Vietnam, par l'approche structurelle vecteur autorégressif (VAR), la thèse montre que la politique monétaire de la banque centrale n’est pas efficace. Donc, il permet de confirmer la nécessité du changement de stratégie monétaire par rapport au cadre actuel. Cependant, notamment parce que la banque centrale n’est pas indépendante, le Vietnam ne peut pas adopter le ciblage d’inflation dans un bref délai. Les recommandations du durcissement de la contrainte budgétaire et de l’augmentation l’indépendance de la banque centrale sont suggérées avant la mise en œuvre de sa stratégie de ciblage d’inflation. / Inflation targeting (hereafter IT) is the newest monetary policy framework in the world. The practice of IT has been chosen by both advanced countries and emerging countries. However, two main issues are still under debate particularly in emerging and developing countries. They are the benefits of IT and preconditions to success adoption. Empirically, we showed that IT is considered as a successful monetary policy framework for emerging countries. In addition, it is not necessary for emerging markets to satisfy all stringent preconditions to successfully adopt IT. In practice, the fiscal situation and the central bank independence play a more important role than other conditions and need to be prepared first.Basing on Structural Vector Autoregression (SVAR), the thesis concludes that Vietnamese monetary policy currently does not effectively control the inflation rate. Inflation targeting framework would be a solution to this. Nonetheless, this thesis concludes that at this moment in time Vietnam is not able to adopt the IT framework, as it still must prepare some of the preconditions required before official adoption. The recommendations of hardening the budget constraint and increase central bank independence in relationship with government are suggested before implementing IT strategy.

Robot motion can be described in several alternative representations, including joint configuration or end-effector spaces. These representations are often used for manipulation or navigation tasks but they are not suitable for tasks that involve close interaction with the environment. In these scenarios, collisions and relative poses of the robot and its surroundings create a complex planning space. To deal with this complexity, we exploit several representations that capture the state of the interaction, rather than the state of the robot. Borrowing notions of topology invariances and homotopy classes, we design task spaces based on winding numbers and writhe for synthesizing winding motion, and electro-static fields for planning reaching and grasping motion. Our experiments show that these representations capture the motion, preserving its qualitative properties, while generalising over finer geometrical detail. Based on the same motivation, we utilise a scale and rotation invariant representation for locally preserving distances, called interaction mesh. The interaction mesh allows for transferring motion between robots of different scales (motion re-targeting), between humans and robots (teleoperation) and between different environments (motion adaptation). To estimate the state of the environment we employ real-time sensing techniques utilizing dense stereo tracking, magnetic tracking sensors and inertia measurements units. We combine and exploit these representations for synthesis and generalization of motion in dynamic environments. The benefit of this method is on problems where direct planning in joint space is extremely hard whereas local optimal control exploiting topology and metric of these novel representations can efficiently compute optimal trajectories. We formulate this approach in the framework of optimal control as an approximate inference problem. This allows for consistent combination of multiple task spaces (e.g. end-effector, joint space and the abstract task spaces we investigate in this thesis). Motion generalization to novel situations and kinematics is similarly performed by projecting motion from abstract representations to joint configuration space. This technique, based on operational space control, allows us to adapt the motion in real time. This process of real-time re-mapping generates robust motion, thus reducing the amount of re-planning. We have implemented our approach as a part of an open source project called the Extensible Optimisation library (EXOTica). This software allows for defining motion synthesis problems by combining task representations and presenting this problem to various motion planners using a common interface. Using EXOTica, we perform comparisons between different representations and different planners to validate that these representations truly improve the motion planning.

To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules.

Since Hurricane Katrina, targeting redevelopment has become the dominant municipal strategy for neighborhood and city-wide revitalization. Since 2009, this strategy has been adopted and is currently being implemented by the New Orleans Redevelopment Authority in several New Orleans neighborhoods. One such area includes the commercial corridor of the Central City neighborhood, Oretha Castle Haley Boulevard (OC Haley). This thesis describes and assesses NORA‘s strategy for revitalizing OC Haley with regards to impacts on Central City‘s economic development and affordable housing—two of the area‘s greatest challenges. Although NORA‘s targeting strategy is proving effective in many respects, it is not without its limitations including creating a gentrifying environment. To address this foreseeable impact, this thesis recommends the incorporation of a Community Land Trust (CLT) into NORA‘s Central City Strategy to aid in effectively revitalizing the neighborhood without compromising affordability.

<p>Understanding how genes affect behavior is critical to develop precise therapies for human behavioral disorders. The ability to investigate the relationship between genes and behavior has been greatly advanced over the last few decades due to progress in gene-targeting technology. Recently, the Tet gene family was discovered and implicated in epigenetic modification of DNA methylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). 5hmC and its catalysts, the TET proteins, are highly abundant in the postnatal brain but with unclear functions. To investigate their neural functions, we generated new lines of Tet1 and Tet3 mutant mice using a gene targeting approach. We designed both mutations to cause a frameshift by deleting the largest coding exon of Tet1 (Tet1Δe4) and the catalytic domain of Tet3 (Tet3Δe7-9). As Tet1 is also highly expressed in embryonic stem cells (ESCs), we generated Tet1 homozygous deleted ESCs through sequential targeting to compare the function of Tet1 in the brain to its role in ESCs. To test our hypothesis that TET proteins epigenetically regulate transcription of key neural genes important for normal brain function, we examined transcriptional and epigenetic differences in the Tet1Δe4 mouse brain. The oxytocin receptor (OXTR), a neural gene implicated in social behaviors, is suggested to be epigenetically regulated by an unknown mechanism. Interestingly, several human studies have found associations between OXTR DNA hypermethylation and a wide spectrum of behavioral traits and neuropsychiatric disorders including autism spectrum disorders. Here we report the first evidence for an epigenetic mechanism of Oxtr transcription as expression of Oxtr is reduced in the brains of Tet1Δe4-/- mice. Likewise, the CpG island overlapping the promoter of Oxtr is hypermethylated during early embryonic development and persists into adulthood. We also discovered altered histone modifications at the hypermethylated regions, indicating the loss of TET1 has broad effects on the chromatin structure at Oxtr. Unexpectedly, we discovered an array of novel mRNA isoforms of Oxtr that are selectively reduced in Tet1Δe4-/- mice. Additionally, Tet1Δe4-/- mice display increased agonistic behaviors and impaired maternal care and short-term memory. Our findings support a novel role for TET1 in regulating Oxtr expression by preventing DNA hypermethylation and implicate TET1 in social behaviors, offering novel insight into Oxtr epigenetic regulation and its role in neuropsychiatric disorders.</p> / Dissertation

This diploma thesis is focused on the description of Inflation Targeting regime in the Czech Republic. The paper is divided into three parts. The first part deals with inflation and its targeting and with the economical circumstances that led to the launch of this monetary policy regime in the Czech Republic. The next part concerns the central bank reaction function, transmission channels, evaluation of the inflation target sets and the description of prognostic models that the central bank uses for forecasting. Then main stress is laid on the new structural dynamic model "g3". The last part describes my own inflation prognosis, which is based on the time series analysis.

The thesis "Inflation targeting in circumstances of low interest rates" describes the monetary policy of the Czech National Bank with main aim on its current problems. The target of the thesis is to analytically prove the disruption of a section of the transmission mechanism when the repo rate should determine the interest rates on the czech interbank market. This disruption should have been caused by the recent financial crisis.