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Le rôle central de la voie mTOR (mammalian Target Of Rapamycin) dans l’homéostasie cellulaire suscite un réel intérêt dans de nombreux domaines thérapeutiques. Les inhibiteurs de mTOR (mTORi) sont utilisés en prévention du rejet de greffe par leur action d’inhibition de l’activation lymphocytaire T et l’induction de lymphocytes T régulateurs (Treg). En cancérologie, les mTORi sont utilisés pour leur action anti-proliférative et anti-angiogénique. Cependant, l’efficacité clinique de ces traitements reste modeste. Bien que des mécanismes de résistance aux mTORi intrinsèques à la cellule tumorale ont été identifiés, leur impact sur le système immunitaire émerge comme un facteur essentiel dans leur efficacité. Notre hypothèse est donc que l’efficacité anti-tumorale des mTORi serait également liée à la modulation de l’immunité anti-tumorale induite par ces traitements.Nous avons réalisé un immunomonitoring, du taux de Treg et de la réponse lymphocytaire Th1 anti-tumorale au sein d’une cohorte prospective de patients atteints de cancer rénal métastatique traités par éverolimus (mTORi).Nous avons observé une augmentation des Treg et de leur fonction suppressive à partir du 2ème mois de traitement dans la quasi-totalité des patients. Paradoxalement, une augmentation des réponses Th1 anti-tumorales a également été observée chez ces patients. Au moment de la progression tumorale, la majorité des patients ont présenté une forte augmentation des Treg associée à une perte de la réponse Th1. Ainsi, nous avons pu définir différents profils immunitaires basés sur la modulation de ces deux paramètres. Les patients présentant une diminution précoce des Treg associée à une augmentation de la réponse Th1 avaient une meilleure survie sans progression par rapport aux autres patients (13.2 vs 4 mois p= 0.02). De façon consistante, cette immunomodulation a été confirmée chez des patients atteints de tumeur neuroendocrine traités par éverolimus. De plus, l’impact du traitement sur les Treg et la réponse Th1 n’était pas influencé par la pharmacocinétique du médicament. Par la suite, nous avons étudié in vivo, chez des souris porteuses de différentes tumeurs, l’impact des mTORi sur la réponse immunitaire anti-tumorale. Comme chez les patients, nous avons observé une augmentation des Treg chez les souris traitées par mTORi. Ainsi, l’utilisation d’anticorps déplétants les Treg ou de souris transgéniques ont permis de démontrer le rôle délétère des Treg sur l’efficacité anti-tumorale des mTORi. Ces résultats suggèrent fortement que les mTORi ont un double effet sur le système immunitaire dans un contexte tumoral, un premier néfaste par l’induction d’un environnement immunosuppresseur et le second positif par l’augmentation d’une réponse Th1 anti-tumorale.Dans un deuxième travail, nous avons exploré l’effet positif des mTORi sur le système immunitaire afin d’optimiser les immunothérapies anti-tumorales. Nous avons montré que l’administration de temsirolimus (mTORi) améliore l’efficacité anti-tumorale d’un vaccin thérapeutique chez la souris. L’effet synergique de cette combinaison était lié à une augmentation de l’infiltration tumorale des LT CD8 anti-tumoraux de phénotype centro-mémoire. L’efficacité de cette combinaison a été nettement améliorée par l’addition d’un antagoniste de CCR4 permettant d’éliminer les Treg induits par le temsirolimus.En conclusion, les mTORi demeurent une stratégie prometteuse en cancérologie malgré la réduction de leur utilisation due à l’arrivée des nouvelles immunothérapies, comme les checkpoints inhibiteurs (notamment dans le cancer du rein) et d’autres thérapies ciblées (inhibiteurs de cycline dans le cancer du sein). En revanche, le futur développement des mTORi devra s’appuyer sur des biomarqueurs prenant en compte l’impact de ces traitements sur le système immunitaire et sur des combinaisons thérapeutiques notamment avec les immunothérapies / The key role of the mTOR (mammalian Target of Rapamycin) pathway in cellular homeostasis raises a real interest in many therapeutics areas. Inhibitors of mTOR (mTORi) are used for graft rejection prevention to inhibit the T lymphocyte (LT) activation and induce regulatory T cells (LTreg). In cancerology, they are used for their antiproliferative and antiangiogenic actions. However, the clinical efficacy of those treatments is low. Although several mTORi resistance mechanisms linked to the tumor cell have been identified, their impact on the immune system appears as a key factor in their efficiency. Thus, our hypothesis is that the clinical efficacy of mTORi could also be dependent of an anti-tumoral immunity modulation resulting from those treatments.We performed an immunomonitoring of the Treg rate and the tumor specific Th1 anti-tumor response among a prospective cohort of patients with a metastatic renal carcinoma treated by everolimus (mTORi). We observed that the Treg rate and the suppressive function increase after the second month of treatment for almost all the patients. Paradoxically, an increase of the Th1 anti-tumoral response has also been observed for these patients. At disease progression, a majority of the patients has shown an important increase of Treg with a decrease of the Th1 response. Thus, we have been able to define different immune profiles based on the modulation of these two parameters. Progression free survival of patients with an earlier decrease of Treg and an increase of Th1 response was significantly longer compared to other patients (13.2 vs 4 months p=0.02). This immunomodulation has been consistently confirmed with patients affected by neuroendocrine tumor and treated with everolimus. The treatment impact on Treg and the Th1 response was not related to the pharmacokinetic of the drug. Thereafter, we have studied in vivo the impact of mTORi on the anti-tumoral immune response with mice affected by different tumors. We have observed the same increase of Treg in mice treated with mTORi as the increase observed in the patients. Thus, using antibodies depleting the Treg or transgenic mice allowed us to confirm the deleterious role of Treg on the anti-tumor mTORi efficacy. Those results strongly suggest that mTORi have a double effect on the immune system, a harmful impact by the induction of an immunosuppressive environment and a positive impact by the increase of the anti-tumor Th1 response.In a second time, we have studied the positive effect of mTORi on the immune system in order to optimize the anti-tumoral immunotherapies. We have shown that the administration of temsirolimus (mTORi) improves the anti-tumoral efficiency of a therapeutic vaccination on mice. Indeed, the synergic effect of this combination is tied with an augmentation of tumor infiltrate anti-tumor T CD8 with a central memory phenotype. The efficiency of this combination has been greatly improved by the addition of an antagonist CCR4 allowing the elimination of Treg generated by temsirolimus.In conclusion, mTORi remain a promising strategy in cancerology even if their use is likely to be reduced as new immunotherapies such as checkpoint inhibitors (renal carcinoma) or other targeted therapies (cycline dependent kinase inhibitors in breast cancer) appeared. In the future, the development of mTORi must integrate biomarkers taking into account the impact of these treatments on the immune system, and therapeutic combination such as the immunotherapy

Heterogeneity in lattice potentials (like random or quasiperiodic) can localize linear, non-interacting waves and halt their propagation. Nonlinearity induces wave interactions, enabling energy exchange and leading to chaotic dynamics. Understanding the interplay between the two is one of the topical problems of modern wave physics. In particular, one questions whether nonlinearity destroys localization and revives wave propagation, whether thresholds in wave energy/norm exist, and what the resulting wave transport mechanisms and characteristics are. Despite remarkable progress in the field, the answers to these questions remain controversial and no general agreement is currently achieved. This thesis aims at resolving some of the controversies in the framework of nonlinear dynamics and computational physics. Following common practice, basic lattice models (discrete Klein-Gordon and nonlinear Schroedinger equations) were chosen to study the problem analytically and numerically. In the disordered linear case all eigenstates of such lattices are spatially localized manifesting Anderson localization, while nonlinearity couples them, enabling energy exchange and chaotic dynamics. For the first time we present a comprehensive picture of different subdiffusive spreading regimes and self-trapping phenomena, explain the underlying mechanisms and derive precise asymptotics of spreading. Moreover, we have successfully generalized the theory to models with spatially inhomogeneous nonlinearity, quasiperiodic potentials, higher lattice dimensions and arbitrary nonlinearity index. Furthermore, we have revealed a remarkable similarity to the evolution of wave packets in the nonlinear diffusion equation. Finally, we have studied the limits of strong disorder and small nonlinearities to discover the probabilistic nature of Anderson localization in nonlinear disordered systems, demonstrating the finite probability of its destruction for arbitrarily small nonlinearity and exponentially small probability of its survival above a certain threshold in energy. Our findings give a new dimension to the theory of wave packet spreading in localizing environments, explain existing experimental results on matter and light waves dynamics in disordered and quasiperiodic lattice potentials, and offer experimentally testable predictions.

Alkaline phosphatase (ALP) is a natural milk enzyme. It has been used as reporter for process controls in food industry. Since ALP denatures at pasteurization temperature (at 63&deg / C or 72&deg / ) its detection in milk confirms the unproper pasteurization. There are different detection procedures such as colorimetric, fluorometric methods and immunoassays for ALP in milk. However, they are time consuming processes and require specific instruments and qualified staff. In this study, new, semiquantitative, disposable, cheap and practical paper bioreporter have been developed for ALP detection. In optimization studies, 1mg/mL p-NPP in 0.1 M glycine buffer at pH 9.5 and 0.5 mg/mL bromocresol green in 1.0 M Tris-HCl buffer at pH 9.5 were determined as optimum for ALP bioreporter as a result of visual inspection and green color intensity analyses.The effects of samples temperature and pH of on the response of bioreporter were tested. Milk samples at pH 5.0, 5.5, 6.0 and 6.5 and milks stored at 37&deg / C, room temperature and 4&deg / C did not affect the response of bioreporter. Also the response of bioreporter against milk samples from different animals (cattle, sheep and goat) and cow&rsquo / s milk from different location in Turkey were evaluated. The appropriate responses were observed by bioreporter. Whatman filter papers, cotton and bandage were used as support materials to construct bioreporter and Whatman filter papers were selected as the most applicaple support material. Finally, stability tests were carried out at 4&deg / C and room temperature and 40 days at 4&deg / C was determined as shelf life of bioreporter.

This thesis is concerned with the solution of linear operator equations by projection methods known as minimal residual (MR) and orthogonal residual (OR) methods. We begin with a rather abstract framework of approximation by orthogonal and oblique projection in Hilbert space. When these approximation schemes are applied to sequences of nested spaces, with a simple requirement relating trial and test spaces in case of the OR method, one can derive at this rather general level the basic relations which have been proved for many specific Krylov subspace methods for solving linear systems of equations in the literature. The crucial quantities with which we describe the behavior of these methods are angles between subspaces. By replacing the given inner product with one that is basis-dependent, one can also incorporate methods based on non-orthogonal bases such as those based on the non-Hermitian Lanczos process for solving linear systems. In fact, one can show that any reasonable approximation method based on a nested sequence of approximation spaces can be interpreted as an MR or OR method in this way. When these abstract approximation techniques are applied to the solution of linear operator equations, there are three generic algorithmic formulations, which we identify with some algorithms in the literature. Specializing further to Krylov trial and test spaces, we recover the well known Krylov subspace methods. Moreover, we show that our general framework also covers in a natural way many recent generalizations of Krylov subspace methods, which employ techniques such as augmentation, deflation, restarts and truncation. We conclude with a chapter on error and residual bounds, deriving some old and new results based on the angles framework. This work provides a natural and consistent framework for the sometimes confusing plethora of methods of Krylov subspace type introduced in the last 50 years.

The Levenberg-Marquardt algorithm is a classical method for solving nonlinear systems of equations that can come from various applications in engineering and economics. Recently, Levenberg-Marquardt methods turned out to be a valuable principle for obtaining fast convergence to a solution of the nonlinear system if the classical nonsingularity assumption is replaced by a weaker error bound condition. In this way also problems with nonisolated solutions can be treated successfully. Such problems increasingly arise in engineering applications and in mathematical programming. In this thesis we use Levenberg-Marquardt algorithms to deal with nonlinear equations, multi-objective optimization and complementarity problems. We develop new algorithms for solving these problems and investigate their convergence properties. For sufficiently smooth nonlinear equations we provide convergence results for inexact Levenberg-Marquardt type algorithms. In particular, a sharp bound on the maximal level of inexactness that is sufficient for a quadratic (or a superlinear) rate of convergence is derived. Moreover, the theory developed is used to show quadratic convergence of a robust projected Levenberg-Marquardt algorithm. The use of Levenberg-Marquardt type algorithms for unconstrained multi-objective optimization problems is investigated in detail. In particular, two globally and locally quadratically convergent algorithms for these problems are developed. Moreover, assumptions under which the error bound condition for a Pareto-critical system is fulfilled are derived. We also treat nonsmooth equations arising from reformulating complementarity problems by means of NCP functions. For these reformulations, we show that existing smoothness conditions are not satisfied at degenerate solutions. Moreover, we derive new results for positively homogeneous functions. The latter results are used to show that appropriate weaker smoothness conditions (enabling a local Q-quadratic rate of convergence) hold for certain reformulations. / Der Levenberg-Marquardt-Algorithmus ist ein klassisches Verfahren zur Lösung von nichtlinearen Gleichungssystemen, welches in verschiedenen Anwendungen der Ingenieur-und Wirtschaftswissenschaften vorkommen kann. Kürzlich, erwies sich das Verfahren als ein wertvolles Instrument für die Gewährleistung einer schnelleren Konvergenz für eine Lösung des nichtlinearen Systems, wenn die klassische nichtsinguläre Annahme durch eine schwächere Fehlerschranke der eingebundenen Bedingung ersetzt wird. Auf diese Weise, lassen sich ebenfalls Probleme mit nicht isolierten Lösungen erfolgreich behandeln. Solche Probleme ergeben sich zunehmend in den praktischen, ingenieurwissenschaftlichen Anwendungen und in der mathematischen Programmierung. In dieser Arbeit verwenden wir Levenberg-Marquardt- Algorithmus für nichtlinearere Gleichungen, multikriterielle Optimierung - und nichtlineare Komplementaritätsprobleme. Wir entwickeln neue Algorithmen zur Lösung dieser Probleme und untersuchen ihre Konvergenzeigenschaften. Für ausreichend differenzierbare nichtlineare Gleichungen, analysieren und bieten wir Konvergenzergebnisse für ungenaue Levenberg-Marquardt-Algorithmen Typen. Insbesondere, bieten wir eine strenge Schranke für die maximale Höhe der Ungenauigkeit, die ausreichend ist für eine quadratische (oder eine superlineare) Rate der Konvergenz. Darüber hinaus, die entwickelte Theorie wird verwendet, um quadratische Konvergenz eines robusten projizierten Levenberg-Marquardt-Algorithmus zu zeigen. Die Verwendung von Levenberg-Marquardt-Algorithmen Typen für unbeschränkte multikriterielle Optimierungsprobleme im Detail zu untersucht. Insbesondere sind zwei globale und lokale quadratische konvergente Algorithmen für multikriterielle Optimierungsprobleme entwickelt worden. Die Annahmen wurden hergeleitet, unter welche die Fehlerschranke der eingebundenen Bedingung für ein Pareto-kritisches System erfüllt ist. Wir behandeln auch nicht differenzierbare nichtlineare Gleichungen aus Umformulierung der nichtlinearen Komplementaritätsprobleme durch NCP-Funktionen. Wir zeigen für diese Umformulierungen, dass die bestehenden differenzierbaren Bedingungen nicht zufrieden mit degenerierten Lösungen sind. Außerdem, leiten wir neue Ergebnisse für positiv homogene NCP-Funktionen. Letztere Ergebnisse werden verwendet um zu zeigen, dass geeignete schwächeren differenzierbare Bedingungen (so dass eine lokale Q-quadratische Konvergenzgeschwindigkeit ermöglichen) für bestimmte Umformulierungen gelten.

The thesis uses the study of an individual’s book collection to examine wider themes in eighteenth century Scottish legal, social, political, and intellectual history. Charles Areskine’s library was made up of the books he needed as an advocate and judge, the texts he wanted to use to better understand the law and its history, and the books he used to enhance his ability to participate in the intellectual milieu of early eighteenth century Britain. Charles Areskine of Alva, Lord Tinwald (1680-1763) was an important Scottish lawyer and judge. Following a legal education in the Netherlands, he became an advocate and was called to the Bar in 1711. Areskine’s legal career was very successful and he attained high positions in the Scottish legal establishment becoming Lord Advocate (1737-1742) and Lord Justice Clerk (1748-1763). He was appointed to the bench as Lord Tinwald in1744. He served in parliament and developed his country estates at Tinwald in Dumfriesshire and at Alva in Clackmannanshire. Areskine is an interesting figure in the early Scottish Enlightenment not least because he began his career not in legal but in academic circles. He was a regent at the University of Edinburgh when he was barely out of his teens and from 1707 to 1734 he was the first Professor of the Law of Nature and Nations at Edinburgh. Areskine was also a traveller, a client of the earl of Ilay, a friend to philosophers, a patron of the arts, and a book collector. A manuscript which lists of the contents of Areskine’s library survives in the National Library of Scotland as NLS MS 3283. ‘Catalogŭs Librorŭm D. Dni. Caroli Areskine de Barjarg, Regiarŭm Causarum Procŭratoris. 1731’ lists 1290 titles divided into books on legal topics, which are not given any specific headings, and ‘Libri Miscellanei’. Although it is clearly dated as 1731, the manuscript was continuously added to and acted as a library catalogue throughout Areskine’s life. The list provides important evidence about Areskine’s participation in the legal, intellectual, and cultural concerns of the early Scottish Enlightenment. Areskine’s law books provide evidence for his scholarly interest in the history of law while showing the types of books lawyers turned to in order to fashion their arguments in the courts. His ‘miscellaneous’ books demonstrate his engagement with the wider cultural concerns of the first half of the eighteenth century. The books that eighteenth century Scottish lawyers owned provide evidence for their interests and influence. Areskine was not unique: his book collecting was part of a wider tradition among Scottish lawyers. Areskine’s legally educated patron, Archibald Campbell, had one of the largest private libraries in Britain and his colleagues on the Bench, Lord Arniston and Lord Hailes, created collections which they stored in specially built rooms in their houses. Because so many of them survive in the Alva Collections of the Advocates Library and the National Library of Scotland, it has been possible to examine Areskine’s books for clues about who owned them before he did and what happened to them after his death. Several inscriptions and bookplates survive in the Alva books which give evidence for a lively book market which was centred on the Scottish legal community. Advocates bought and sold many of their books at auctions. This study shows that books on topics of interest to Scottish lawyers changed hands and stayed in use for decades.

Cette thèse d'histoire contemporaine traite de la vie du républicain et chimiste François-Vincent Raspail (1794-1878). Son objectif est de comprendre ce qu'est le républicanisme au XIXe siècle. Pour ce faire, on tente de saisir, à travers le cas de Raspail, l'évolution des idées républicaines, à l'échelle individuelle. En outre, Raspail a la particularité de conjuguer ses théories politiques et scientifiques. Enfin, on analyse et on déconstruit les mythes politiques qui entourent Raspail : le lutteur infatigable, l'homme incorruptible ou encore le médecin des pauvres. / This thesis in contemporary history deals with the life of the republicain and chemist François-Vincent Raspail (1794-1878). Its objective is to understand that is the republicanisme in the XIXth century. To do so, throughout the case of Raspail, we attempt to capture the evolution of the republicain ideas at the individual level . In addition, Raspail has the particularity to combine political and scientific theories. Finally, the political myths surrounding Raspail are analyzed and deconstructed : the tireless fighter, the incorruptible man and the doctor to the poor.

Das vorliegende dreibändige Werk stellt die Entwicklungsgeschichte von ca. 5300 Siedlungsnamen (einschließlich der Wüstungsnamen) dar, die in den Grenzen des heutigen Freistaates Sachsen überliefert wurden. Hinzu kommt der Namenbestand des thüringischen Kreises Altenburg (Altenburger Land), der siedlungs- und territorialgeschichtlich jahrhundertelang zum ehemaligen Reichsterritorium Pleißenland (in Westsachsen) und zum wettinischen Territorialstaat gehörte. Die schriftliche Überlieferung der Namen von Siedlungsplätzen im Raum östlich der Saale beginnt – abgesehen von seltenen Ausnahmen der fränkischen Zeit – mit der Errichtung der deutschen Oberherrschaft über das seit etwa 600 von (Alt-)Sorben besiedelte ostsaalisch-ostelbische Gebiet durch König Heinrich I. in den Jahren 929/930. Rund 60% der sächsischen Ortsnamen sind slawischer Herkunft, wobei dieses Sprachgut in der Mehrheit nicht von Slawen, sondern von Deutschen aufgezeichnet wurde. In den ersten beiden Bänden wird die in einer möglichst lückenlosen Belegkette erfasste Geschichte jedes einzelnen Namens dargestellt: von den ältesten urkundlich tradierten Schreibungen über die Entwicklung seiner weiteren Formen bis zur heutigen Gestalt einschließlich seiner mundartlichen Lautung. Geboten werden Informationen zu Herkunft, Wortbildung, Etymologie und Typologie, zu sprachgeschichtlichen Sachverhalten, Problemen der Integration slawischer (altsorbischer) Toponyme ins Deutsche sowie zu soziolinguistischen Merkmalen der Siedlungsbenennungen. Der dritte Band enthält neben dem Apparat auswertende Register, die das lexikalische Material detailliert erschließen.

Das vorliegende dreibändige Werk stellt die Entwicklungsgeschichte von ca. 5300 Siedlungsnamen (einschließlich der Wüstungsnamen) dar, die in den Grenzen des heutigen Freistaates Sachsen überliefert wurden. Hinzu kommt der Namenbestand des thüringischen Kreises Altenburg (Altenburger Land), der siedlungs- und territorialgeschichtlich jahrhundertelang zum ehemaligen Reichsterritorium Pleißenland (in Westsachsen) und zum wettinischen Territorialstaat gehörte. Die schriftliche Überlieferung der Namen von Siedlungsplätzen im Raum östlich der Saale beginnt – abgesehen von seltenen Ausnahmen der fränkischen Zeit – mit der Errichtung der deutschen Oberherrschaft über das seit etwa 600 von (Alt-)Sorben besiedelte ostsaalisch-ostelbische Gebiet durch König Heinrich I. in den Jahren 929/930. Rund 60% der sächsischen Ortsnamen sind slawischer Herkunft, wobei dieses Sprachgut in der Mehrheit nicht von Slawen, sondern von Deutschen aufgezeichnet wurde. In den ersten beiden Bänden wird die in einer möglichst lückenlosen Belegkette erfasste Geschichte jedes einzelnen Namens dargestellt: von den ältesten urkundlich tradierten Schreibungen über die Entwicklung seiner weiteren Formen bis zur heutigen Gestalt einschließlich seiner mundartlichen Lautung. Geboten werden Informationen zu Herkunft, Wortbildung, Etymologie und Typologie, zu sprachgeschichtlichen Sachverhalten, Problemen der Integration slawischer (altsorbischer) Toponyme ins Deutsche sowie zu soziolinguistischen Merkmalen der Siedlungsbenennungen. Der dritte Band enthält neben dem Apparat auswertende Register, die das lexikalische Material detailliert erschließen. Das „Historische Ortsnamenbuch von Sachsen“ erschien als Band 21 der Schriftenreihe „Quellen und Forschungen zur sächsischen Geschichte“.:Vorwort Einführung 1 Zur Forschungsgeschichte 2 Namenüberlieferung und historische Quellen 2.1 Quellenübersicht 2.2 Quellenkritik 3 Historische Sichtung und geographische Verbreitung der Ortsnamen 4 Entwicklung der Ortsnamen 4.1 Entwicklung der altsorbischen Namen vor ihrer Eindeutschung zum Ansatz altsorbischer Grundformen 4.2 Die Namen als Zeugnisse der deutschen Sprachgeschichte 4.2.1 Namenlautung und Namenschreibung 4.2.2 Namenstrukturen und Namensemantik 4.3 Entlehnungserscheinungen: Lautersatz und Mischnamen 4.4 Soziolinguistische Merkmale der Siedlungsbenennungen Namenbuch Anlage der Namenartikel [A–L] Freistaat Sachsen. Übersichtskarte