Thesis (D.M.A.)--University of North Texas, 2006. / System requirements: Adobe Acrobat Reader. Accompanied by 4 recitals, recorded Apr. 3, 2000, Sept. 17, 2001, Oct. 13, 2003, and Oct. 24, 2006. Includes bibliographical references (p. 84-89).

Les médicaments à base de substances naturelles telles que les plantes et les venins sont de plus en plus développés dans l’industrie pharmaceutique. Le contrôle qualité des matières premières ou teintures mères d’origine végétales ou animales, obligatoire dans un environnement BPF, est bien plus complexe que celui des petites molécules pharmaceutiques de synthèse. En effet, les substances responsables de l’activité thérapeutique recherchée sont souvent mal identifiées et on observe une variabilité qualitative et quantitative naturelle parfois importante, ce qui peut modifier de façon significative leur efficacité. Afin de s’assurer de l’homogénéité de chaque souche reçue, il est demandé, entre autre, de développer des méthodes de contrôle analytique permettant d’obtenir un « profil ou empreinte » analytique de la souche considérée, assimilable à une « carte d’identité » qui servira de référence pour le contrôle des lots utilisés en production. L’empreinte analytique (spectre, chromatogramme, électrophérogramme …) devra permettre une séparation la plus complète possible de l’ensemble des composés présents dans la souche considérée tout en tenant compte de sa « variabilité naturelle » afin d’assurer un contrôle qualitatif et semi-quantitatif.L’étude présentée a consisté à développer une approche analytique originale, combinant électrophorèse capillaire et chimiométrie, afin d’établir des profils électrophorétiques spécifiques («fingerprint») permettant d’effectuer le contrôle qualité de souches brutes de venins de serpents utilisés en thérapeutique. Les venins de serpent sont des mélanges complexes de peptides et de protéines, de plus en plus utilisés dans la conception de nouveaux médicaments. Comme toutes les substances naturelles, la composition des venins de serpents est sujette à une variabilité intra et inter individus relativement importante. De fait, la qualité de la matière première pour la production de médicament devient un challenge. Dans cette étude, l’électrophorèse capillaire s’est révélée comme une technique efficace pour la séparation des divers constituants composant les souches brutes de venins de serpent et l’obtention de leurs empreintes analytiques. L’étude a porté sur 4 venins de serpent, Lachesis muta, Bothrops lanceolatus, Vipera aspis aspis, Naja naja qui sont parmi les plus utilisés en thérapeutique. Une approche chimiométrique a alors été développée afin de tenir compte de variabilité qualitative et quantitative observée entre différents lots. Cette approche originale nous a permis d’extraire les pics d’intérêts (i.e. présents dans chaque lot d’un même venin) et d’établir une empreinte analytique de référence avec des seuils de conformité quantitatifs. / Although the therapeutic potential of natural substances is known for thousands of years in traditional medicine, it knows an increasing renewed interest in modern pharmaceutical industry as being an inexhaustible source of therapeutic active substances for various diseases.However, the quality control of these products, which is necessary to obtain reproducible biological activities and new commercial approvals, remains a great analytical challenge. Indeed, natural substances show a myriad of biological activities that can result from a specific or synergistic effects of many different components and this information remains still mostly unknown. Furthermore, because they are derived from living organisms and hence are affected by biotic and abiotic factors, it is extremely difficult to ensure a constant qualitative and quantitative composition for these natural substances among different batches. Consequently, there is a need to develop analytical strategies able to assess the “sameness” of natural productions that is analytical strategies able to assess required similarity between different batches by integrating acceptable qualitative and quantitative variations.To achieve this, the concept of analytical fingerprint has become more and more popular and is now starting to be accepted by regulatory authorities such as the FDA. This so-called “pattern-approach” aims at: (i) gaining effective and stable information about common features of a given strain (ii) evaluating similarity and difference with chemometric methods.If this concept has been quite largely studied for the quality assessment of herbal medicines, it is very still very little developed for animal active substances like snake venoms, which are of increasing interest in therapeutic research due to their rich composition in peptides and proteins. The routine quality control of venom raw substances is still often limited to a single gel electrophoresis which is clearly insufficient in terms of components resolution to achieve similarity-/dissimilarity between strains.MethodsIn this context, we have developed an original analytical fingerprint strategy that combines capillary electrophoresis and chemometrics. CE is a particularly well suited technique for peptides/proteins separation allowing to obtain complex specific fingerprints. Batches of different snake venoms have been analyzed with many replicates. All electropherograms have been processed using several chemometrics approaches (baseline correction, signals alignment, automatic recognition of common peaks …) to obtain a representative analytical trace that can be used for the quality assessment of different production lots.ResultsWe show that CE is a very well adapted method to produce highly specific and repeatable analytical profiles of different venom strains. Chemometric methods applied are very efficient to produce an average fingerprint for each strain that integrates features common to all batches and define acceptable variations in quantitative composition. Similarity/dissimilarity of different batches can then be assessed in an automatic manner.ConclusionAll presented results show the efficacy of CE combined with chemometrics to assess the quality of snake venom raw substances. It can be easily implemented in industrial quality control. This strategy can be implemented in future for other type of therapeutic substances of animal origin.

Submitted by Viviane Lima da Cunha (viviane@biblioteca.ufpb.br) on 2016-12-21T11:40:50Z No. of bitstreams: 1 arquivototal.pdf: 1555797 bytes, checksum: 063ae5f4dd1ed3591350e393890fa193 (MD5) / Made available in DSpace on 2016-12-21T11:40:50Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1555797 bytes, checksum: 063ae5f4dd1ed3591350e393890fa193 (MD5) Previous issue date: 2015-07-16 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The origin of mythic narrative is recognized in all ancient traditions. During this period its relationship with the sacred was intrinsically present in everyday acts, without any distinction between the sacred and the profane because their activities were conditioned with divine in such a way that in the early stages the relation of the cultivation of plants and everything that came from the groud, the earth for the survival, was a depiction, a portrayal of Mother when she was related to fertilizing streghth. This way we find the Mother as a divine portrayal, the same way as there is also an identification of animals in such a way when they are food, nourishment. Their sacrifice indicated a sacral idea and that episode ocurred in a ritual, ceremony. Our main objective was to analise the mythic serpent in four semitic texts: the hymn to Ptah; The Gilgamesh epopee; The Elish enema and , The hebraic myth of creation. Therefore we historically contextualized the semitic traditions, especially the Egiptian, the Mesopotamia, (Sumerian, Babylon) and Israel. Consequently, we have also started a research on the mythic serpent on these traditions in evidence. The myths about the origin give us support to understand the serpent archetype, as we have seen that its symbolic representation indicates the polarities as well as a cyclical journey. To do só it was applied the yunguian analitic instrumentation when it develops the archetype concept, mainly in the title: “The archetypes and the collective unconsciousness.” Methodologically, it was used the comparative and symbolic hermeneutics of Mircea Eliade, mainly in its titles “The sacred and the profane” and “The myth of the eternal return”, as well as an effort to interlace the vision that leads, indicates according to Carlo Ginsburg in the interpretative understanding of critique hermeneutics, in other words, throughout the clues found in the texts. / Reconhecemos nas tradições antigas a origem das narrativas míticas. Neste período a relação com o sagrado estava intrinsecamente presente no cotidiano, não havia distinção entre o sagrado e o profano, pois suas atividades se condicionavam ao divino de tal modo que nos primórdios a relação da criação das plantas, tudo o que surgia da terra para a sobrevivência era representada pela Mãe quando a associavam ao poder fecundante. Deste modo encontramos a Mãe como representação divina, assim como também há uma identificação dos animais quando são reverenciados pela sua força e também quando são o alimento. O seu sacrifício indicava uma sacralidade e este episódio se dava ritualmente. Nosso objetivo foi analisar a serpente mítica em quatro textos semíticos: o hino a Ptah, a Epopeia de Gilgamesh, o Enuma Elish e o Mito hebraico da criação. Portanto contextualizamos historicamente as tradições semitas, especificamente o Egito, a Mesopotâmia (Suméria, Babilônia) e Israel. Por sequência pesquisamos a serpente mítica nestas tradições e por fim descobrimos o arquétipo da serpente nas tradições que destacamos. Os mitos de origem nos dão respaldo para compreensão arquetípica da serpente, pois vemos que a sua representação simbólica indica as polaridades assim como uma jornada cíclica. Para tanto aplicamos a instrumentação analítica junguiana quando desenvolve o conceito de arquétipo, principalmente na obra: “Os arquétipos e o inconsciente coletivo”. Metodologicamente utilizamos da hermenêutica simbólica e comparada de Mircea Eliade principalmente em suas obras: “O sagrado e o profano” e “O mito do eterno retorno” e buscamos entrelaçar a visão indiciária conforme Carlo Ginsburg com a intelecção interpretativa da hermenêutica crítica, ou seja, através das pistas interpretamos os textos.

As doenças neurodegenerativas (DN), incluindo doença de Alzheimer e doença de Parkinson, estão entre as principais causas de mortalidade e morbidade nos países ocidentais. Não há ainda um tratamento definitivo para estas neuropatias, mas os estudos têm apontado para mecanismos comuns de toxicidade, que incluem disfunção mitocondrial, estresse oxidativo e apoptose. Assim, as mitocôndrias constituem alvos importantes para futuras estratégias de neuroproteção visando tratar, prevenir ou retardar a neurodegeneração. A biodiversidade da fauna brasileira representa uma fonte promissora e ainda pouco explorada de novas moléculas com (i) atividade neuroprotetora e, portanto, potencial para originar novos fármacos para o tratamento destas doenças; ou ainda com (ii) atividade neurotóxica, podendo ser utilizadas como ferramentas de estudo de mecanismos de neurotoxicidade. O presente estudo teve por objetivo investigar o possível potencial neuroprotetor e/ou neurotóxico de peptídeos de baixo peso molecular, obtidos a partir do veneno de diferentes espécies de serpentes do gênero Bothrops por meio da investigação dos efeitos destes compostos na função mitocondrial de cérebro de rato. Duas das frações estudadas (obtidas a partir do veneno da B. atrox e da B. jararaca) apresentaram um interessante potencial protetor contra o intumescimento osmótico mitocondrial e a produção de espécies reativas de oxigênio (ERO), eventos associados à transição de permeabilidade mitocondrial e à morte celular. Por outro lado, outra fração, obtida a partir do veneno da B. pirajai, apresentou potencial neurotóxico. Estes achados podem ser úteis para estudos mecanísticos e também no estabelecimento de futuras estratégias de tratamento das doenças neurodegenerativas, tendo as mitocôndrias como alvos terapêuticos (terapia alvo). / The neurodegenerative diseases, including Alzheimer\'s and Parkinson\'s diseases, are among the main causes of morbidity and mortality in Western countries. A definitive treatment for these neuropathies has not yet been found, but studies have indicated common mechanisms of toxicity, including mitochondrial dysfunction, oxidative stress and apoptosis. Therefore, mitochondria represent important targets for the future neuroprotective strategies aimed to treat, prevent or delay the neurodegeneration. The Brazilian fauna biodiversity represents a promising and under explored source of new molecules with (i) neuroprotective activity and potential to originate new drugs for the treatment of these diseases; or yet, with (ii) neurotoxic activity, representing tools to study neurotoxicity mechanisms. The present study aimed to investigate the possible neuroprotective and/or neurotoxic potential of low-molecular-mass peptides extracted from the venom of different species of Bothrops genus snakes by investigating their effects on rat brain mitochondrial function. Two of the studied fractions (from B. atrox and B. jararaca venoms) presented an interesting protective potential against both the mitochondrial swelling and reactive oxygen species (ROS) production, events associated with mitochondrial permeability transition and cell death. On the other hand, other fraction (from B. pirajai venom) presented a neurotoxic potential. These findings might be useful for mechanistic studies and also for the establishment of future strategies of neurodegenerative diseases treatment, using mitochondria as therapeutic targets (targeted therapy).

No Brasil, ocorrem anualmente mais de 20.000 acidentes ofídicos, sendo mais de 80 por cento por espécies do gênero Bothrops. Envenenamentos por serpentes desse gênero raramente causam óbito mas, muitas vezes, levam a necrose e infecção secundária, que podem determinar a perda de um membro acometido ou de segmento desse. A dose de soro antibotrópico utilizada para o seu tratamento é baseada na gravidade do envenenamento ao exame inicial. Vários fatores têm sido associados a essa gravidade, mas poucos são os dados científicos e nenhuma avaliação foi feita para acidentes comprovadamente causados por B. jararaca. O presente estudo teve como objetivo identificar: as variáveis associadas à ocorrência de necrose; as variáveis asociadas à ocorrência de abscesso; os fatores prognósticos independentes para a ocorrência de necrose; os fatores prognósticos independentes para a ocorrência de abscesso. Foram analisados no presente estudo 779 casos de acidentes por B. jararaca atendidos no Hospital Vital Brazil do Instituto Butantan, no período de 1982 a 1990. Os dados foram levantados a partir de prontuários médicos arquivados nesse hospital. Os casos que apresentaram necrose e os que evoluiram para abscesso, foram comparados no que se refere a uma série de variáveis, respectivamente, com aqueles que não apresentaram necrose e não evoluiram para abscesso. Correlacionaram-se estatisticamente à análise bivariada com necrose e abscesso (p < 0,05) o acidente por serpentes de grande porte (> 60cm), a picada em perna, o uso de torniquete, a presença de dor, edema, equimose, bolha, choque, sangramento fora da região da picada. Acidentes em determinados meses do ano, picadas nos dedos da mão e alteração da coagulação sanguínea só se correlacionaram com necrose (p < 0,05). Mostraram-se fatores prognósticos independentes para necrose à análise multivariada: tamanho da serpente, conforme diferentes faixas de comprimento, 60 - 80cm, 80 - lOOcm, 100 - 140cm; mês de ocorrência; acidentes com pessoas do sexo feminino; picadas no dedo da mão, e na perna; uso de torniquete; ocorrência de sangramento. Mostraram-se fatores prognósticos independentes para abscesso, à análise multi variada: tamanho da serpente, conforme diferentes faixas de comprimento 60-80cm, 80- lOOcm, 100-140cm; mês de ocorrência; acidentes com pessoas do sexo feminino; picada na perna; alteração da coagulação sanguínea; ocorrência de sangramento. Conclui-se que, as variáveis relacionadas com necrose e aquelas relacionadas com abscesso, os fatores prognósticos independentes para necrose e aqueles para abscesso, são os apresentados acima e que o porte de B. jararaca é o fator prognóstico independente mais importante para necrose e, principalmente, para abscesso, que são tanto mais freqüentes quanto maior o comprimento da serpente. / There is an annual incidence of over 20 000 snakebite cases in Brazil; of these over 80 per cent are caused by Bothrops species. Bothropic envenoming commonly causes necrosis and secondary infection which may lead to loss of part or of all the bitten limb. Fortunately fatalities are rare. During treatment, the dose of antivenom administered is based on the clinical severity of the envenoming. Several factors have been shown to be associated with the severity of the envenoming, however data are scarce and no such studies on Bothrops jararaca exist. The objective of this study was to identify the following: the variables associated with necrosis; the variables associated with abscess formation; the independent prognostic factors of necrosis; the independent prognostic factors of abscess formation. The study analysed 779 B. jararaca envenoming cases admitted from the Hospital Vital Brazil of the Instituto Butanatan in the period from 1982 to 1990. Data were taken from medical records in this hospital. Occurrence of necrosis or of abscesses was independently compared, in the light of a series of specific variables, with cases in which, necrosis or abscesses did not occur. Occurrence of necrosis and of abscess (p<0,05) was correlated by bivariable statistical analysis with the following: bites caused by large-sized snakes (>60cm in length); bites on the leg; use of tourniquet; presence of pain, oedema, equimosis, blisters, shock; and systemic bleeding. Occurrence of necrosis (p<0.05) was only correlated with bites on the fingers, impaired blood coagulability, and with accidents grouped according to the month of the year. The following were shown, on multivariate analysis, to be independent prognostic factors for necrosis: size of snake (grouped according to length 60-80cm/ 80- l00cm/ 100-140cm); month in which bite occured; female sex of the victim; bites on fingers and legs; use of tourniquet; and the presence of haemmorrhage. The following were shown, on multivariate analysis, to be independent prognostic indicators for abscess formation: size of snake (grouped according to length 60-80cm/ 80-l00cm/ 100-140cm); month in which bite occured; female sex of the victim; bites on the leg; impaired blood coagulability; and the presence of haemmorrhage. It is concluded that the forementioned are: associated factors of necrosis and abscess formation; and the independent prognostic factors of necrosis; and independent prognostic factors of abscess. The size of B. jararaca responsible for the bite was shown to be the most important independent prognostic factor of necrosis and, even more so, of abscess.

Ce travail avait pour objectif de mieux évaluer les critères intrinsèques d’un antivenin et de son utilisation afin d’être le plus efficace possible dans le traitement des envenimations ophidiennes survenant sur le territoire de France métropolitaine. L’immunothérapie est à ce jour le seul traitement étiologique efficace dans la prise en charge des victimes d’envenimation ophidienne. La qualité des antivenins est un élément clé dans l’efficacité et la tolérance de ces traitements. Pour une efficacité optimale, l’immunothérapie doit être administrée le plus rapidement possible. Il ressort enfin que les caractéristiques des envenimations sont en évolution constante sur le territoire métropolitain : émergence de signes neurotoxiques dans les envenimations vipérines ; développement de l’importation de serpents exotiques. Tous ces éléments incitent à une surveillance spécifique par des structures expertes et spécialisées dans le domaine. / This work aimed to assess antivenom criteria in order to be most effective in the treatment of snake bites occurring in metropolitan France. Immunotherapy is the only effective etiological treatment in snake envenomation, considered as a gold standard. Quality of antivenoms is a key element for effectiveness and safety. Immunotherapy should be administered as soon as possible. Finally, it appears that the characteristics of envenomation are constantly changing on the mainland : emergence of neurotoxic signs in viper envenomation; importation of exotic snakes. All these emerging elements need a specific monitoring by expert and specialized structures in France.

This thesis is a study of three of the.literary works of Jacques Benoit: Jos Carbone, Les Princes and Gisèle et le serpent. It will be an attempt to combine different spatial elements of the texts, literal and symbolic, in order to define and explore the imaginary universe of our author. In our first text, Jos Carbone, we look to establish the role of the unconscious. The background predominance of night and dark elements, unseen invaders, habitations, in short, the forest in general appears as a metaphor for the unconscious mind of the hero Jos Carbone. In our analysis, we attempt to explore this imaginary universe with intent to establish the theme of the territorial quest as it might apply to the central couple Jos and Myrtie. In our analysis of Benoit's novel, Les Princes, we endeavour to explore the allegorical world with an emphasis on the nonverbal communication of both the topography and the inhabitants of la Ville. We observe the confrontation of men and dogs in an effort to examine the role of what is considered civil or animal, pet or prey. The impotency and frustration of Coquin society coupled with corrupt Grâligean authority evoke the ideas of Jean-Jacques Rousseau on social inequality. We shall, therefore, attempt to apply some of his beliefs to imaginary elements of the novel. Finally, we shall examine the unvoiced refutation of the Grâligean's verbal law and the possible future outcome of la Ville's violent upheaval. Gisèle et le serpent will be studied in terms of a creative quest to write on the part of the hero and narrator, Gregoire Rabouin. We will take into account the displacement, transformation and constant motion of the text as well as the combination of fantastic and conventional elements. The role of the protagonist Gisèle is to be examined in terms of her capacity as role model, motivation to write and magical force behind the liberation of the hero's creative drive. We shall show the conflict created by the doctor's frustration with his rational profession and examine the unblocking of his creativity as portrayed by his relinquishing of control. Furthermore, an analysis of the parodies of his occupation, the deformation of language and patients as well as the fairy-tale format of the novel will confirm his desire to renounce medicine in favour of literary creation. Finally, we see the completion of Rabouin's narrative voyage in the discovery of his ability to write. In conclusion we shall state general observations about the imaginary universe as it applies to the comparison of our three texts. Specifically, this will entail the unconscious world, the violent and disruptive element and Benoit's tendency to stray from the rules of standard literary genres. / Arts, Faculty of / French, Hispanic, and Italian Studies, Department of / Graduate

The sensitivity of two operational output parameters, criticality and isotopic composition during burnup, to specific design and operational reactor parameters in a Sodium Cooled Fast Reactor, is investigated. The computational simulation tool Serpent is used. The parameters varied include Uranium enrichment, Plutonium content, rod thickness, fuel temperature, and sodium density. In burnup, the development of the fraction of fissile isotopes, isotopes used for measurements, the isotopic composition of Plutonium, and isotopes that complicate fuel reprocessing is displayed. A surrogate model, optimized for use in determining how criticality develops between data points, is used. The results are displayed as plots created in Matlab. The results are discussed, with a focus on how large an effect varying different parameters have on different outputs related to the reactor's operation. It is concluded that the Plutonium content has the largest effect on the isotopic composition and that, based on the performed simulations, MOX fuel is potentially safer than Zirconium alloy fuel in a practical setting.

La première partie de cette thèse s’inscrit dans le domaine des cartes aléatoires, qui est un sujet à la frontière des probabilités, de la combinatoire et de la physique statistique. Nos travaux complètent une série de résultats de convergence de différents modèles de cartes aléatoires vers la carte brownienne, qui est un espace métrique compact aléatoire. Plus précisément, on montre que la limite d’échelle d’une carte de loi uniforme sur l’ensemble des cartes biparties enracinées à n arêtes, munie de la distance de graphe renormalisée par (2n)^(−1/4), est, au sens de Gromov–Hausdorff, la carte brownienne. Pour prouver ce résultat, les arguments importants sont d’une part l’utilisation d’une bijection combinatoire entre cartes biparties et arbres multitypes, et d’autre part des théorèmes de convergence pour les arbres de Galton–Watson multitypes étiquetés. Dans un deuxième temps, le but est de présenter une théorie des excursions pour le mouvement brownien indexé par l’arbre brownien. De manière analogue à la théorie d’Itô des excursions pour le mouvement brownien, chaque excursion correspond à une composante connexe du complémentaire des zéros du mouvement brownien indexé par l’arbre, et l’excursion est définie comme un processus indexé par un arbre continu. On explique comment mesurer la longueur de la frontière de ces excursions, de sorte que la famille de ces longueurs coïncide avec les sauts d’un processus de branchement à temps continu de mécanisme de branchement stable d’indice 3/2. De plus, conditionnellement aux longueurs des frontières, les excursions sont indépendantes et leur loi conditionnelle est déterminée à l’aide d’une mesure d’excursion explicite que l’on introduit et décrit. Dans ce travail, le serpent brownien apparaît comme un outil particulièrement important. / The first part of this thesis concerns the area of random maps, which is a topic in between probability theory, combinatorics and statistical physics. Our work complements several results of convergence of various classes of random maps to the Brownian map, which is a random compact metric space. More precisely, we prove that the scaling limit of a map which is uniformly distributed over the class of rooted planar maps with n edges, equipped with the graph distance rescaled by (2n)^(−1/4), is, in the Gromov-Hausdorff sense, the Brownian map. To establish this result, the main arguments are the use of a combinatorial bijection between bipartite maps and multitype trees, together with convergence theorems for Galton-Watson multitype trees. We then aim to develop an excursion theory for Brownian motion indexed by the Brownian tree. Analogous to the Itô excursion theory for Brownian motion, each excursion corresponds to a connected component of the complement of the zero set of the tree-indexed Brownian motion, and the excursion is defined as a process indexed by a continuous tree. We explain how to measure the length of the boundary of these excursions, in a way that the collection of these lengths coincides with the collection of jumps of a continuous-state branching process with a 3/2-stable branching mechanism. Moreover, conditionally on the boundary lengths, the excursions are independent and their conditional distribution is determined in terms of an excursion measure that we introduce and study. In this work, the Brownian snake appears as a particularly important tool.

The Department of Physics and Astronomy in Uppsala is planning to construct a source-based neutron irradiation facility at Ångströms laboratory. The purpose of this facility will, as of now, mainly be for students and employees to conduct scientific experiments and to calibrate the university's neutron scintillator detectors. A vital part of the construction is the shielding of the source, for both safety reasons and practicality issues. In this project, a series of simulations were made to determine the necessary dimensions of the shielding to ensure that the radiation dose levels stayed under the stipulated 6 mSv per year. Two types of shielding materials were tested, borated and non-borated polyethylene. It was found that the borated polyethylene performed better in shielding the source, but not enough to justify the higher material cost. The optimal dimensions of the shielding for non-borated polyethylene were found to be 60x60x74cm.