Systems biologists use interaction graphs to model the behaviour of biological systems at the molecular level. In an iterative process, such biologists observe the reactions of living cells under various experimental conditions, view the results in the context of the interaction graph, and then propose changes to the graph model. These graphs represent dynamic knowledge of the biological system being studied and evolve as new insight is gained from the experimental data. While numerous graph layout and drawing packages are available, these tools did not fully meet the needs of our immunologist collaborators. In this thesis, we describe the data display needs of these immunologists and translate these needs into visual encoding decisions. These decisions led us to create Cerebral, a system that uses a biologically guided graph layout and incorporates experimental data directly into the graph display. Our graph layout algorithm uses simulated annealing with constraints, optimized with a uniform grid to have an expected runtime of o(E/V). Small multiple views of different experimental conditions and a measurement-driven parallel coordinates view enable correlations between experimental conditions to be analyzed at the same time that the measurements are viewed in the graph context. This combination of coordinated views allows the biologist to view the data from many different perspectives simultaneously. To illustrate the typical analysis tasks performed, we analyze two datasets using Cerebral. Based on feedback from our collaborators, we conclude that Cerebral is a valuable tool for analyzing experimental data in the context of an interaction graph model.

Systems biologists use interaction graphs to model the behaviour of biological systems at the molecular level. In an iterative process, such biologists observe the reactions of living cells under various experimental conditions, view the results in the context of the interaction graph, and then propose changes to the graph model. These graphs represent dynamic knowledge of the biological system being studied and evolve as new insight is gained from the experimental data. While numerous graph layout and drawing packages are available, these tools did not fully meet the needs of our immunologist collaborators. In this thesis, we describe the data display needs of these immunologists and translate these needs into visual encoding decisions. These decisions led us to create Cerebral, a system that uses a biologically guided graph layout and incorporates experimental data directly into the graph display. Our graph layout algorithm uses simulated annealing with constraints, optimized with a uniform grid to have an expected runtime of o(E/V). Small multiple views of different experimental conditions and a measurement-driven parallel coordinates view enable correlations between experimental conditions to be analyzed at the same time that the measurements are viewed in the graph context. This combination of coordinated views allows the biologist to view the data from many different perspectives simultaneously. To illustrate the typical analysis tasks performed, we analyze two datasets using Cerebral. Based on feedback from our collaborators, we conclude that Cerebral is a valuable tool for analyzing experimental data in the context of an interaction graph model.

Systems biologists use interaction graphs to model the behaviour of biological systems at the molecular level. In an iterative process, such biologists observe the reactions of living cells under various experimental conditions, view the results in the context of the interaction graph, and then propose changes to the graph model. These graphs represent dynamic knowledge of the biological system being studied and evolve as new insight is gained from the experimental data. While numerous graph layout and drawing packages are available, these tools did not fully meet the needs of our immunologist collaborators. In this thesis, we describe the data display needs of these immunologists and translate these needs into visual encoding decisions. These decisions led us to create Cerebral, a system that uses a biologically guided graph layout and incorporates experimental data directly into the graph display. Our graph layout algorithm uses simulated annealing with constraints, optimized with a uniform grid to have an expected runtime of o(E/V). Small multiple views of different experimental conditions and a measurement-driven parallel coordinates view enable correlations between experimental conditions to be analyzed at the same time that the measurements are viewed in the graph context. This combination of coordinated views allows the biologist to view the data from many different perspectives simultaneously. To illustrate the typical analysis tasks performed, we analyze two datasets using Cerebral. Based on feedback from our collaborators, we conclude that Cerebral is a valuable tool for analyzing experimental data in the context of an interaction graph model. / Science, Faculty of / Computer Science, Department of / Graduate

Yes / The thermodynamic stability of caffeine (CA) cocrystals with dicarboxylic acids (DAs) as coformers was investigated in the presence of a range of structurally related dicarboxylic acids (SRDs). Two experimental conditions (slurry and dry-grinding) were studied for mixing the cocrystal and the SRD additive. The additives oxalic, malonic and glutaric acid led to the replacement of the acid coformer for certain cocrystals. Interestingly, a change in stoichiometry was observed for the CA:maleic acid system. A stability order among the cocrystals was established depending on their tendency to replace the coformer. To understand the factors controlling the relative stabilities, lattice energies were calculated using dispersion corrected Density Functional Theory (DFT). Gibbs free energy changes were calculated from experimental solubilities. The observed stability order corroborated well with lattice energy and Gibbs free energy computations.

A papaína, enzima proteolítica extraída do fruto da Carica papaya Linnaeus, apresenta grande perspectiva para carreamento de fármacos devido propriedade anti-inflamatória, antitumoral e aumento da permeação. O presente trabalho teve como objetivo estudar as variáveis de processo da síntese radio-induzida, com o propósito de avaliar a influência destes parâmetros na formação da nanopartícula além do seu potencial como nanocarreador. A síntese foi realizada na presença (20%, v/v) e ausência de etanol, tampão fosfato e radiação gama (10 kGy) para reticulação e esterilização simultânea. As amostras foram avaliadas através da técnica de espalhamento dinâmico de luz, para verificar diâmetro hidrodinâmico, UV e fluorescência para verificação do conteúdo proteico e estrutura secundária, respectivamente. A atividade enzimática foi avaliada utilizando o substrato N-alfa-benzoil-DL-arginina-4-nitroanilida (BAPA). Parâmetros como concentração proteica, molaridade do tampão, pH, tempo e temperatura de solvatação e taxa de dose foram estudados. Posteriormente, foi realizado estudo da estabilidade por 180 dias e demonstração da capacidade de radiomarcação utilizando o tecnécio-99m, além da natureza da reticulação e esterilização das amostras. Conclui-se que a síntese otimizada das nanopartículas de papaína ocorre a 10 mg.mL-1 utilizando tampão fosfato 50 mM com (pH 7) à 0°C, tempo de solvatação de 1 a 6 horas e taxa de dose de 5 kGy.h-1. Ao usar essas condições, a formação de nanopartículas ocorrerá de maneira mais efetiva e com atividade proteolítica preservada. A reticulação das nanopapaínas, nas condicões descritas acima, ocorrem majoritariamente por natureza intramolecular e apresenta esterilidade na dose estabelecida de 10 kGy. As amostras se mostraram estáveis por até 30 dias quando mantidas sob 0°C. A radiomarcação com 99mTc por via direta obteve eficiência de 90% e demonstrou o grande potencial da nanopartícula como nanocarreador. / Papain, proteolytic enzyme extracted from the fruit of Carica papaya Linnaeus, presents great prospect for drug delivery due to the anti-inflammatory and antitumor proprieties and increased permeation. The present work aims to study variable process conditions of radio-induced synthesis, with the purpose of evaluating the influence of the parameters on the nanoparticle formation and potential for radiopharmaceutical loading. The synthesis was performed in the presence (20%, v/v) and absence of ethanol, phosphate buffer and ionizing radiation at 10 kGy, using 60Co as a radioactive source to promote crosslinking and simultaneous sterilization. The samples were evaluated by dynamic light scattering to verify hydrodynamic diameter, UV and fluorescence for verification of protein content and secondary structure, respectively. The enzymatic activity was evaluated using N-alpha-benzoyl-DL-arginine-4-nitroanilide (BAPA) as specific substrate. Parameters such as protein concentration, buffer molarity, pH, time and temperature of solvation and dose rate were studied in order to evaluate the changes and the effect of each condition on the formation of the nanoparticle. Subsequently, a study of the stability of the samples for 180 days and the efficiency of the radiolabeling with technetium-99m were carried out. Additionally, the nature of protein crosslinking and the sterilization was studied. It was concluded that the optimized synthesis of papain nanoparticles occurs at 10 mg.mL-1 using 50 mM phosphate buffer (pH 6-7) at 0°C, solvation time of 1 to 6 hours and dose rate of 5 kGy.h-1. By using these conditions, the formation of nanoparticles will occur more rapidly, with preserved proteolytic activity and considerable levels of cross-linking. Papain crosslinking are intramolecular and 10 kGy demonstrate sterilized potential. Samples were stable for 20-30 days when kept at 20°C and 0-4°C, respectively. Radiolabeling with technetium by direct route obtained efficiency of 90% and demonstrated great potential as a nanocarrier.

L'imagerie par résonance magnétique fonctionnelle (IRMf) est une technique non invasive permettant l'étude de l'activité cérébrale au travers des changements hémodynamiques associés. Récemment, une technique de détection-estimation conjointe (DEC) a été développée permettant d'alterner (1) la détection de l'activité cérébrale induite par une stimulation ainsi que (2) l'estimation de la fonction de réponse hémodynamique caractérisant la dynamique vasculaire; deux problèmes qui sont généralement traités indépendamment. Cette approche considère une parcellisation a priori du cerveau en zones fonctionnellement homogènes et alterne (1) et (2) sur chacune d'entre elles séparément. De manière standard, l'analyse DEC suppose que le cerveau entier peut être activé par tous les types de stimuli (visuel, auditif, etc.). Cependant la spécialisation fonctionnelle des régions cérébrales montre que l'activité d'une région n'est due qu'à certains types de stimuli. La prise en compte de stimuli non pertinents dans l'analyse, peut dégrader les résultats. La sous-famille des types de stimuli pertinents n'étant pas la même à travers le cerveau une procédure de sélection de modèles serait très coûteuse en temps de calcul. De plus, une telle sélection a priori n'est pas toujours possible surtout dans les cas pathologiques. Ce travail de thèse propose une extension de l'approche DEC permettant la sélection automatique des conditions (types de stimuli) pertinentes selon l'activité cérébrale qu'elles suscitent, cela simultanément à l'analyse et adaptativement à travers les régions cérébrales. Des exemples d'analyses sur des jeux de données simulés et réels, illustrent la capacité de l'approche DEC parcimonieuse proposée à sélectionner les conditions pertinentes ainsi que son intérêt par rapport à l'approche DEC standard. / Functional magnetic resonance imaging (fMRI) is a noninvasive technique allowing the study of brain activity via the measurement of hemodynamic changes. Recently, a joint detection-estimation (JDE) framework was developed and relies on both (1) the brain activity detection and (2) the hemodynamic response function estimation, two steps that are generally addressed in a separate way. The JDE approach is a parcel-based model that alternates (1) and (2) on each parcel successively. The JDE analysis assumes that all delivered stimuli (e.g. visual, auditory, etc.) possibly generate a response everywhere in the brain although activation is likely to be induced by only some of them in specific brain areas. Inclusion of irrelevant events may degrade the results. Since the relevant conditions or stimulus types can change between different brain areas, a model selection procedure will be computationally expensive. Furthermore, criteria are not always available to select the relevant conditions prior to activation detection, especially in pathological cases. The goal of this work is to develop a JDE extension allowing an automatic selection of the relevant conditions according to the brain activity they elicit. This condition selection is done simultaneously to the analysis and adaptively through the different brain areas. Analysis on simulated and real datasets illustrate the ability of our model to select the relevant conditions and its interest compare to the standard JDE analysis.

Στην παρούσα ερευνητική εργασία που είναι επανάληψη της έρευνας των Steinbrink και Klatte (2008) γίνεται προσπάθεια να διερευνηθεί η σχέση ανάμεσα στην ικανότητα άμεσης σειριακής συγκράτησης φωνολογικών πληροφοριών και την αναγνωστική και ορθογραφική ικανότητα παιδιών, που έχουν ως μητρική γλώσσα την ελληνική. Πολλές έρευνες έχουν δείξει ότι παιδιά με αναγνωστικές και ορθογραφικές δυσκολίες δεν χρησιμοποιούν με τον πιο αποτελεσματικό τρόπο τις φωνολογικές στρατηγικές σε έργα σειριακής ανάκλησης. Σε μια ομάδα 15 μαθητών της Γ’ Δημοτικού χωρίς αναγνωστικές και ορθογραφικές δυσκολίες και σε μια αντίστοιχη ομάδα 15 μαθητών με αναγνωστικές και ορθογραφικές δυσκολίες, παρουσιάστηκαν λίστες με τέσσερα ερεθίσματα η κάθε μία, τα οποία αντιστοιχούσαν σε ουσιαστικά υψηλής συχνότητας, με σκοπό την άμεση σειριακή ανάκλησή τους. Το μέγεθος της λέξης και η φωνολογική ομοιότητα καθώς και ο τρόπος παρουσίασης (οπτικός και ακουστικός) και ο τύπος ανάκλησης (οπτικός και προφορικός) ποίκιλαν, σε ένα μεικτό σχεδιασμό με χειρισμό των ανεξάρτητων μεταβλητών εντός υποκειμένων. Σε όλες τις πειραματικές συνθήκες, οι καλοί αναγνώστες απέδωσαν καλύτερα από τους φτωχούς αναγνώστες. Η φωνολογική ομοιότητα δεν επηρέασε τις επιδόσεις και στις δυο ομάδες των παιδιών. Αντίθετα, η επίδραση του μεγέθους των λέξεων διέφερε μεταξύ των ομάδων, πράγμα που ίσως δείχνει ελλιπή φωνολογική κωδικοποίηση και εσωτερική επανάληψη στα παιδιά με αναγνωστικές και ορθογραφικές δυσκολίες. Αναφορικά με τη σειρά παρουσίασης του ερεθίσματος, οι δύο ομάδες μαθητών έκαναν χρήση παρόμοιων στρατηγικών στις περισσότερες πειραματικές συνθήκες. Τα αποτελέσματα δείχνουν ότι οι φτωχοί αναγνώστες χρησιμοποιούν το φωνολογικό κύκλωμα. Αντί αυτού, οι δυσκολίες αυτές πηγάζουν από την ανεπαρκή εφαρμογή διαφόρων στρατηγικών λόγω ελλειμμάτων στη φωνολογική επεξεργασία. / The current study sought to investigate the relation between serial recall of phonological information and reading ability in Greek students. It has been proposed that dyslexic readers show inefficient application of phonological strategies during serial recall tasks. A group of 15 third graders with typical reading performance and 15 with reading impairments were presented with four-item lists of common nouns for immediate serial recall. Word length and phonological similarity as well as presentation modality (visual vs. auditory) and type of recall (visual vs. verbal) were varied as within subject factors in a mixed design. In all conditions, overall performance was significantly lower in poor readers. Phonological similarity did not affect performance in both groups of children. Word length effects differed between groups indicating deficient phonological coding and rehearsal in dyslexic students. With regard to the order of presentation, the two groups made use of similar strategies in the majority of the experimental conditions. The results demonstrate that, poor readers use the phonological loop. Instead, their difficulties stem from inadequate application of various strategies due to deficits in phonological processing.