La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative affectant les neurones moteurs supérieurs et inférieurs menant éventuellement à une paralysie générale du patient. Le décès du patient survient généralement entre 2 à 5 ans subséquemment à l’apparition des premiers symptômes. La SLA consiste en la maladie neurologique causant le plus décès chez l’adulte et il est estimé qu’environ 10% des cas sont familiaux (fSLA) et 90% sont sporadiques (sSLA). De plus, 15% des patients souffrant de la SLA développent également une démence fronto-temporale (DFT) s’illustrant par des troubles de comportements ainsi qu’un changement de personnalité majeur. Il a été démontré que la SLA et la DFT partagent un spectre génétique commun et les patients atteints de DFT démontrent une protéinopathie caractérisée par une accumulation anormale de certaines protéines dans le cytoplasme des neurones et des cellules gliales, tout comme pour les patients souffrant de SLA. Plusieurs gènes mutés ont été identifiés au cours des dernières années pour la forme fSLA, notamment superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), ubiquilin-2 (UBQLN2), Fused in sarcoma (FUS), optineurin (OPTN), etc. Un des gènes le plus étudié et le mieux décrit est celui codant la protéine TDP-43. Cette protéine nucléaire, lorsque mutée, est délocalisée dans le cytoplasme, où elle forme des inclusions anormales et persistantes. Ces agrégats, lorsque formés, renferment également plusieurs autres composés, notamment d’autres protéines telles qu’UBQLN2, différentes nucléoporines, ubiquitine, etc. UBQLN2 est une protéine ayant un rôle primordial dans le système de dégradation du protéasome (UPS) ainsi que pour l’autophagie. Cette protéine est responsable de la liaison entre les protéines destinées à être dégradées avec l’UPS. Il a été démontré dernièrement in vitro et in vivo que la mutation d’UBQLN2 est liée à l’agrégation de TDP-43. Cependant, le mécanisme exact de ce phénomène reste grandement incompris et nécessite encore beaucoup d’attention et de travail. Dans ce mémoire, nous avons utilisé pour notre étude des cellules en culture afin de surexprimer les formes natives et mutantes d’UBQLN2 humain (hUBQLN2) pour étudier l’effet d’UBQLN2 sur la protéine TDP-43. Notre équipe a réussi à démontrer dernièrement dans les cellules de neuroblastome de souris (Neuro2a) que la surexpression de l’UBQLN2 entraînait une délocalisation de TDP-43 du noyau vers le cytoplasme en plus de son accumulation anormale dans des agrégats. De plus, l’effet synergique entre les formes mutées de TDP-43 et UBQLN2 a également été démontré dans un modèle murin dans notre article paru en 2018 comme quoi la mutation d’UBQLN2 influence grandement la protéinopathie de TDP-43. À la suite de ces constats, nous avons orienté nos études sur le phénomène synergique entre UBQLN2 et TDP-43 qui est encore grandement méconnu. Pour ce faire, une analyse complète et exhaustive de la littérature a été effectuée afin de bien comprendre la mutation UBQLN2 et consiste en la première revue littéraire couvrant la totalité des ouvrages publiés sur la mutation d’UBQLN2 dans la SLA. Par la suite, nous avons convenu d’étudier l’effet de la mutation d’UBQLN2P497H sur le transport nucléo-cytoplasmique dans les cellules Neuro2a ainsi que dans les tissus de souris transgéniques. Les souris utilisées sont les mêmes que pour l’article Picher-Martel et al., 2018, soit des souris simple transgénique UBQLN2P497H et TDP-43G348C ainsi que la première souris double transgénique arborant UBQLN2P497H/TDP-43G348C. Les souris doubles transgéniques se sont avérées très intéressantes. En effet, elles ont développé les caractères typiques retrouvés chez les patients SLA/DFT avec une perte motoneuronale accompagnée de dégénérescence axonale, atrophie musculaire, gliose, trouble moteur ainsi que cognitif en plus d’agrégations cytoplasmique de TDP-43 importantes. À l’aide de ce modèle unique nous avons approfondi notre compréhension des déficits observés au niveau du transport nucléo-cytoplasmique, déficit grandement observé chez les patients SLA. Nous avons observé que le transport nucléo-cytoplasmique était davantage et significativement altéré dans les cellules co-transfectées avec les gènes encodant pour les deux protéines mutées plutôt que transfectées avec une seule. Nous avons également observé pour les souris double transgéniques comparées aux souris simples pour l’une ou l’autre de ces protéines. Nos résultats suggèrent donc que la mutation d’UBQLN2 exacerbe significativement la protéinopathie de TDP-43 et engendre une perturbation importante du transport nucléo-cytoplasmique ainsi que des complexes du pore nucléaire. En conclusion, ce mémoire démontre un rôle important de la mutation d’UBQLN2 sur TDP-43 et leur grande affinité à augmenter les déficits du transport nucléo-cytoplasmique. Ceci suggère donc qu’UBQLN2 et TDP-43 sont intimement liés et peuvent jouer un rôle synergique dans la physiopathologie de la SLA. Le modèle murin double transgénique pourra indubitablement être utilisé en laboratoire afin de tester de nouvelles approches thérapeutiques.

INTRODUCTION : Les interventions prescrites en lombalgie chronique (LC) ont un effet modeste sur la douleur. Afin d’optimiser l’efficacité des traitements et diminuer l’hétérogénéité de la population LC, la stratification basée sur les mécanismes de la douleur a été proposée : une douleur nociceptive résulte de l’activation des nocicepteurs alors qu’une douleur nociplastique est caractérisée par une nociception altérée. Les exercices entraînent une diminution de sensibilité à la douleur chez les individus en santé (hypoalgésie induite par l’exercice [HIE]). Considérant que de multiples mécanismes centraux interviennent dans l’HIE et que ces mêmes mécanismes semblent fonctionner différemment chez les sous-groupes de LC (nociceptif versus nociplastique), il est possible que les sous groupes nociceptive et nociplastique présentent des réponses différentes à l’exercice. OBJECTIF : Déterminer l’effet d’exercice sur la modulation de la sensibilité à la douleur chez différents sous-groupes d’individus souffrant de LC. MÉTHODOLOGIE : Vingt-neuf adultes présentant une LC et 24 sujets sains ont été recrutés. Trois physiothérapeutes ont procédé à la stratification basée sur les mécanismes des sujets LC selon l’évaluation clinique. Tous les sujets ont réalisé des exercices isométriques du poignet et du bas du dos. Les seuils de douleur à la pression localement au dos et à distance ont été évalués pré/post-exercice et le pourcentage de changement représentait la magnitude de l’HIE. RÉSULTATS : Seize sujets ont été attribués au sous-groupe LC nociceptive et 12 ont été classifiés LC mixte (composantes dominantes nociceptive et nociplastique) en l’absence de consensus entre les évaluateurs. Une réduction de l’HIE a été observée chez le sous groupe mixte en comparaison avec le groupe contrôle. Aucune différence n’a été observée entre les sous-groupes LC. CONCLUSION : La diminution d’HIE chez le sous-groupe LC mixte comparativement au groupe contrôle suggère un processus de modulation de la douleur en réponse à l’exercice altéré. / BACKGROUND: Research in chronic low back pain (CLBP) shows modest effect of available treatments. In order to achieve better treatment results and reduce heterogeneity of CLBP population, mechanism-based stratified care has been proposed: a nociceptive pain results essentially from the activation of nociceptors where as a nociplastic pain is characterized by an altered nociception. Exercises induce a reduction in pain sensitivity, known as the paradigm of exercise-induced hypoalgesia (EIH). Considering that EIH involved multiple central mechanisms and that these same mechanisms seems to function differently in subgroups of CLBP (nociceptive vs. nociplastic), individuals with CLBP presenting predominant nociplastic and nociceptive pains may respond differently to exercise. OBJECTIVE: To determine the effect of exercises on the modulation of pain sensitivity in different subgroups of individuals presenting CLBP. METHODS: Twenty-nine adults with CLBP and 24 healthy controls (HC) were recruited. Three physiotherapists proceeded to mechanism-based stratification of CLBP participants from clinical evaluation. Each participant performed isometric exercises of the wrist and the back. Pressure pain thresholds were assessed locally at the back and remotely pre/post-exercise and the percentage of change was calculated as the EIH magnitude. RESULTS: Sixteen participants were allocated to the nociceptive CLBP subgroup and 12 were classified as mixed pain (nociceptive/nociplastic) in the absence of consensus amongst physiotherapists. A significant reduction of EIH was observed in the mixed subgroup when compared to HC. No EIH difference was detected between the two CLBP subgroups. CONCLUSION: The significant reduction of EIH in the mixed CLBP subgroup suggests an altered pain modulation process in response to exercise in this subgroup.

This thesis attempts to provide an encompassing account for the centuries-old question concerning how aspect and modality are grammaticalized in the verbal system in Biblical Hebrew. To this end, the semantics of the three verb forms qatal, yiqtol, and qotel are investigated by means of a theory-unbiased observation on the Biblical text. It is argued that Biblical Hebrew has an aspectual opposition of the perfective and the imperfective and that the two aspects are encoded by the verb forms qatal and qotel, respectively. Concerning the modal system in Biblical Hebrew, it is suggested that the Biblical Hebrew broadly distinguishes the realis and irrealis and that the irrealis is marked by a single verb form yiqtol. Finally, the verbs occasioned in the Book of Isaiah 52:13-53:12 are thoroughly examined in the light of the present study. The examination on the Isaiah passage consequently ascertains that the present study largely removes the existing obstacles in understanding Biblical Hebrew verb conjugations and lays the significant grounds toward the proper linguistic understanding of the Biblical text. / text

This dissertation investigates the verbal system of Persian and is focused on the interaction of modality, tense, aspect and negation in this language. The dissertation challenges the idea that the syntactic structure maps on to the semantic interpretation or vice-versa.It is argued that modals are raising constructions in some languages (Wurmbrand 1999). Modals in Persian, which do not have subject-raising constructions, show different behavior. First, the root complex modals are generally syntactic control in Wurmbrand's (1998, 2001) proposal. There are just a few gaps with respect to dynamic root modals. Second, all epistemic modals which are either defective auxiliary modals or complex modals take default agreements and are pseudo-raising constructions. Third, the syntactic structures of modals show that there is no one-to-one correspondence between the structural positions and semantic interpretations of modals in Persian except in the auxiliary modal bâyad 'must'.The second contribution of this dissertation is that the class of restructuring verbs varies across languages. German semantic control verbs are instances of restructuring constructions (Wurmbrand 2001) while the only case of restructuring in Persian is the functional restructuring which appears in auxiliary modals such as bâyad 'must' and šâyad 'may' since they are mono-clausal and do not have a CP.This dissertation also investigates the structure of complex verbal forms in Persian. It is argued that Persian future tense is an instance of Serial Verb Constructions. However, progressives which are bi-clausal constructions are Aspectual Complex predicates.In the case of the structural analysis of the interaction of Persian modals and negation, this dissertation shows that the syntactic structure maps on the semantic interpretation or vice-versa. There are just a few gaps with respect to the scope possibilities of particular modals.The final contribution of this dissertation is related to the problem of the word order of NV elements and LV within complex predicates. This research provides three suggestions regarding the clausal complement position in complex predicates, and suggests that the vP remnant movement is the most reasonable one, since it is compatible with the recent trends of syntactic theories and suggested for some other languages (Mahajan 2003).

This thesis presents a feature-based approach to aspect. I argue that both viewpoint aspect and lexical aspect are generated from the presence of functional properties that operate at three levels of syntactic structure: lexical, predicate, and clausal. The same aspectual feature has a different effect on the aspectual properties of the clause as a whole depending on the level at which it is active and the contrasts in which it participates. I illustrate this for English and Japanese, showing that a small number of syntactic features can capture the differences and similarities between the aspectual systems. I propose that aspect in English is determined by two functional heads: AspQ, which encodes quantity (i.e., telicity), and AspA, which encodes atomicity (i.e., punctuality). AspQ may either be a root modifier, lexically encoding quantity, or head a separate functional projection within the vP system, where it is licensed by a quantized argument. AspA may also be a root modifier, lexically encoding atomicity; it may also appear in the inflectional domain, where it encodes clausal non-atomicity (i.e., imperfective aspect). I propose that Japanese is like English in that AspA may be active at the root level; however, it differs from English in that AspA may also be active at the vP level, where it encodes the fact that the predicate is represented as a single unit. Japanese also differs from English in that it does not make use of the feature AspQ, meaning that Japanese has no quantity distinction, and makes use of the feature State, which heads a functional projection where light verbs such as iru ‘be’ are merged. Thus, the differences in the aspectual systems of English and Japanese are attributed to a few features that are active at different levels of syntactic structure.

This thesis presents a feature-based approach to aspect. I argue that both viewpoint aspect and lexical aspect are generated from the presence of functional properties that operate at three levels of syntactic structure: lexical, predicate, and clausal. The same aspectual feature has a different effect on the aspectual properties of the clause as a whole depending on the level at which it is active and the contrasts in which it participates. I illustrate this for English and Japanese, showing that a small number of syntactic features can capture the differences and similarities between the aspectual systems. I propose that aspect in English is determined by two functional heads: AspQ, which encodes quantity (i.e., telicity), and AspA, which encodes atomicity (i.e., punctuality). AspQ may either be a root modifier, lexically encoding quantity, or head a separate functional projection within the vP system, where it is licensed by a quantized argument. AspA may also be a root modifier, lexically encoding atomicity; it may also appear in the inflectional domain, where it encodes clausal non-atomicity (i.e., imperfective aspect). I propose that Japanese is like English in that AspA may be active at the root level; however, it differs from English in that AspA may also be active at the vP level, where it encodes the fact that the predicate is represented as a single unit. Japanese also differs from English in that it does not make use of the feature AspQ, meaning that Japanese has no quantity distinction, and makes use of the feature State, which heads a functional projection where light verbs such as iru ‘be’ are merged. Thus, the differences in the aspectual systems of English and Japanese are attributed to a few features that are active at different levels of syntactic structure.

Thesis (M.S.)--University of Texas at Dallas, 2007. / Includes vita. Includes bibliographical references (leaves 101-105)

Title from title page (viewed March 10, 2009) College of Computer and Information Science. Includes bibliographical references (p. 177-182).

With the upsurge of Web 2.0, customers are able to share their opinions and feelings about products and services, politics, economic shifts, current events and any number of other topics on the Web. This information, if leveraged effectively, can provide rich and valuable insights, such as: input for vendors to create successful marketing strategies, understanding of areas of improvement in products and services and tracking political opinion. The problem with this information is that it is unorganised and unstructured, therefore, it is difficult to assess automatically and in bulk. Studies in the field of sentiment analysis aim to provide a solution to determining the polarities of, and gain an overview of, the wider public opinion behind certain topics in a large volume of textual data. This research provides a novel framework and a solid, practical implementation of the proposed framework for fine-grained sentiment analysis. The framework supports mixed-opinion text and multiword expressions when analysing the sentiments expressed and the aspects that those sentiments relate to. This research uses datasets across two domains in the customer reviews area (phone products and hotel services) to evaluate the proposed framework for its reliability and validity. A sizeable performance improvement was noted whereby the proposed methodology yielded a result of 91.3% accuracy in sentiment classification, as compared to the baseline (SentiWordNet), which had a result of 71.0%. In addition, an accuracy of 92.5% was observed for the aspect analysis automatically generated across the two domains tested.

With the advent of multicore processors, there is an increasing amount of interest in building concurrent applications capable of fully utilising their features. Developing applications for these platforms to take full advantage of the power of multicore capabilities remains a complex, error-prone, and challenging endeavour. Unfortunately, concurrency is not uniformly and externally expressed in most existing application models. The result is that concurrency and thread management are hidden within objects or components and intermixed with their functionalities. After demonstrating the tangling of code that results from the interaction of these two major concerns, this thesis describes a method of improving the concurrent program by applying a novel technique to separate the concerns: aspect-oriented programming, which aims to encapsulate concerns that crosscut the main program flow in separate entities into aspects. The most mature aspect-oriented tool available at the time this project was being undertaken is AspectJ, which is an extension of Java. AspectJ can be used to write an aspect to a separate concern in a sequential program to avoid code tangling, but it is often inapplicable for concurrent programs. The problem lies in the fact that the points where parallelisation should occur are not natural join points in AspectJ (i.e. points where AspectJ can intervene). Consequently, this thesis proposes a set of fine-grained join points capable of completely handling concurrent programs. This model goes beyond present AspectJ models and demonstrates the need to recognise complex behaviour for an effective separation of concerns. Finally, aspects for implementing concurrent programs according to different schemes are presented, together with evaluation results. This highlights the flexibility of aspects for implementing concurrent programs, a flexibility which is always a cross-cutting concern with respect to the main concern of base applications.