Mineração de dados tem sido cada vez mais aplicada em distintas áreas com o objetivo de extrair conhecimento interessante e relevante de grandes conjuntos de dados. Nesse contexto, aprendizado de máquina fornece alguns dos principais métodos utilizados em mineração de dados. Dentre os métodos empregados em aprendizado de máquina destacam-se os simbólicos que possuem como principal contribuição a interpretabilidade. Entretanto, os métodos de aprendizado de máquina tradicionais, como árvores e regras de decisão, não consideram a informação temporal presente nesses dados. Este trabalho propõe uma metodologia para extração de conhecimento de séries temporais por meio da extração de características e da identificação de motifs. Características e motifs são utilizados como atributos para a extração de conhecimento por métodos de aprendizado de máquina. Essa metodologia foi avaliada utilizando conjuntos de dados conhecidos na área. Foi realizada uma análise comparativa entre a metodologia e a aplicação direta de métodos de aprendizado de máquina sobre as séries temporais. Os resultados mostram que existe diferença estatística significativa para a maioria dos conjuntos de dados avaliados. Finalmente, foi realizado um estudo de caso preliminar referente ao monitoramento ambiental do reservatório da Usina Hidrelétrica Itaipu Binacional. Nesse estudo somente a identificação de motifs foi aplicada. Foram utilizadas séries temporais referentes à temperatura da água coletadas em distintas regiões do reservatório. Nesse estudo observou-se a existência de um padrão na distribuição dos motifs identificados para cada região do reservatório, corroborando com resultados consagrados na literatura / Data mining has been applied to several areas with the objective of extracting interesting and relevant knowledge from large data bases. In this scenario, machine learning provides some of the main methods employed in data mining. Symbolic learning are among the most used machine learning methods since these methods can provide models that can be interpreted by domain experts. However, traditional machine learning methods, such as decision trees and decision rules, do not take into account the temporal information present into data. This work proposes a methodology to extract knowledge from time series data using feature extraction and motif identification. Features and motifs are used as attributes for knowledge extraction performed by machine learning methods. This methodology was evaluated using some well-known data sets. In addition, we compared the proposed methodology to the approach that feeds machine learning algorithms with raw time series data. Results show that there are statistically significant differences for most of the data sets employed in the study. Finally, it is presented a preliminary study with environmental monitoring data from the Itaipu reservoir, made available by Itaipu Binacional. This study is restricted to the application of motif identification. We have used time series of water temperature collected from several regions of the reservoir. In this study, a pattern in motif distribution was observed for each region of the reservoir, agreeing with some well-known literature results

Ferramentas bioinformática têm se tornado a escolha para auxiliar pesquisadores tanto para a anotação de novos genes, como para estudar genes em condições fisiológicas de interesse. Entre essas ferramentas destacam-se os algoritmos de agrupamento filogenético e os algoritmos de predição de padrões curtos de DNA, como, por exemplo, predições de sítios para ligação de fatores de transcrição. Desenvolver uma abordagem mista com o objetivo de agrupar genes baseando-se unicamente nos sinais transcricionais preditos em suas seqüências é um desafio de difícil transposição. No presente trabalho, apresentamos nossos resultados para tentar superar tal limitação que podem ser subdividos em duas seções: a primeira aonde desenvolvemos uma abordagem para a melhoria das predições computacionais de sítios de ligação e a segunda, onde passamos a agrupar genes com base nos seus sinais transcricionais preditos em seqüências conservadas flanqueadoras. A primeira seção de nosso trabalho foi focada no estudo de uma seqüência de indução de transcrição próxima ao gene Aldh1a2 de camundongo aonde foram preditos sítios para fatores de transcrição que foram posteriormente testados biologicamente e se mostraram associados ao controle da expressão desse gene. A partir de uma profunda pesquisa bibliográfica, nós determinamos um grupo de 57 fatores de transcrição já associados com a especialização de subpopulações de neurônios durante o desenvolvimento neuroembrionário de vertebrados. Nossa abordagem de seleção de sítios de alto valor biológico foi agora testada em seqüências conservadas próximas a cada um desses genes que codificam esses fatores de transcrição associados e os sítios de ligação para fatores de transcrição foram preditos. Tais sítios foram contabilizados e utilizados com entrada para nossa abordagem de agrupamento. A análise dos resultados do agrupamento determinou que, nossa abordagem se mostrou suficientemente sensível para construir uma árvore solução com boas relações com os padrões, já conhecidos, de expressão para esses genes agrupados. Essa abordagem poderá ser utilizada tanto para anotar funcionalmente genes de interesse quanto para minerar informações dentro de um grupo de genes previamente selecionado. / Bioinformatics tools are becoming the choice for aiding scientists for gene annotation and for studying gene in physiological conditions of interest. Among those efforts, phylogenetics clustering algorithms and tools for predicting short DNA patterns, such as binding sites for transcription factor, are outlined as essential. To develop a mixture procedure merging this two distant fields of bioinformatics research is a challenge hard to overcome. In the present study, we present our results of trying to overcome such limitation and it be easily subdivided in two distinct sections: initially we develop a procedure to improve the computational prediction of binding site for transcription factors and the second one where genes were grouped based solely in their transcriptional patterns predicted in conserved flanking sequences. The first section of the present study was focused in the study of an enhancer near Aldh1a2 gene in mouse where binding sites were predicted and latter biologically tested and showed strong influence in expression control of this gene. By a comprehensive bibliographic research we determined a group of 57 transcription factors which were already associated with neuron subpopulations specialization during the neuroembryonary development in vertebrates. Our computational procedure for selection of high biological value binding sites was applied in conserved flanking sequence in each of these genes encoding these associated transcription factors and a large group of binding sites were predicted. This sites were counted and use as an input for our clustering procedure. Clustering results analyses determined that our procedure showed to be sufficiently sensible to construct a solution tree showing good relations with, already determined, expression patterns of grouped genes. This procedure could be for functionally annotation of genes and for data mining in a group of already determined genes of interest.

Cette thèse explore les résurgences de motifs liés aux cultures celtiques dans les pièces de Shakespeare, c'est-à-dire la manière dont les cultures pré-chrétienne et pré-romaine des îles britanniques imprègnent l’œuvre théâtrale de William Shakespeare. Ces motifs n’apparaissent pas toujours de manière évidente à la surface du texte. Cela arrive parfois, mais ils requièrent souvent une analyse précise et approfondie. Cette question est jusqu’à présent restée relativement inexplorée ; en ce sens nous pouvons parler d’une construction de sens. Cependant, les cultures en question appartenant à un passé antique, il est possible d’accepter l’idée d’une ‘reconstruction’ d’un passé jusque là oublié. Basé sur une définition rigoureuse du terme ‘celtique’, cette étude examine en détail la présence des motifs, tout d’abord dans les chroniques auxquelles Shakespeare a pu avoir accès, sans oublier les notions d’oralité et de ‘discours’, inhérentes à l’analyse d’une culture avant tout orale. La figure du roi Arthur et la matière arthurienne, perçus comme la voie d’entrée dans le sujet, sont étudiés en relation avec les œuvres du dramaturge. Dans les pièces historiques, l’analyse des personnages venant des ‘marges’, i.e. le Pays-de-Galles, l’Irlande et l’Écosse informent sur la vision pré-moderne de ces ‘frontaliers’. Seules deux œuvres sont situées dans un contexte historique celtique : Cymbeline et Le Roi Lear, mais de nombreux motifs surgissent aussi dans d’autres pièces telles que Macbeth, Le songe d’une nuit d’été, La tempête, Le Conte d’hiver et d’autres. Ce travail de recherche révèle un substrat qui produit une nouvelle lecture enrichissante des œuvres de William Shakespeare / This dissertation explores the resurgence of motifs related to Celtic cultures in Shakespeare’s plays, that is to say the way the pre-Christian and pre-Roman cultures of the British Isles permeate the dramatic works of William Shakespeare. Such motifs do not always evidently appear on the surface of the text. They sometimes do, but most often, they require a thorough in depth exploration. This issue has thus far remained relatively unexplored; in this sense we can talk of a ‘construction’ of meaning. However, the cultures in question belong to an Ancient time, therefore, we may accept the idea of a ‘reconstruction’ of a forgotten past. Providing a rigorous definition of the term ‘Celtic’ this study offers to examine in detail the presence of motifs, first in the Chronicles that Shakespeare could have access to, and takes into account the notions of orality and discourse, inherent to the study of a primarily oral culture. The figure of King Arthur and the matter of Britain, seen as the entrance doors to the subject, are studied in relation to the plays, and in the Histories, the analysis of characters from the ‘margins’, i.e. Wales, Ireland and Scotland provides an Early Modern vision of ‘borderers’. Only two plays from the Shakespearean corpus are set in a Celtic historical context – Cymbeline and King Lear – but motifs surge in numerous other works, such as Macbeth, A Midsummer Night’s Dream, The Tempest, The Winter’s Tale and others. This research reveals a substrate that produces a new enriching reading of the plays

Die vorliegende Arbeit wurde im Rahmen einer kooperativen Promotion zwischen der TU Dresden und der Hochschule Mittweida angefertigt. In dieser werden neuartige, computerorientierte Ansätze für die Analyse von Membranproteinen vorgestellt. Membranproteine sind von essentieller Bedeutung für eine Vielzahl biologischer Prozesse innerhalb eines Organismus und stellen wichtige Zielmoleküle für eine breite Palette von Pharmazeutika dar. Ihre Sequenzen liefern wertvolle und teilweise noch nicht entschlüsselte Informationen über die dreidimensionale Struktur und funktionale Eigenschaften. Innerhalb der Proteomik und Genomik stellen Analysen an Membranproteinstrukturen einen wichtigen Teil für das Verständnis komplexer biologischer Prozesse dar. Im Zuge von Untersuchungen an Membranproteinen konnte eine Vielzahl kurzer wiederkehrender Muster, sogenannte Motive, in den Sequenzen von Membranproteinen beobachtet werden. Diese Motive unterstützen das Verständnis, wie sich Membranproteine in der Zellmembran falten. Im Fokus dieser Arbeit stehen derartige Sequenzmotive. Innerhalb von drei Projekten bilden ausschließlich sequenzmotivbasierte Ansätze die Grundlage für nähere Untersuchungen an Membranproteinstrukturen. Letztendlich liefern die in dieser Arbeit postulierten Methoden wertvolle Erkenntnisse über die strukturelle und funktionelle Rolle von Sequenzmotiven, auf deren Grundlage dazu beigetragen wird, den komplexen Aufbau von Membranproteinen besser verstehen zu können. Generell wird die Zusammenführung proteomischer und mutagener Informationen intensiviert. Nicht zuletzt wird dazu beigetragen, die in dieser Arbeit zusammengetragenen Ergebnisse, für die Planung von in vitro Experimenten sowie weiterführenden Arbeiten auf dem Gebiet der Membranproteinanalyse, der Wissenschaft zur Verfügung zu stellen. / The present work was written as part of a cooperative doctorate between the TU Dresden and the University of Applied Sciences Mittweida. In the doctoral thesis, novel, computer-oriented approaches for the analysis of membrane proteins are presented. Membrane proteins are essential for many cellular processes and are important targets for a wide range of pharmaceuticals. Their sequences provide valuable and partly not yet decoded information about their three-dimensional structure and functional characteristics. The analysis of membrane proteins is an important part for the understanding of complex biological processes in the context of proteomics and genomics. Research of membrane proteins revealed a large number of short, distinct sequence motifs. The motifs found so far support the understanding of the folded protein in the Membrane environment. In this dissertation, in three different approaches it is shown how the output of sequence motif-based methods can support the understanding of structural and functional properties of membrane proteins. In general, the junction of proteomic and mutagenic information is intensified. Last but not least, the results of this work are made available for the planning of in vitro experiments as well as for further works in the field of membrane Protein analysis.

MicroRNAs (miRNAs) are short non-coding RNAs that function in post-transcriptional gene silencing and mRNA regulation. Although the number of nucleotides of miRNAs ranges from 17 to 27, they are mostly made up of 22 nucleotides. The expression of miRNAs changes significantly in cancer, causing protein alterations in cancer cells by preventing some genes from being translated into proteins. In this research, a structural analysis of 587 miRNAs that are differentially expressed in myeloid cancer was carried out. Length distribution studies revealed a mean and median of 22 nucleotides, with an average of 21.69 and a variance of 1.65. We performed nucleotide analysis for each position where Uracil was the most observed nucleotide and Adenine the least observed one with 27.8% and 22.6%, respectively. There was a higher frequency of Adenine at the beginning of the sequences when compared to Uracil, which was more frequent at the end of miRNA sequences. The purine content of each implicated miRNA was also assessed. A novel motif analysis script was written to detect the most frequent 3–7 nucleotide (3–7n) long motifs in the miRNA dataset. We detected CUG (42%) as the most frequent 3n motif, CUGC (15%) as a 4n motif, AGUGC (6%) as a 5n motif, AAGUGC (4%) as a 6n motif, and UUUAGAG (4%) as a 7n motif. Thus, in the second part of our study, we further characterized the motifs by analyzing whether these motifs align at certain consensus sequences in our miRNA dataset, whether certain motifs target the same genes, and whether these motifs are conserved within other species. This thorough structural study of miRNA sequences provides a novel strategy to study the implications of miRNAs in health and disease. A better understanding of miRNA structure is crucial to developing therapeutic settings.

In many countries, cancer is one of the biggest threats for citizens’ health, especially among aged people. Genomic mutations play a crucial role in cancer cell development. In previous decades, cancer research has been mainly focused on mutations in coding regions. These mutations can directly change the encoded protein sequences and influence their functions. In recent years, as the function of non-coding regions has been gradually understood, a growing number of studies have focused on the role of non-coding mutations in cancer. Transcription factor (TF) is an important group of gene regulatory factors. These factors only bind to specific sequences called transcription factor binding motifs (TFBMs) in the genome. Mutations in these motifs can disrupt the TF binding and thus influence gene regulation. A framework called funMotifs was made to predict and annotate functional TFBMs in the human genome. And a research has been made to intersect the mutation information from Pan-Cancer Analysis of Whole Genomes (PCAWG) to motifs in funMotifs, aiming to give a general view of influence of cancer-related mutations on functional TF motifs. But the research only focused on the existing motifs that were identified previously from the normal genome, while de novo motifs that could be potentially created by mutations were disregarded. An instance near the TERT promoter has been found, showing that mutations create a de novo ETS binding site and up-regulate the TERT expression.  My study aims to extend the borderline of funMotifs, from existing motifs to de novo motifs created by cancer-related mutations. I extended the original motifs in funMotifs database and merged the overlapping motifs into longer regulatory elements. Then I mutated these elements according to the mutation data from PCAWG. Next I scan through the mutated elements and identify TF motifs. These motifs were then intersected with original motifs in funMotifs database to remove the redundant results. After intersection and filtering, 2,525,771 de novo motifs were retained. These motifs mainly come from C2H2 zinc finger factors, tryptophan cluster factors, STAT domain factors, fork head/winged helix factors, MADS box factors and homeo domain factors. Even though the de novo motifs I found in this study still need further verification and analysis, for example the change of information content in the mutated sites of the motifs, the result I obtained can be a useful data source for further research on regulatory impact from cancer-related mutations. / <p></p><p></p><p></p><p></p><p></p>

Ce mémoire porte sur le texte de Huon de Méry intitulé Le Tournoi de l’Antéchrist. Il s’agit d’un ouvrage de 3544 vers dont la date d’écriture est estimée à la première moitié du XIIIe siècle. Ce texte a retenu notre attention pour son utilisation de la psychomachia comme matrice principale et son écriture en langue vernaculaire. Le Tournoi relate l’aventure de Huon qui va assister à l’affrontement de l’armée du Christ, composée de vertus, contre celle de l’Antéchrist où s’alignent les vices. La narration conjugue écriture autobiographique, romanesque et récit allégorique, présentant ainsi une figure de narrateur-auteur intéressante. La singularité de l’écriture de Huon réside dans cette articulation d’éléments hétérogènes. L’auteur fait intervenir deux autorités littéraires, Chrétien de Troyes et Raoul de Houdenc, qui ont une influence majeure sur son oeuvre. L’univers romanesque et allégorique est combiné à des éléments mythologiques, littéraires et bibliques. Cette convocation de traditions différentes pose un problème de généricité qu’il faut adresser pour la compréhension du texte. C’est le point de départ de notre réflexion qui nous permettra d’exposer la relation entre la structure d’affrontement du texte, l’écriture allégorique et les visées didactiques de l’auteur. Ces trois éléments s’articulent autour d’un principe double, commun dans la pensée médiévale. Ce principe est à la base de notre hypothèse qui soutient l’idée selon laquelle la pensée du double permet de former une dynamique entre les éléments hétérogènes du Tournoi et met en lumière le message de conversion de l’auteur. / The subject of this master’s thesis is Huon de Méry’s Le Tournoi de l’Antéchrist. This book is composed of 3544 verses and the writing date is estimated to be around the first half of the 13th century. This subject caught our attention because of the author Huon de Mery’s unusual use of the psychomachia as the principal matrix of the text and because of his writing in vernacular. The Tournoi describes the adventures of Huon who in the story is destined to be the spectator of the confrontation between Christ’s army, which represents virtues, against the Antichrist’s which represents vices. The narrative achieves an interesting author-narrator representation by combining elements of autobiographica land Romanesque writing, along with an allegorical storyline. The singularity of Huon’s writing resides in the articulation of heterogeneous elements. Chrétien de Troyes and Raoul de Houdenc as literary authority are major influences for the book. The fictionaland allegorical universes combine, with mythological elements, different literary traditions and biblical influences. This diversity of traditions poses the question of the genericity which is essential to address for a better understanding of the text. This is the starting point of our reflection which allows us to expose the relationship between the text’s confrontational structures, its allegorical writing and the shared principle in medieval’s binary thinking culture. This articulation is the basis of our hypothesis which puts forward the idea that medieval binary thinking forms a dynamic among the elements of the Tournoi and highlights the religious conversion message of the author.

Cet essai tente de démontrer que les concepts freudiens de condensation et de déplacement qui caractérisent le travail du rêve peuvent également être associé au travail d'écriture des scènes de rêve du scénario Coulisses ainsi qu'à quelques scènes oniriques de films de Federico Fellini, Ingmar Bergman et David Lynch.

The oncoprotein MDM2 has an integral role in cancer development via multiple signalling pathways. Two proteomic mass spectrometry screens, label-free with spectral counting quantitation and 8-plex iTRAQ were used to identify proteins up or downregulated over time by the MDM2 targeting drug Nutlin. A subset of previously identified MDM2 binding partners were identified as altered after Nutlin treatment, along with proteins which have not as yet been linked to MDM2 or p53. Proteins altered two hours after Nutlin treatment were screened for sequence similarity to an MDM2 binding consensus motif based on the BOX-I region of p53. Peptides corresponding to this motif were validated for MDM2 binding, and the mode of binding investigated using competition ELISA and thermal denaturation assays. Known MDM2 ligands such as Nutlin were shown to have a range of effects on the binding of these newly identified MDM2 peptides, which may be attributed to allosteric regulation of MDM2. The effects of Nutlin on two full length proteins identified by the MS screens, CypB and NPM, were confirmed in vivo. In vitro binding of MDM2 to CypB and PK, which contain BOX-I like motifs, was also demonstrated validating proteomic mass spectrometry screens as a method to identify new protein-protein interactions. To further investigate the potential of linear motifs to modulate protein-protein interactions, a peptide aptamer targeting the protein AGR2 was tested for effect on AGR2 and p53 in a cancer cell line.

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy