Target-based screening projects for bioactive (orphan) compounds have been shown in many cases to be insufficiently predictive for in vivo efficacy, leading to attrition in clinical trials. Phenotypic screening has hence undergone a renaissance in both academia and in the pharmaceutical industry, partly due to this reason. One key shortcoming of this paradigm shift is that the protein targets modulated need to be elucidated subsequently, which is often a costly and time-consuming procedure. In this work, we have explored both improved methods and real-world case studies of how computational methods can help in target elucidation of phenotypic screens. One limitation of previous methods has been the ability to assess the applicability domain of the models, that is, when the assumptions made by a model are fulfilled and which input chemicals are reliably appropriate for the models. Hence, a major focus of this work was to explore methods for calibration of machine learning algorithms using Platt Scaling, Isotonic Regression Scaling and Venn-Abers Predictors, since the probabilities from well calibrated classifiers can be interpreted at a confidence level and predictions specified at an acceptable error rate. Additionally, many current protocols only offer probabilities for affinity, thus another key area for development was to expand the target prediction models with functional prediction (activation or inhibition). This extra level of annotation is important since the activation or inhibition of a target may positively or negatively impact the phenotypic response in a biological system. Furthermore, many existing methods do not utilize the wealth of bioactivity information held for orthologue species. We therefore also focused on an in-depth analysis of orthologue bioactivity data and its relevance and applicability towards expanding compound and target bioactivity space for predictive studies. The realized protocol was trained with 13,918,879 compound-target pairs and comprises 1,651 targets, which has been made available for public use at GitHub. Consequently, the methodology was applied to aid with the target deconvolution of AstraZeneca phenotypic readouts, in particular for the rationalization of cytotoxicity and cytostaticity in the High-Throughput Screening (HTS) collection. Results from this work highlighted which targets are frequently linked to the cytotoxicity and cytostaticity of chemical structures, and provided insight into which compounds to select or remove from the collection for future screening projects. Overall, this project has furthered the field of in silico target deconvolution, by improving the performance and applicability of current protocols and by rationalizing cytotoxicity, which has been shown to influence attrition in clinical trials.

Améliorer l'interaction entre un utilisateur et un environnement 3D est un défi de recherche primordial pour le développement positif des technologies 3D interactives dans de nombreux domaines de nos sociétés, comme l'éducation. Dans ce document, je présente des interfaces utilisateur 3D que nous avons développées et qui contribuent à cette quête générale. Le premier chapitre se concentre sur l'interaction 3D pour des terminaux mobiles. En particulier, je présente des techniques dédiées à l'interaction à partir de touches, et à partir de gestes sur les écrans tactiles des terminaux mobiles. Puis, je présente deux prototypes à plusieurs degrés de liberté basés sur l'utilisation de flux vidéos. Dans le deuxième chapitre, je me concentre sur l'interaction 3D avec les écrans tactiles en général (tables, écrans interactifs). Je présente Navidget, un exemple de technique d'interaction dédié au controle de la caméra virtuelle à partir de gestes 2D, et je discute des défis de l'interaction 3D sur des écrans multi-points. Finalement, le troisième chapitre de ce document est dédié aux environnements virtuels immersifs, avec une coloration spéciale vers les interfaces musicales. Je présente les nouvelles directions que nous avons explorées pour améliorer l'interaction entre des musiciens, le public, le son, et les environements 3D interactifs. Je conclue en discutant du futur des interfaces utilisateur 3D.

Title: Characteristics of team game performance and their comparison in youth teams in Lithuania and Czech republic Aims: The main goal of my thesis is a comparison of selected indicators of team game performance of both teams accompanied by a possibility to record the frequency of combinations based on setting screens, finding the most significant differences in indicators of both teams and determine the reasons for these differences. Methods: Using quantitative (numerical) observations of selected indicators supplemented by the game to record the accompanied by a possibility to record the frequency of combinations based on setting screens to determine differences in the team game performance of U14 teams in Lithuania and the Republic. Results: Acquired selected statistical indicators have shown the most significant phenomena of the game performance of youth teams in Lithuania and the Czech republic and the differences between them. Key words: Team game performance, offensive combinations based on setting screens, statisticals indicators, youth basketball, quantitative analysis.

No description available.

This study investigates the impact that loading animations have on perceived  performance. Two sets of usability tests were conducted to obtain the data for this study. In the first set of usability tests, 15 participants were observed. The second set was performed online with 45 participants who answered a questionnaire after using the prototype. Five different loading animations were tested: Spinner, Loading bar, a detailed animation, an animation with aquote and a skeleton loading screen. The participants were asked at the end of the usability tests to rate which one of the loading screens were the fastest and the slowest. Results suggested the kind of animation used in a loading screen does have an effect on perceived performance. The loading screen with no animation received a generally lower rating compared to the one with animations. Loading animations intended to entertain and distract the user received a higher rate compared to common loading animations such as Spinners and Loading bars.

Le protéasome est une protéase multimérique essentielle et hautement conservée au cours de l’évolution. Le protéasome 26S eucaryote est l’unité catalytique du système Ubiquitine-Protéasome et contrôle de ce fait de nombreux processus cellulaires. Son dysfonctionnement participe à la pathogenèse de nombreuses maladies. Le protéasome émerge notamment comme une cible thérapeutique de choix dans le traitement de cancers. Il semble donc important d’identifier l’ensemble des processus cellulaires dans lesquels le protéasome est impliqué ainsi que l’ensemble de ses régulateurs.Mon travail de thèse a consisté à identifier et caractériser de nouveaux partenaires physiques et fonctionnels du protéasome par une approche multi-technique. Nous étudions ces facteurs dans l’organisme modèle S. cerevisiae et déterminons s’ils sont fonctionnellement conservés dans les cellules de Mammifères.Après avoir identifié des partenaires physiques et fonctionnels au moyen de cribles à grande échelle, j’ai analysé les données et établi une bibliothèque pondérée de ces partenaires. J’ai ainsi mis en évidence de nouveaux acteurs potentiellement impliqués dans le fonctionnement du protéasome. De plus, j’ai caractérisé les protéines Spg5p et Poc5p. Mes données suggèrent que Spg5p participe à la régulation du protéasome en quiescence. Poc5p, présente à la fois chez l’Homme et la levure, participe à la régulation du protéasome à au moins deux niveaux différents : elle joue un rôle de point de contrôle dans l’assemblage du complexe et un rôle inhibiteur sur son activité. / The proteasome is a highly conserved essential proteolytic machine. The eukaryotic 26S proteasome is the hydrolytic heart of the ubiquitin-mediated degradation pathway and therefore controls many cellular pathways. Its dysfunction is involved in the pathogenesis of numerous diseases. Notably, the proteasome has emerged as an interesting drug target for anti-cancer therapy. It seems therefore important to identify all cellular processes in which the proteasome is involved and all of its regulators.My work was to identify and characterize new physical and functional partners of the proteasome by a multi-technical approach. We characterize these factors in the model organism S. cerevisiae and determine if they are functionally conserved in mammalian cells.After identifying physical and functional partners through large-scale screens, I analyzed the data and developed a weighted library of these partners. I have thus highlighted new actors potentially involved in the proteasome functioning. In addition, I characterized the Spg5p and Poc5p proteins. My data suggest that Spg5p participates in the regulation of proteasome during quiescence. Poc5p, presents both in human and yeast, is involved in the regulation of proteasome at at least two different levels: it acts as a checkpoint in the complex assembly and have an inhibitory effect on its activity.

Science fiction has long promised the digitalization of books. Characters in films and television routinely check their palm-sized (or smaller) electronic displays for fast-scrolling information. However, this very technology, increasingly prevalent in today's world, has not been embraced universally. While the convenience of pocket-sized information pieces has the techno-savvy entranced, the general public still greets the advent of the e-book with a curious reluctance. This lack of enthusiasm seems strange in the face of the many advantages offered by the new medium - vastly superior storage capacity, searchability, portability, lower cost, and instantaneous access. This dissertation addresses the need for research examining the reading comprehension and the role emotional response plays in the perceived performance on e-document formats as compared to traditional paper format. This study compares the relative reading comprehension on three formats (Kindle, iTouch, and paper) and examines the relationship of subject's emotional response and relative technology exposure as factors that affect how the subject perceives they have performed on those formats. This study demonstrates that, for basic reading comprehension, the medium does not matter. Furthermore, it shows that, the more uncomfortable a person is with technology and expertise in the requested task (in this case, reading), the more they cling to the belief that they will do better on traditional (paper) media - regardless of how well they actually do.

Boutons « J’aime », tweets ancrés… Toutes ces formes sont générées par des interfaces de programmation ou API, outils d’écriture informatique qui ont integré la chaîne de production des textes de réseau contemporains. Cette thèse interroge la fonction éditoriale des API, soit leur rôle dans la production, la standardisation et la circulation des « petites formes » des textes de réseau. Avec comme corpus les API de Facebook et de Twitter ainsi que les petites formes qu’elles permettent de produire, notre analyse techno-sémiotique s’articule en cinq chapitres. Le premier est une généalogie des API du point de vue de l’écriture combinatoire. Nous montrons que cette conception de l’écriture est un trait saillant de la programmation et de l’informatique. Le second chapitre interroge les imaginaires de l’écriture informatique, entre chiffre, combinatoire et méthode scientifique universelle. Le troisième chapitre est une analyse des conséquences sémiotiques de cet universalisme combinatoire, où nous montrons que les API proposent une conception du texte comme ensemble abstrait de blocs combinables. Abstraction du texte qui sert une « économie des passages », objet de notre quatrième chapitre, dans laquelle les API sont des lieux d’industrialisation d’une « pratique lettrée » : elles établissent des critères de lisibilité et de reproductibilité du texte. Parmi ces critères, nous notons une invisibilisation du rôle pourtant fondamental du calcul informatique. Nous proposons donc, dans un cinquième chapitre, des pistes pour développer une sémiotique qui prenne en compte le calcul comme mode d’expression propre aux médias numériques. / « Like » buttons, embedded tweets… All of these visual forms are produced by Application Programming Interfaces (APIs). APIs are digital writing tools which have become part of the publishing process of contemporary web pages. This thesis aims at understanding the « publishing function » of APIs : their role in the production, standardization and circulation of the « little forms » of online texts. Focused on Facebook’s and Twitter’s APIs, our work is divided into five chapters. The first one is a genealogy of the APIs, starting from their combinatorial aspect, a conception of writing which trace back to early programming and the invention of computer science. The second chapter is an inquiry about the imaginaries of calculus as a kind of writing, torn between the imaginary of numbers, of combinatorics and the search for a universal scientific method. The third chapter is a study of the semiotic consequences of this combinatorial universalism. We show how APIs are based on an idea of text as an abstract, modular object. This abstraction of the text is beneficial to an « economy of passages ». In this economy where circulation produce value, APIs are a place of « literate practices » (chapter four). They establish visual standards for the readability, production and circulation of online texts. Among these standards, there’s a systematic invizibilisation of the action of machines, although calculus is a necessary part of the production of digital texts. Therefore, in the fifth chapter, we give some epistemological elements towards non-anthropocentric semiotics, meaning : semiotics which would take into account computational machines as a part of the utterance of digital texts.

Submitted by Cláudia Bueno (claudiamoura18@gmail.com) on 2016-03-03T20:22:51Z No. of bitstreams: 2 Dissertação - Thamer Horbylon Nascimento - 2015.pdf: 3404276 bytes, checksum: 8b96b87a1ad94259e867e586b0cdde9b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-03-04T11:20:16Z (GMT) No. of bitstreams: 2 Dissertação - Thamer Horbylon Nascimento - 2015.pdf: 3404276 bytes, checksum: 8b96b87a1ad94259e867e586b0cdde9b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-03-04T11:20:16Z (GMT). No. of bitstreams: 2 Dissertação - Thamer Horbylon Nascimento - 2015.pdf: 3404276 bytes, checksum: 8b96b87a1ad94259e867e586b0cdde9b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-10-13 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / This paper proposes a method for gesture-based text input to be used in devices with touch screens. The steps required for this are: recognizing gestures, identify actions needed to enter letters and recognize letters with up to two interactions. To the recognition of gestures, we used the incremental recognition algorithm, which works so that it is not necessary to finish a gesture for this to be recognized, that is, works with continuous gesture recognition. Furthermore, a template is used as a reference for the recognition of gestures. The algorithm identifies the likelihood of the gesture being a running the template. As the incremental recognition algorithm did not have curves in templates using the reduced equation of the circle, was created a template with curves and straight lines were also added in it. The template created served to create a database for entering the letters of the alphabet from A to Z, using user gestures. This base was used for training of a Naïve Bayes classifier, which identifies the probability of inserting a letter entered by the user based on the gestures. Three experiments were conducted to test the method developed. It was found that most users entered a letter using up to two interactions when inserted the five vowels and the five most frequent consonants. When inserting the five vowels and five consonants less frequent, users were also able to enter the letters with up to two interactions. Thus, there is evidence that the method to solve the problem which has been proposed as a solution. / Este trabalho propõe um método para entrada de texto baseado em gestos para ser usado em dispositivos com telas sensíveis ao toque. Os passos necessários para isso são: reconhecer gestos, identificar gestos necessários para inserir letras e reconhecer letras com até duas interações. Para fazer o reconhecimento dos gestos, foi utilizado o algoritmo de reconhecimento incremental, o qual trabalha de forma que não seja necessário terminar um gesto para que este seja reconhecido, ou seja, trabalha com reconhecimento contínuo de gestos. Além disso, um template é utilizado como referência para o reconhecimento dos gestos, assim, o algoritmo identifica a probabilidade de o gesto em execução ser um do template. Como o algoritmo de reconhecimento incremental não possuía curvas em seus templates, utilizando a equação reduzida da circunferência, foi criado um template com curvas e foram também adicionadas retas nele. O template criado serviu para a criação de uma base de dados para a inserção das letras do alfabeto de A a Z, utilizando gestos de usuários. Essa base foi utilizada para treinamento de um classificador Naïve Bayes, que identifica a probabilidade de inserção de uma letra baseado nos gestos inseridos pelo usuário. Foram realizados três experimentos para testar o método desenvolvido. Verificouse que a maioria dos usuários inseriu uma letra utilizando até duas interações, quando inseriram as cinco vogais e as cinco consoantes mais frequentes. Ao inserir as cinco vogais e cinco consoantes menos frequentes, os usuários também conseguiram inserir as letras com até duas interações. Assim, há evidências de que o método resolva o problema para qual foi proposto como solução.

Amyloidoses comprise a group of gain-of-toxic function protein misfolding diseases, in which normally soluble proteins in their functional state undergo conformational changes into highly organized and generally intractable thread-like aggregates, termed amyloid fibrils. These structures accumulate predominantly in the extracellular space but growing evidence suggests that amyloids may start to form intracellularly. At least 26 different human proteins, intact or in fragmented form, are known to form amyloid, which is linked with many debilitating neurodegenerative diseases such as Alzheimer’s disease (AD), Creutzfeldt-Jakob disease, and transthyretin (TTR)-related amyloidosis (ATTR). In this work, we focus on ATTR, which is one of the most frequent systemic amyloid diseases. A functional link was established between hereditary ATTR, a severe and fatal disorder and the enhanced propensity of the human plasma protein transthyretin (TTR) to form aggregates, caused by single point mutations in the TTR gene. The disease is heterogeneous and clinical symptoms vary from cardiomyopathy to progressing sensorimotor polyneuropathy depending on TTR variant involved and the amyloid deposition site. Despite the fact that TTR-derived amyloid accumulates in different organs such as heart, kidney, eyes, and predominantly in the peripheral nerves of ATTR patients, the exact mechanism of the disease development is not understood. In contrast to the case of AD, it has been difficult to generate an animal model for ATTR in transgenic mice that would be useful in understanding TTR aggregation processes and the mechanisms of the associated toxicity as these mice did not develop any neuropathic phenotype besides amyloid deposits. Therefore, we created a disease-model in Drosophila due to its huge repertoire of genetic techniques and easy genotype – phenotype translation, as well as its success in modeling human neurodegeneration. We have generated transgenic flies that over-express the clinical amyloidogenic variant TTRL55P, the engineered variant TTR-A (TTRV14N ⁄ V16E), and the wild-type protein. All TTR variants were found in the secreted form in the hemolymph where misfolding occurred and depending on the pool of toxic species, the fate of the fly was decided. Within a few weeks, both mutants (but not the wild-type TTR) demonstrated a time-dependent aggregation of misfolded molecules in vivo. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability, and shortened life span. In contrast, expression of the wild-type TTR had no discernible effect on either longevity or fly behavior. In this work, we also addressed the correlation between TTR transgene dosage and thus, protein levels, with the severity of the phenotypes observed in TTR-A flies which developed a “dragged wing” phenotype. Remarkably, we established that degenerative changes such as damage to the retina strictly correlated with increased levels of mutated TTR but inversely with behavioral alterations and the dragged wing phenotype. We characterized formation of aggregates in the form of 20 nm spherules and amyloid filaments intracellularly in the thoracic adipose tissue and brain glia (both tissues that do not express the transgene). Moreover, we detected a fraction of neurotoxic TTR-A in the hemolymph of young but not old flies. We proposed that these animals counteract formation and persistence of toxic TTR-A species by removal from the circulation into intracellular compartments of glial and fat body cells and this is part of a mechanism that neutralizes the toxic effects of TTR. We validated the fly model for ATTR by applying a genetic screen during study of modifier genes. We found Serum amyloid P component (a product of the APCS gene) as a potent modifier of TTR amyloid-induced toxicity that was effective in preventing the apoptotic response in cell culture assay and capable of reducing the dragged wings when co-expressed in TTR-A flies. Finally, we optimized this fly model in order to screen for therapeutic compounds effective against ATTR. Feeding assays showed the effectiveness of several compounds among known native-state kinetic stabilizers of TTR against its aggregation. We described several early endpoints in this model, which can be used as a rapid and cost-effective method for optimizing concentrations and pre-screening of drug candidates. As the proof of principle, by feeding flies with increasing doses of diflunisal analogue (an FDA-approved Non-Steroidal Anti-Inflammatory Drug) a dose-dependent reduction of the dragged wings was observed.