La conception de médicaments est un long processus complexe impliquant de nombreuses disciplines différentes. Entre la découverte de la touche (molécule active initiale) puis de la tête de série (molécule optimisée), jusqu’à la mise sur le marché du produit fini (médicament), il s’écoule en général une dizaine d’année, pour un coût avoisinant le milliard d’euros. Afin d’optimiser ce processus, de nombreuses approches sont développées pour identifier plus rapidement les molécules les plus prometteuses pour une cible thérapeutique donnée. Les protéines kinases (PK) jouent un rôle majeur dans la signalisation moléculaire et dans les mécanismes cellulaires. La dérégulation d’une PK peut engendrer des pathologies graves telles que des maladies neurodégénératives ou le cancer ; la conception d’inhibiteurs de PK (PKI) est ainsi un domaine de recherche thérapeutique extrêmement actif. Dans ce manuscrit de thèse, deux approches de chémoinformatique complémentaires sont explorées pour l’identification de nouveaux PKI. Tout d’abord, un criblage virtuel de produits naturels a été réalisé dans un contexte de recherche de molécules bioactives à finalité cosmétique ou thérapeutique. Pour ce travail, il a d’abord été nécessaire de développer un outil in silico de préparation de molécules, VSPrep, qui s’appuie sur des outils gratuits pour les chercheurs académiques. Enfin, un nouvel outil de conception de molécules bioactives à partir de fragments moléculaires (FBDD) a également été développé. L’implémentation de cet outil, Frags2Drugs, ainsi que sa validation dans des projets FBDD sont décrites dans ce manuscrit. / Drug design is a long and complex multidisciplinary process. From the discovery of the initial hit (bioactive molecule), to the lead (optimized compound), and finally to the commercialization of the end product (drug), almost 10 years are necessary and this process costs an average of $1 billion dollars. In order to optimize this process, new methods are relentlessly developed so that novel promising molecules might be identified faster for a given target. Protein kinases (PK) play a central role in most molecular pathways and are essential to control cellular mechanisms. The mutation of one PK can lead to severe pathologies such as neurodegenerative diseases or cancer, making the research of PK inhibitors (PKI) an intense area of therapeutic research. In this manuscript, two complementary chemoinformatics approaches are discussed for identifying PKI, and both depend on the preparation of small molecules (ligands). For this specific task, a new workflow protocol, VSPrep, was developed using only freely available tools for academics. First, a virtual screening approach of natural products was performed in order to identify bioactive molecules for cosmetics or therapeutic applications. Second, a novel in silico Fragment-Based Drug Discovery (FBDD) tool, Frags2Drugs, was developed specifically for kinase research. It combines molecular fragments derived from PKI into novel inhibitors bound to specific protein kinases. The tool was validated on several internal kinase projects leading to novel protein kinase inhibitors with acceptable drug-like properties.

La thèse examine la relation de la rhétorique, de l’éthique et de la politique dans les fragments des œuvres perdues d’Aristote, et la recherche porte plus largement sur le lien de cette relation avec l’ensemble de la philosophie d’Aristote. Cette étude tente donc de savoir si Aristote, par opposition à ses prédécesseurs, est bien « l’inventeur » de la rhétorique – à laquelle il confère le rang de technique avec une méthode et un objet propres dans le traité éponyme – dès ses premières œuvres de jeunesse, ou bien si sa conception a évolué au cours du temps. Ce faisant et en considérant les aspects éthico-politiques des ces œuvres perdues, l’examen discute les grandes hypothèses interprétatives qui ont été proposées à ce sujet pour soutenir la thèse d’une cohérence de la pensée d’Aristote plutôt que celle d’une évolution. L’étude comporte deux grands moments. Le premier consiste en l’édition, la traduction parfois inédite en langue française, et l’annotation des fragments des Librorum deperditorum relatifs à la rhétorique et la politique, avec la présentation des apparats critiques correspondants. Le second se consacre à l’examen de la cohérence de la pensée aristotélicienne au moyen du commentaire des fragments et de leur comparaison aux œuvres des sophistes (Protagoras, Gorgias, Isocrate, Lycophron), de Platon (Gorgias, Phèdre) et des traités aristotéliciens. Pour ce faire, le travail propose une étude lexicale du vocabulaire employé par Aristote, une analyse philosophique de certains concepts importants (andreia, eleutheriotês, eugeneia, metron, orgê, phronêsis) justifiée par leur emploi dans les fragments et le reste du Corpus aristotelicum, et une exégèse d’ensemble. / The thesis investigates the relationship between rhetoric, ethics and politics in the fragments of Aristotle’s lost works, and more globally its relation in Aristotle’s entire philosophy. This study intends to understand if Aristotle, in opposition to his predecessors, is the « inventor » of the rhetoric – to which he awards the value of technique with a proper methodology and object in the eponym treatise – from is early years works, or if his conception of it evolved in time. In doing so, and considering the ethico-political aspects of these lost works, the thesis discusses the main interpretative hypothesis that have been proposed on this subject in order to support the theory of Aristotle’s thought consistency, more than its evolution. The study stands in two main parts. The first one consists in the edition, the translation sometimes unprecedented in French language, and the annotation of Librorum deperditorum’s fragments related to rhetoric and politics, including the corresponding critical apparatus. The second inspects the consistency of Aristotle’s thought using the fragments’ comments and in comparison to the works of the sophists (Protagoras, Gorgias, Isocrates, Lycophron), of Plato (Gorgias, Phaedrus) and of the aristotelian treatises. To proceed, a lexical study of the vocabulary used by Aristotle, a philosophic analysis of a few main concepts (andreia, eleutheriotês, eugeneia, metron, orgê, phronêsis) justified by their presence in the fragments and the rest of the Corpus aristotelicum, and a comprehensive textual exegesis have been undertaken.

Cette thèse propose de nouveaux outils pour la caractérisation locale de familles de protéines au niveau de la séquence et de la structure. Nous introduisons les fragments en contact (CF) comme des portions de structure conciliant localité spatiale et voisinage séquentiel. Nous montrons qu'ils bénéficient d'une meilleure prédictibilité de structure depuis la séquence que des fragments contigus ou encore que des paires de fragments qui ne seraient pas en contact en structure. Pour comparer structuralement ces CF, nous introduisons l'ASD, une nouvelle mesure de similarité ne nécessitant pas d'alignement préalable, respectant l'inégalité triangulaire tout en étant tolérante aux décalages de séquences et aux indels. Nous montrons notamment que l'ASD offre des meilleures performances que les scores classiques de comparaison de fragments sur des tâches concrètes de classification non-supervisée et de fouille structurale. Enfin, grâce à des techniques d'apprentissage automatique, nous mettrons en œuvre la détection de CF à partir de la séquence pour l'identification de protéines de virus avec l'outil VIRALpro développé au cours de cette thèse. / This thesis investigates the local characterization of protein families at both structural and sequential level. We introduce contact fragments (CF) as parts of protein structure that conciliate spatial locality together with sequential neighborhood. We show that the predictability of CF from the sequence is better than that of contiguous fragments and of structurally distant pairs of fragments. In order to structurally compare CF, we introduce ASD, a novel alignment-free dissimilarity measure that respects triangular inequality while being tolerant to sequence shifts and indels. We show that ASD outperforms classical scores for fragment comparison on practical experiments such that unsupervised classification and structural mining. Ultimately, by integrating the identification of CF from the sequence into a statistical machine learning framework, we developed VIRALpro, a tool that enables the detection of sequences of viral structural proteins.

Enigmatique, poétique, fragmentaire, foisonnante, réitérative, l’œuvre de Pascal Quignard attire par son univers complexe composé de fiction, de vécu personnel, de récits fabuleux, d’érudition, de pensées philosophiques, dans lequel on rencontre des lieux qui constituent des ports d’attache et qui détiennent les secrets du temps. Ces lieux semblent structurer l’œuvre. L’auteur s’intéresse à l’esprit des lieux comme pour mieux souligner les liens invisibles et imaginaires qui se tissent entre l’homme, son territoire et son passé. Etudier l’esprit des lieux et le mythe de l’origine chez Quignard, c’est essayer de comprendre l’évocation récurrente de ce territoire devenu obsédant et sa puissance de représentation dans la création de l’écrivain. Avec le choix du double corpus, romanesque et philosophique, avec le choix d’une méthode de recherche pluridisciplinaire (critique littéraire, anthropologie, imaginaire), notre thèse se construit en trois parties, qui abordent successivement la question de l’attirance des lieux, celle du glissement de l’enchantement à la mélancolie, ainsi que les caractéristiques de l’écriture poétique et mythique de Quignard. Nous trouvons des lieux enchantés qui reflètent la Weltanschauung de l’auteur. Véritables sources de vie, de l’imagination et de la création, ils suscitent la réconciliation entre l’homme et son passé, son territoire et son identité, même si la mélancolie y demeure fondamentale. Les personnages de Quignard sont extrêmement sensibles à tout ce qui est perdu et oublié, à des maisons et lieux abandonnés, à des hommes qui sont présentés comme des enfants d’Eve exilés. Le désir de ré-enraciner, de se ré-ancrer dans le lieu d’autrefois révèle l’attachement mais aussi la défaillance, car l’homme se trouve vite confronté à ce qui est perdu, au vide. L’enchantement reste éphémère, la mélancolie nous ouvre la porte des lieux sombres. Pour mettre en lumière l’esprit des lieux, Pascal Quignard a recours à une écriture riche en réminiscences, en images, en mythes. Son œuvre est le fruit de l’imaginaire, de l’intuition. Les relations complexes entre Fragments, Réminiscences, Mémoire dans son écriture révèlent la profondeur poétique de l’œuvre, tandis que le narrateur suit l’instant, la trace des êtres, les appels lointains, toujours avec son intuition, et ses impressions de poète mélancolique. L’écrivain sert également d’anciens mythes, les transforme et les enrichit comme un moyen efficace pour créer son propre mythe des lieux : mythe du perdu, mythe du retour et mythe de l’origine. / Enigmatic, poetic, fragmentary, abundant, the attraction of Pascal Quignard's work comes from the complex universe of fiction, personal experiences, fabulous stories, extensive documentation and philosophical thoughts, in which some places are homeports, holding the secrets of time. Such places seem to structure the work. The author favors the spirit of places, as if to underline the invisible imaginary links between man, his territory and his past. To study the spirit of places and the origin of myth in the work of Quignard one has to try to understand the recurring evocation, which has become obsessive, of this territory, and his power of creation as writer. With the choice of a double corpus, fiction and philosophy, and a method of interdisciplinary research (literary criticism, anthropology, imagination), our thesis divides into three parts, which will examine in succession the attractiveness of places, then proceed from enchantment to melancholy, and eventually determine the characteristics of the poetic and (the) mythical writing of Quignard. We will find enchanted places that reflect the worldview of the author. They are the true sources of life, imagination and creativity, bringing about reconciliation between man and his past, his territory and his identity, even if melancholy remains fundamental in them. The characters of Quignard are extremely sensitive to all that is lost and forgotten, abandoned homes and places, and to men who are Eve's children in exile. The desire to re-root oneself into the place of the past reveals attachment but also failure, because man is quickly confronted with loss and emptiness. The enchantment remains elusive; melancholy appears constant and opens somber places in his work. To enhance the spirit of place, Quignard makes use of a rich choice of reminiscences, images and myths. His work is at the same time search for, analysis and a quest on man and his place on earth, but it is also a product of imagination and intuition. The complex relations between Fragments, Reminiscences, and Memory in his writing reveal the poetic depth of the work. The narrator also follows moment and instinct, always with the intuition and feelings of a melancholy poet. The writer also uses ancient myths and transforms and enriches them as an effective way to create his own myth of place: myth of (the) loss, myth of (the) return and the myth of (the) origin.

L’étude du microbiote intestinal et de ses produits de sécrétion est un domaine de recherche en expansion en raison des perspectives thérapeutiques que cela peut ouvrir pour les maladies nutritionnelles telles que l’obésité ou les TCA. La Caseinolytic peptidase B (ClpB) est une protéine bactérienne produite par les entérobactéries qui présente un mimétisme moléculaire avec l’α-MSH, un neuropeptide anorexigène signalant la satiété au niveau de l’hypothalamus. Des études récentes ont cherché à évaluer si la protéine ClpB pouvait induire des effets anorexigènes similaires à ceux de l’α-MSH, en situation physiopathologique et dans des modèles de troubles nutritionnels. Dans ce contexte, l’objectif de cette thèse a été d’étudier les potentiels effets pharmacologiques de la protéine ClpB, intacte ou fragmentée sur les différents mécanismes de régulation de la prise alimentaire impliquant l’axe microbiote-intestin-cerveau et l’influence des nutriments. La première étude a évalué in vitro l’impact de trois macronutriments sur la production et l’expression de la protéine ClpB par les bactéries E. coli : seul l’apport protéique augmentait significativement la production de ClpB. Nous avons montré que la ClpB augmentait la sécrétion de PYY par les cellules entéro-endocrines intestinales de rat en culture. La deuxième d’étude a été réalisée chez des souris dans un modèle d’anorexie (ABA). La restriction alimentaire, avec ou sans activité physique, augmentait la concentration plasmatique de ClpB, qui était associée à une augmentation de la proportion d’entérobactéries dans le microbiote, ce qui suggère son implication possible dans la physiopathologie de l’anorexie mentale. Enfin, la troisième étude a évalué in vivo chez le Rongeur, les effets pharmacologiques de la protéine ClpB sur la prise alimentaire. La prise alimentaire était réduite par l’injection de ClpB intacte ou fragmentée, mais pas par son fragment de 25 kDa. Ces résultats confortent le rôle de la protéine ClpB, produite par les entérobactéries, dans la régulation physiologique de la prise alimentaire et incitent à poursuivre l’étude de son implication dans les troubles anorexiques et son application thérapeutique dans les situations d’excès de poids. / The study of the gut microbiota and especially the effect of its secretory products is an expanding field of research in order to open therapeutic perspectives for nutritional diseases such as obesity or TCA. Among these molecules, the Caseinolytic peptidase B (ClpB) is a bacterial protein having a molecular mimicry in common with α-MSH, a neuropeptide whose anorectic actions are peripheral and central and possible via a microbiota-intestinal-brain communication. Current studies attempt to demonstrate whether this molecular mimicry can confer similar anorectic effects at the ClpB protein. The aim of this thesis was studied the potential pharmacological effects of ClpB protein the regulation of eating behavior. Given that the composition of the gut microbiota is dependent on the food present, the first study was evaluated in vitro the impact of three types of macronutrients on the production and expression of the ClpB protein by E. coli bacteria. Then, it was evaluated whether this protein could influence the secretion of satietogenic peptides like PYY by intestinal enteroendocrine cells using a primary culture of rat intestinal cells. Previous studies of U 1073 laboratory have shown that this protein has been found at the plasma level, the second study was performed in mice submitted to an anorexia model (ABA) to clarify the impact of dietary restriction on the ClpB protein, to better understand its possible involvement in the physiopathology of anorexia nervosa. Finally, the third study was evaluated the pharmacological effects of ClpB protein on food intake in vivo in rodents. The impact of the natural fragmentation of this protein and particularly of one of its fragments on food intake was also evaluated.

Master of Science / Department of Animal Sciences and Industry / Terry A. Houser / Nursery age pigs (n=198) were used to evaluate the difference in the occurrence of injection site abscesses between needle-free jet injection and conventional needle-and-syringe injection systems. Pigs were fed for 21 d prior to treatment administration to acclimate the pigs to the environment of the Kansas State University Segregated Early Weaning (SEW) unit. On d 21 each pig was injected with aluminum hydroxide adjuvant in the neck and ham with needle-free jet injection (Pulse Needle-Free Systems, Lenexa, KS) and conventional needle-and-syringe injection. Needle-free and conventional needle-and-syringe injections were randomly assigned to pig side yielding a total of 396 injections per treatment with a total of 792 injections sites. Immediately prior to injection, the external surface of the injection sites were contaminated with an inoculum of Arcanobacterium pyogenes, a bacterium commonly associated with livestock abscesses. The pigs were then fed for a period of 27 or 28 d. On d 27 or d 28 the pigs were humanely euthanized and sent to the Kansas State Veterinary Diagnostics Laboratory where necropsies were performed and the injection sites harvested for histopathological evaluation. The needle-free jet injection system was associated with more injection site abscesses than the conventional needle-and-syringe injection method for both neck (P=0.0625) and ham (P=0.0313) injection sites. Twelve abscesses were found at injection sites administered via needle-free jet injection method while only 1 abscess was found with the conventional needle-and-syringe injection method. 5 abscesses were found at the neck injection sites and 8 abscesses were found at ham injection sites. There were no significant differences seen in tissue granulation resulting from reaction to the adjuvant. In summary, the implementation of needle-free jet injection systems in market hog production will be beneficial to eliminate needles and needle fragments in meat products but, when in the presence of Arcanobacterium pyogenes, it may increase the occurrence of injection site abscesses in pork carcasses that will need to be trimmed in pork processing plants. Although more abscesses were associated with needle-free jet injection, their occurrence was observed at a very low rate given that all injection sites were intentionally contaminated prior to injection.

Ideology is a powerful means of persuasion in contemporary audience appeals. Through the means of ideographic and fragmentary analyses provided by Michael Calvin McGee (1980, 1990) and Saindon (2008), I examine the rhetorical appeals made by the Liberty Counsel, an evangelical Christian organization, which provides legal counsel for cases regarding “religious liberty.” Through an ideographic and fragmentary analysis, I conclude that the Counsel utilizes the ideograph as a superseding means of denoting its ideology. Further, I argue that is the ideograph that represents the ontological nature of the organization’s philosophy and serves as the guiding principle for many of the other ideographs that the organization employs. Further, the ideograph displays relative influence for the Liberty Counsel with and from other organizations, as illustrated when is compared to competing ideologies, such as that from the Southern Poverty Law Center. The importance of the ideograph is incumbent upon its utility in understanding a “snapshot” of the rhetorical situation. Rather than attempting to draft ideological archetypes, as the initial ideographic form attempted, this new ideographic form accepts the relativistic cultural influences and accounts for them synchronically.

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.

O aumento do conhecimento sobre os mecanismos macromoleculares de diversas doenças tem permitido a identificação de vários alvos terapêuticos, porém o desenvolvimento de fármacos para esses alvos não seguiu na mesma velocidade. Além disso, a presença de padrões estruturais inovadores nesses fármacos é baixa. Neste cenário, buscamos, ao mapear o espaço químico medicinal de compostos heteroaromáticos, introduzir novos fragmentos úteis no desenvolvimento de compostos bioativos inovadores. Para tanto, duas abordagens foram avaliadas: 1) Estudo da viabilidade de síntese de dois núcleos heteroaromáticos sem síntese descrita na literatura. 2) Estudo de uma nova rota sintética para obtenção do núcleo furo[2,3-b]piridina, bem como a viabilidade de sua funcionalização e aplicação no desenvolvimento de compostos com atividade antituberculose. Em relação a primeira abordagem (Capítulo 1), para o núcleo 22 (piridazina-piridona) foi possível explorar uma rota sintética que, embora, ainda não tenha sido possível obter o composto desejado, o mesmo necessita apenas de uma etapa de aromatização para ser obtido. Já para o núcleo 20 (pirido-piridazinona), após o estudo de diversas estratégias sintéticas, foi possível obtê-lo, em baixos rendimentos, e, portanto, a otimização da rota sintética, bem como a completa caracterização dele, ainda serão necessários. Durante a exploração das diversas estratégias para a síntese do núcleo 20, foi possível, a partir de resultado inesperado em uma delas, verificar uma nova rota sintética para compostos furo[2-3-b]piridina substituídos nas posições C-2 e C-3, o que foi objeto de estudo da segunda abordagem descrita nesta tese (Capítulo 2). Utilizando condições brandas e livre de metais, foi possível obter diversas furanopiridinas com diferentes substituições em C-2 (arílico ou alquílico), utilizando diversos cloretos de ácidos ou anidridos. Além disso, foi verificado que o anel furânico do núcleo furanopiridínico é estável na reação de hidrólise do éster em C-3, porém quando na presença de hidrazina é formado um novo padrão estrutural com anel pirazolona, proveniente da abertura do anel furano. Em relação a reatividade química da porção piridínica desse núcleo, em reações de ativação da ligação C-H, foi possível realizar a borilação seguida de acoplamento cruzado de Suzuki na posição C-5. Já arilação radicalar ocorreu em C-4 e a fluorinação direta em C-6. Porém, os rendimentos destas reações não foram satisfatórios. Com isso, foi avaliado a reatividade do derivado N-óxido da furanopiridina com diferentes agentes ativantes e nucleófilos. Com o uso de anidrido tríflico como agente ativante, foi possível a iodação em C-5, bromação em C-4 e hidroxilação em C-4 e C-6. Já utilizando PyBroP, como ativante, foi possível realizar reações de aminação nas posições C-4, C-5 e C-6. Esses compostos tiveram a atividade biológica contra Mycobacterium tuberculosis avaliada, onde um dos compostos apresentou atividade promissora, tanto contra cepas laboratoriais, quanto cepas de isolados clínicos multirresistentes. Além disso, esse composto apresentou alto índice de seletividade, e por ser um fragmento, permitirá futuras otimização estruturais. / The increasing knowledge about the macromolecular mechanisms of different diseases allowed the identification of several therapeutic targets over the years. However, the development of drugs to these targets did not follow the same rate. In addition, the introduction of innovative frameworks in new drugs is unsatisfactory. In this scenario, we aim to introduce new useful fragments for application in the development of innovative bioactive compounds, by charting the medicinal chemical space of heteroaromatic compounds. For this purpose, two approaches were evaluated: 1) Develop a feasible synthetic strategy to obtain two new heteroaromatic cores (Cores 20 and 22); 2) Develop a new synthetic route to obtain the furo[2,3-b]pyridine core, chemical elaborate it and screening it against Mycobacterium tuberculosis. For the first approach (Chapter 1), one aromatization step is needed to obtain core 22 (pyridazine-pyridone). On the other hand, after evaluating several synthetic strategies, it was possible to obtain core 20 (pyrido-pyridazinone) in low yields. Therefore, a synthetic route optimization and a complete characterization are still required for 20. An unexpected result in attempt to obtain core 20, resulted in a new synthetic route to furo[2-3-b]pyridine, C-2 and C- 3 substituted, that was explored in the second approach (Chapter 2). Using mild and metal-free conditions, it was possible to obtain various furopyridines with different substitutions patterns at C-2 (aryl or alkyl) using either acyl chlorides or anhydrides. In addition, the furan moiety in this core, showed to be stable under the C-3-ester hydrolysis, however, in solution, hydrazine opens the furan ring to form a new pyrazolone ring. Regarding the chemical reactivity of the pyridine moiety in the furopyridine core, it was possible to perform the C-H borylation followed by Suzuki coupling reaction at the C-5 position. Furthermore, radical arylation at C-4 and direct fluorination at C-6 had not satisfactory yields. Therefore, the reactivity of the furopyridine N-oxide derivative with nucleophiles using different activating agents was studied. Using triflic anhydride, as an activating agent, it was possible to iodinate at C-5, brominated at C-4 and hydroxylated at C-4 and C-6. Using PyBroP, as an activator, it was possible to perform amination reactions at positions C-4, C-5 and C-6. In the end, our in-house library of furopyridines was screened against Mycobacterium tuberculosis and it was found a promising selective bioactive compound against different multidrug-resistant strains of this mycobacteria. Furthermore, this compound is a fragment, which will allow future structural optimization.

Aurora occurs in various shapes, one of which is the hitherto unreported phenomenon of auroral fragments. For three periods of occurrence of these fragments their properties were studied in detail during this master’s thesis, using mainly ground-based instrumentation located near Longyearbyen on Svalbard, Norway. A base dataset was constructed from 103 all-sky camera images, manually marking 305 fragments for further analysis. This thesis reports and describes the fragment observations during the observed events, including the auroral and geomagnetic context. Fragments generally seem to fall into two categories, the first being singular, apparently randomly distributed fragments, and the second being periodic fragments that occur in groups with a regular spacing close to auroral arcs. A typical fragment has a small horizontal size below 20 km, a short lifetime of less than a minute and shows no field-aligned extent in the emission. The fragments appear mainly west of zenith (73%) during the three observation nights, whereas their north-south distribution is symmetric around the zenith. Almost all of them exhibit westward drift, the estimated speed for one of the fragments passing the field of view of ASK is ∼1 km/s. A spectral signature can be seen in the green auroral wavelength of O at 557.7 nm and red emission line of N2 at 673.0 nm, but no emission enhancement was observed in the blue wavelengths. One fragment passing the EISCAT Svalbard radar’s field of view shows a local ion temperature increase in a small altitude range of ∼15 km, whereas there is no visible increase in electron density. This could be explained by fragment generation due to locally strong horizontal electric fields. A potential mechanism for this might be electric fields of atmospheric waves superposing with the converging electric fields of auroral arcs created by particle precipitation and the corresponding field-aligned currents. The resulting field would be perpendicular to the magnetic field and the auroral arcs, leading to wave-like density variations of excited plasma close to the arcs. Further study is required to verify this hypothesis and improve the understanding of fragment properties determined from the limited dataset used for this thesis.