Neurons are polarized cells with dendrites and an axon projecting from their cell body. Due to this polarized structure a major challenge for neurons is the transport of material to and from the cell body. The transport that occurs between the cell body and axons is called Axonal transport. Axonal transport has three major components: molecular motors which act as vehicles, microtubules which serve as tracks on which these motors move and microtubule associated proteins which regulate the transport of material. Axonal transport maintains the integrity of a neuron and its dysfunction is linked to neurodegenerative diseases such as, Alzheimer’s disease, Frontotemporal dementia linked to chromosome 17 and Pick’s disease. Therefore, understanding the process of axonal transport is extremely important. Single particle tracking is one method in which axonal transport is studied. This involves fluorescent labelling of molecular motors and microtubule associated proteins and tracking their position in time. Single particle tracking has shown that both, molecular motors and microtubule associated proteins exhibit motion with multiple components. These components are directed, where motion is in one direction, diffusive, where motion is random, and static, where there is no motion. Moreover, molecular motors and microtubule associated proteins also switch between these different components in a single instance of motion. We have developed a MATLAB program, called MixMAs, which specializes in analyzing the data provided by single particle tracking. MixMAs uses a sliding window approach to analyze trajectories of motion. It is capable of distinguishing between different components of motion that are exhibited by molecular motors and microtubule associated proteins. It also identifies transitions that take place between different components of motion. Most importantly, it is not limited by the number of transitions and the number of components present in a single trajectory. The analysis results provided by MixMAs include all the necessary parameters required for a complete characterization of a particle’s motion. These parameters are the number of different transitions that take place between different components of motion, the dwell times of different components of motion, velocity for directed component of motion and diffusion coefficient for diffusive component of motion. We have validated the working of MixMAs by simulating motion of particles which show all three components of motion with all the possible transitions that can take place between them. The simulations are performed for different values of error in localizing the position of a particle. The simulations confirm that MixMAs accurately calculates parameters of motion for a range of localization errors. Finally, we show an application of MixMAs on experimentally obtained single particle data of Kinesin-3 motor.

The microtubule-associated protein tau is known for its ability to bind to and stabilize microtubules and for its ability to nucleate microtubule assembly. In neurodegenerative tauopathies such as Alzheimer's disease, tau becomes hyperphosphorylated and loses the capacity for microtubule binding, possibly contributing to microtubule destabilization and axonal degeneration. However, evidence now indicates that soluble forms of hyperphosphorylated tau might have a toxic gain of function linked to abnormal signal transduction and cell cycle events in normally post-mitotic neurons. In support of this hypothesis, tau has been found to associate with numerous signaling proteins such as tyrosine kinases, adaptor proteins, and scaffold proteins. During early brain development, fetal tau is also more phosphorylated than tau in the adult brain and weakly binds microtubules, suggesting tau has functions in addition to microtubule stabilization. The aim of this dissertation research is to investigate the possible role of tau in neuronal signaling, using tau-expressing and tau-depleted cell lines. Here, we provide evidence that during growth factor stimulation of neuronal cells, tau functions in advance of the neurite elongation stage. Tau is required for neurite initiation in a manner that does not require its microtubule binding function, and in addition, tau potentiates AP-1 transcription factor activation in response to nerve growth factor (NGF). The effect of tau on AP-1 activation is mediated through the enhanced activation of extracellular signal-regulated kinase (ERK), in response to both NGF and epidermal growth factor (EGF). We show that phosphorylation of tau at Thr231 also occurs in response to NGF and is required for tau to impact on ERK signaling, whereas the ability of tau to bind to microtubules is not required. Together, these findings indicate a new functional role for tau in neuronal signal transduction and have implications for tau function during early brain development and in neurodegenerative disease.

Behavioral characterization of animal models for Alzheimer's Disease is critical for the development of potential therapeutics and treatments against the disease. While there are several known animal models of AD, three current models--APPsw, P301L, and APPsw+P301L--have not been well characterized, if at all. This study, therefore, aimed to perform a full behavioral characterization of these three models in order to better understand the impairments associated with each one. Between 5 and 8.5 months of age, animals were behaviorally tested in a variety of sensorimotor, anxiety, and cognitive tasks. The number of tau+ neurons in the forebrains of P301L mice was then compared to their behavioral performance. Results of this study indicate that retinal degeneration (rd) seriously impairs the performance of mice in behavioral tasks. Animals that carry the homozygous allele of this mutation must, therefore, be eliminated from any such study requiring visual acuity. After this elimination, my findings indicate that APP mice are impaired in several cognitive tasks (including platform recognition, Morris maze, Y-maze, and radial-arm water maze) at a young early age (5 to 8.5 months of age). These mice have fairly normal sensorimotor function, showing significant impairment only in balance beam performance starting at 5 months. Although P301L mutant Tau mice, as a group, did not have significant impairments in any sensorimotor or cognitive task, correlation analysis revealed that higher numbers of tau+ neurons in cortex and hippocampus were associated with poorer cognitive performance. Finally, discriminant function analysis (DFA) appears able to accurately discriminate between the three transgenic groups of mice using only an 8-measure data set. In conclusion, this study provides the first comprehensive, multiple task behavioral assessment of the APPsw and P301L animal models of AD, indicating that APPsw mice are cognitively impaired at an early age while P301L mice are largely unimpaired through 8.5 months. Nonetheless, correlational analysis implicates the formation of neurofibrillary tangles in the onset of cognitive impairments. Finally, my findings recommend the continued use of DFA to determine if groups of animals, based on different transgenicity or therapeutic treatment, could be discriminated between from their behavior alone.

One of the main advantages of the Gantry-Tau machine is a large accessible workspace\footprint ratio compared to many other parallel machines. The Gantry-Tau improves this ratio further by allowing a change of assembly mode without internal link collisions or collisions between the links and the moving TCP platform. In this Thesis some of the features of the Gantry-Tau structure are described and results are presented from the analysis of the kinematic, elastostatic and elastodynamic properties of the PKM. However, the optimal kinematic, elastostatic and elastodynamic design parameters of the machine are still difficult to calculate and this thesis introduces a multi-objective optimisation scheme based on the geometric approach for the workspace area, unreachable area, joint angle limitations and link collisions as well as the functional dependencies of the elements of the static matrix and the Laplace transform to define the first resonance frequency and Cartesian and torsional stiffness. The method to calculate the first resonance frequency assumes that each link and universal joint can be described by a mass-springdamper model and calculates the transfer function from a Cartesian (TCP) force or torque to Cartesian position or orientation. The geometric methods involve the simple geometric shapes (spheres, circles, segments, etc) and vectors. The functional dependencies are based on the properties between the kinematic parameters. These approaches are significantly faster than analytical methods based on the inverse kinematics or the general Finite Elements Method (FEM). The reconfigurable Gantry-Tau kinematic design obtained by multi-objective optimisation gives the following features: • Workspace/footprint ratio more than 3.19. • First resonance frequency greater than 48 Hz. • Lowest Cartesian stiffness in the workspace 5N/μm. • The unreachable space in the middle of the workspace is not detected. • No link collisions. The results show that by careful design of the PKM, a collision free workspace without the unreachable area in the middle can be achieved. High stiffness and high first resonance frequency are important parameters for the the Gantry-Tau when used in industrial applications, such as cutting, milling and drilling of steel or aluminium and pick-and-place operations. These applications require high static and dynamic accuracy in combination with high speed and acceleration. The optimisation parameters are the support frame lengths, actuator positions,endeffector kinematics and the robot’s arm lengths. Because of the fast computational speed of the geometric approaches and computational time saving of the methods based on the functional dependency, they are ideal for inclusion in a design optimisation framework, normally a nonlinear optimisation routine. In this Thesis the evolutionary algorithm based on the complex search method is used to optimise the 3-DOF Gantry-Tau. The existing lab prototype of this machine was assembled and completed at the University of Agder

Les oscillations de neutrinos occupent la majeure partie des expériences s'intéressant à cette particule. Ce mécanisme utilise le fait que les neutrinos soient massifs pour permettre de passer d'un état de saveur à un autre. L'expérience OPERA commencera à prendre des données au printemps 2006. Son but est de prouver sans ambiguïté ce mécanisme en observant l'apparition de neutrinos tauïques dans le faisceau CNGS composé de neutrinos muoniques. Cette thèse présente une description des faisceaux de neutrinos, en s'appuyant sur le faisceau CNGS, tiré du CERN vers le laboratoire italien du Gran Sasso. Le flux de ces neutrinos est recalculé, et des simulations sont menées pour étudier les défauts d'alignement des éléments de la ligne de faisceau. Le détecteur OPERA est composé de briques faites d'un empilement de plaques de plomb et de films d'émulsion photographique, de deux trajectrographes et de deux spectromètres. La haute résolution en position des émulsions (<1 mu m) permet d'identifier les tau crées par l'interaction par courant chargé des neutrinos tauïques. La localisation des briques touchées par un neutrino est faite à l'aide d'un réseau de scintillateurs. La reconstruction des traces dans ces scintillateurs, ainsi que dans les spectromètres, fait partie des travaux présentés dans cette thèse. Un algorithme d'identification des muons a également été développé dans cette thèse. Il permet une réduction d'un facteur 20 du bruit de fond charmé. Le futur de la physique des oscillations de neutrinos passe par la construction de faisceaux de neutrinos de plus en plus intenses, pour arriver à mesurer les derniers paramètres inconnus (theta13 et deltaCP). Le projet de faisceau du CERN vers le tunnel de Fréjus est revisité dans la dernière partie de cette thèse. Une optimisation complète de la ligne de faisceau est proposée, et permet d'atteindre une sensibilité de theta13 de l'ordre du degré.

Ce travail est issu de plusieurs constats. Premièrement, il est admis aujourd'hui que la capacité à percevoir et à retirer les informations visuelles les plus pertinentes d'une action adverse est un facteur déterminant de la performance sportive et ce d'autant plus si l'action est incertaine et faussée. Le second constat, découlant du premier, est que la tromperie est mise en jeu dans bon nombre d'interactions humaines, mais qu'elle est particulièrement déterminante et prépondérante dans lecadre des stratégies sportives. Enfin, le dernier constat est que l'exploration de la performance sportive, pour des raisons méthodologiques ou théoriques, ne permet pas dans certains cas d'expliquer pourquoi un expert est meilleur qu'un novice.L'objectif de notre travail est de comprendre ces déterminants (perceptivo-moteurs) de l'expertise lors d'un duel 1 vs. 1 en rugby présentant une tentative de feinte de l'attaquant. Nous résumons ce travail en trois questions concrètes auxquelles nous répondons: Comment réaliser une feinte de corps en rugby? Comment la détecter? Comment y faire face? La première étude s'attache à analyser les différences biomécaniques observables entre un mouvement de simple changement de direction et un mouvement de feinte de corps en rugby. La seconde étude, en immersion virtuelle, met en lien les informations prospectives émanant des mouvements de feinte et la prise de décision du défenseur de rugby (expert ou novice). Enfin, en se basant sur une méthodologie quasi similaire, la troisième étude vient immerger les participants dans une situation complète de défense, nous permettant d'explorer leur stratégie perceptivo-motrice. L'ensemble de ce processus nous permet de témoigner de l'effet de l'expertise mais surtout d'expliquer pourquoi l'expert est meilleur en dressant les différences de stratégie perceptivo-motrice le caractérisant. Si les implications concernent majoritairement le domaine du rugby (connaissances fondamentales et entrainement), elles présentent au sens plus large, un éclairage justifié et démontré des processus mis en jeu lors de toute interaction, humaine ou animal, sollicitant la tromperie. Nous en sommes persuadés; un prédateur animal, un joueur de poker, un défenseur de basket... se doivent deprésenter des stratégies quasi-similaires pour détecter l'intention de bluff chez l'opposant

Le diagnostic de la maladie d'Alzheimer (MA) est tardif et présente un manque de fiabilité en regard de l'examen neuropathologique postmortem permettant de confirmer ce diagnostic. En effet, les présentations cliniques de la MA peuvent être multiples et parfois atypiques. Des anomalies dans les concentrations des protéines tau, tau phosphorylées et amyloïdes bêta, au sein du liquide céphalorachidien (LCR), ont permis d'améliorer le diagnostic du vivant du patient. Nous avons évalué la performance de ces marqueurs, dans le LCR, utilisés pour le diagnostic de la MA dans les formes syndromiques atypiques. L'utilisation de ces marqueurs augmente la précision du diagnostic lors de ces différentes présentations cliniques. De plus, nous avons mis au point un test diagnostic biochimique postmortem des différentes tauopathies permettant de mieux les caractériser en complément de l'examen neuropathologique. Enfin, nous avons conçu et caractérisé des anticorps spécifiquement dirigés contre la protéine tau phosphorylée en position 231. Cet outil nous a permis de développer un test ELISA dans le LCR. Des résultats préliminaires suggéreraient une interaction in vivo entre les protéines tau et Prion. Ces résultats, décrits pour la première fois, sont corrélés à nos observations histologiques.

<p>The present study assessed olfactory and cognitive abilities in two strains of Alzheimer’s disease (AD) model mice and in healthy control mice over a four month time period. To this end an operant conditioning paradigm using an automated olfactometer and a spatial learning test with non-olfactory cues were employed and data on olfactory learning and memory, discrimination, and sensitivity as well as spatial learning and memory were collected. The mice were between 6 to 7 month old at the beginning of the study and 9 to 10 months old at the end of the data collection, that is, in the age range when the animals are supposed to display marked neuroanatomical changes typical of AD. The results demonstrate that there were no systematic differences in olfactory performance and spatial learning and memory abilities of AD model mice and the control mice up to the age they were tested. Further, there was no indication of an age-related decline in performance in any of the mouse strains across the testing period. Several reasons might account for the observed lack of difference in olfactory and cognitive performance between the mouse strains tested here: the AD model mice might not develop amyloid plaques and neurofibrillary tangles at all or they might develop them later than stated by the supplier. Alternatively, the AD model mice may have developed AD-typical neuroanatomical changes but these do not, or not yet, affect their olfactory performance and/or spatial learning and memory capabilities. Ongoing data collection will help to evaluate which of these explanations holds true.</p>

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

Support for the use of progress monitoring results for high-stakes decisions is emerging in the literature, but few studies support the reliability of the measures for this level of decision-making. What little research exists is limited to oral reading fluency measures, and their reliability for progress monitoring (PM) is not supported. This dissertation explored methods rarely applied in the literature for summarizing and analyzing progress monitoring results for medium- to high-stakes decisions. The study was conducted using extant data from 92 "low performing" third graders who were progress monitored using mathematics concept and application measures. The results for the participants in this study identified 1) the number of weeks needed to reliably assess growth on the measure; 2) if slopes differed when results were analyzed with parametric or nonparametric analyses; 3) the reliability of growth; and 4) the extent to which the group did or did not meet parametric assumptions inherent in the ordinary least square regression model. The results indicate reliable growth from static scores can be obtained in as few as 10 weeks of progress monitoring. It was also found that within this dataset, growth through parametric and nonparametric analyses was similar. These findings are limited to the dataset analyzed in this study but provide promising methods not widely known among practitioners and rarely applied in the PM literature.