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αB-crystallin is a small heat-shock chaperone protein (sHSP) required for the homeostasis of multiple tissues including eye lens, retina, heart and brain. Correspondingly, mutation or altered levels of αB-crystallin are associated with multiple degenerative diseases including cataract, retinal degeneration, cardiomyopathy and Lewy body disease. Based on its wide-ranging importance understanding the protective and homeostatic properties of α B-crystallin is critical for understanding degenerative diseases and could lead to the development of therapies to treat these diseases. αB-crystallin is localized to the mitochondria suggesting a direct effect on mitochondrial function. My thesis work has examined those molecular pathways required for translocation of αB-crystallin to the mitochondria and to identify the downstream pathways controlled by mitochondrial translocation of αB-crystallin that could be important for cellular protection and differentiation. My results point to a novel role of αB-crystallin in regulation of key apoptotic pathways that mediate the balance between cell survival and differentiation. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

There are sex differences in degenerative disease prevalence in humans. Most models of degenerative disease use male animals. Examining female and male responses to stress may give insight into disease prevalence. Heat shock proteins are chaperones linked to damaged proteins in degenerative diseases and may be expressed differentially in females and males. My goal was to characterize the induced expression of Hsp70 and Hsp27 in the brain and heart of female and male rats. Rats were heat shocked, brains and hearts were removed 24 hours after, and western analyses were done to quantify the expression of these proteins. Immunofluorescence was used to localize Hsp70 and Hsp27 in the hippocampus. Overall, male rats have significantly greater induced expression of both Hsp70 and Hsp27 in the brain. In the hippocampus, Hsp70 was localized in blood vessels and microglia, and Hsp27 was localized in astrocytes, following heat shock.

With societies aging all around the world, the global burden of degenerative diseases is expected to increase exponentially. From the perspective drug development, degenerative diseases represent an especially challenging class. Clinical trials, in this context often termed disease progression studies, are long, costly, require many individuals, and have low success rates. Therefore, it is crucial to use informative study designs and to analyze efficiently the obtained trial data. The development of novel approaches intended towards facilitating both the design and the analysis of disease progression studies was the aim of this thesis. This aim was pursued in three stages (i) the characterization and extension of pharmacometric software, (ii) the development of new methodology around statistical power, and (iii) the demonstration of application benefits. The optimal design software PopED was extended to simplify the application of optimal design methodology when planning a disease progression study. The performance of non-linear mixed effect estimation algorithms for trial data analysis was evaluated in terms of bias, precision, robustness with respect to initial estimates, and runtime. A novel statistic allowing for explicit optimization of study design for statistical power was derived and found to perform superior to existing methods. Monte-Carlo power studies were accelerated through application of parametric power estimation, delivering full power versus sample size curves from a few hundred Monte-Carlo samples. Optimal design and an explicit optimization for statistical power were applied to the planning of a study in Alzheimer's disease, resulting in a 30% smaller study size when targeting 80% power. The analysis of ADAS-cog score data was improved through application of item response theory, yielding a more exact description of the assessment score, an increased statistical power and an enhanced insight in the assessment properties. In conclusion, this thesis presents novel pharmacometric methods that can help addressing the challenges of designing and planning disease progression studies.

De nos jours, on attribue une myriade d’effets bénéfiques aux polyphénols alimentaires. Ces affirmations reposent la plupart du temps sur des études in vitro, sur quelques études in vivo et presque jamais sur des essais cliniques. On se rend compte de plus en plus que l’intérêt des polyphénols ne résiderait pas uniquement dans leur pouvoir antioxydant mais également dans leur capacité à cibler de multiples cibles moléculaires comme l’inflammation. De plus, de nombreuses études commencent à prendre en compte la biodisponibilité des polyphénols dans l’organisme et leur interaction avec le microbiote intestinal. C’est pourquoi en plus de nous intéresser à deux polyphénols issus de la Pomme-grenade, nous nous sommes intéressés à deux de leurs dérivés métaboliques. Pratiquement aucune étude ne s’était penchée sur l’effet de ces molécules dans un contexte de maladies neuro-dégénératives. Pour se faire, nous avons testé la punicalagine, l’acide ellagique, l’urolithin A et l’urolithin B sur des modèles C. elegans de la SLA et de la maladie de Huntington qui présentaient des phénotypes moteurs, de la neuro-dégénérescence et de l’inflammation. Enfin, nous avons utilisé un modèle de souris ayant subi une axotomie du nerf optique pour confirmer le pouvoir neuro-protecteur de l’urolithin A. Nos résultats ont montré que ces composés dans des proportions différentes étaient en mesure de réduire la toxicité neuronale de protéines liées à la SLA et HD et ainsi diminuer les niveaux de paralysie et de neuro-dégénérescence de nos modèles C. elegans. En parallèle, nous avons observé que cette neuro-protection se faisait au travers une diminution de l’inflammation et pour l’urolithin A une amélioration de la morphologie des mitochondries via la mitophagie. En dernier, nous avons constaté que l’urolithin A était en mesure de promouvoir la survie neuronale chez la souris à la suite d’une lésion du nerf optique. Pour conclure, cette étude par son approche in vivo de multiples maladies neuro-dégénératives renforce les preuves existantes de l’effet bénéfique de la consommation de Pomme-grenade et encourage l’utilisation pharmacologique de l’urolithin A. / Nowadays, a myriad of beneficial effects is attributed to dietary polyphenols. Most of these claims are based on in vitro studies, some in vivo studies, and almost never on clinical trials. It is increasingly realized that the interest of polyphenols does not only lie in their antioxidant power but also in their ability to target multiple molecular pathways such as inflammation. In addition, many studies are beginning to take into account the bioavailability of polyphenols in the body and their interaction with the gut microbiota. That's why in addition to two polyphenols from Pomegranate, we looked at two of their metabolic derivatives. Almost no study has examined the effect of these molecules in the context of neurodegenerative diseases. To do this, we tested punicalagin, ellagic acid, urolithin A and urolithin B on C. elegans models of ALS and Huntington's disease that had motor phenotypes, neurodegeneration and inflammation. Furthermore, we used a mouse model that underwent an axotomy of the optic nerve to confirm the neuroprotective power of urolithin A. Our results showed that these compounds in different proportions were able to reduce the neuronal toxicity of proteins. related to ALS and HD and thus decrease the levels of paralysis and neuro-degeneration of our C. elegans models. In parallel, we observed that this neuroprotection was done through a reduction of the inflammation and for urolithin A an improvement of the morphology of mitochondria via mitophagy. Lastly, we found that urolithin A was able to promote neuronal survival in mice as a result of optic nerve injury. To conclude, this study by its in vivo approach to multiple neuro-degenerative diseases reinforces existing evidence of the beneficial effect of pomegranate consumption and encourages the pharmacological use of urolithin A.

Use of biochemical markers (Lipoprotein phospholipase A2 and hyaluronic acid) for laboratory diagnosis of metabolic and degenerative diseases of the musculoskeletal system Abstract Musculoskeketal disorders currently belong to the most common diseases. The presented work describes the use of biochemical markers (Lipoprotein phospholipase A2 and hyaluronic acid) for laboratory diagnosis of metabolic and degenerative diseases of the musculoskeletal system. Concentrations of LP-PLA2 were significantly elevated in the patients with bone resorption compared to the control group of healthy individuals. Serum levels of Lp-PLA2 also negatively correlated with decreased levels of serum osteocalcin in patients. HA concentrations in synovial fluid did not differ from published reference values in synovial fluid. Patients who underwent arthroscopy had significantly elevated synovial HA concentration than patients who underwent total knee endoprosthesis. HA positively correlates with osmotic pressure determined by examination of osmolality in synovial fluid. Lipoprotein phospholipase A2 concentrations are elevated in patients with bone density impairment. LpPLA2 concentrations correlate with the severity of bone density impairment expressed by the T score. Hyaluronic acid concentrations in patients with knee...

Cette thèse est motivée par le diagnostic et l’évaluation des maladies neuro-dégénératives et dans le but de diagnostique sur la base de l’attention visuelle.Néanmoins, le dépistage à grande échelle de la population n’est possible que si des modèles de prédiction automatique suffisamment robustes peuvent être construits. Dans ce contexte nous nous intéressons `a la conception et le développement des modèles de prédiction automatique pour un contenu visuel spécifique à utiliser dans l’expérience psycho-visuelle impliquant des patients atteints des maladies neuro-dégénératives. La difficulté d’une telle prédiction réside dans une très faible quantité de données d’entraînement. Les modèles de saillance visuelle ne peuvent pas être fondés sur les caractérisitiques “bottom-up” uniquement, comme le suggère la théorie de l’intégration des caractéristiques. La composante “top-down” de l’attention visuelle humaine devient prépondérante au fur et à mesure d’observation de la scène visuelle. L’attention visuelle peut-être prédite en se basant sur les scènes déjà observées. Les réseaux de convolution profonds (CNN) se sont révèlés être un outil puissant pour prédire les zones saillantes dans les images statiques.Dans le but de construire un modèle de prédiction automatique pour les zones saillantes dans les vidéos naturels et intentionnellement dégradées, nous avons conçu une architecture spécifique de CNN profond. Pour surmonter le manque de données d’apprentissage,nous avons conçu un système d’apprentissage par transfert dérivé de la méthode de Bengio.Nous mesurons ses performances lors de la prédiction de régions saillantes. Les r´esultatsobtenus sont int´eressants concernant la r´eaction des sujets t´emoins normaux contre leszones d´egrad´ees dans les vid´eos. La comparaison de la carte de saillance pr´edite des vid´eosintentionnellement d´egrad´ees avec des cartes de densit´e de fixation du regard et d’autresmod`eles de r´ef´erence montre l’int´erˆet du mod`ele d´evelopp´e. / This thesis is motivated by the diagnosis and the evaluation of the dementia diseasesand with the aim of predicting if a new recorded gaze presents a complaint of thesediseases. Nevertheless, large-scale population screening is only possible if robust predictionmodels can be constructed. In this context, we are interested in the design and thedevelopment of automatic prediction models for specific visual content to be used in thepsycho-visual experience involving patients with dementia (PwD). The difficulty of sucha prediction lies in a very small amount of training data.Visual saliency models cannot be founded only on bottom-up features, as suggested byfeature integration theory. The top-down component of human visual attention becomesprevalent as human observers explore the visual scene. Visual saliency can be predictedon the basis of seen data. Deep Convolutional Neural Networks (CNN) have proven tobe a powerful tool for prediction of salient areas in static images. In order to constructan automatic prediction model for the salient areas in natural and intentionally degradedvideos, we have designed a specific CNN architecture. To overcome the lack of learningdata we designed a transfer learning scheme derived from bengio’s method. We measureits performances when predicting salient regions. The obtained results are interestingregarding the reaction of normal control subjects against degraded areas in videos. Thepredicted saliency map of intentionally degraded videos gives an interesting results comparedto gaze fixation density maps and other reference models.