Frontotemporal dementia (FTD) is the second most common early-onset dementia. A rare mutation in CHMP2B gene was found to be associated with FTD linked to chromosome 3. Previous studies have shown that mutant CHMP2B could lead to impaired autophagy pathway and altered RNA metabolism. However, it is still unknown what genes mediate the crosstalk between different pathways affected by mutant CHMP2B. Genetic screens designed to identify genes interacting with mutant CHMP2B represents a key approach in solving the puzzle. Expression of mutant CHMP2B (CHMP2Bintron5) in Drosophila eyes leads to a neurodegenerative phenotype including melanin deposition and disrupted internal structure of ommatidia. The phenotype is easily quantified by estimating the percentage of black dots on the surface of the eyes. Using this established Drosophila model, I searched for genes encoding RNA binding proteins that genetically modify CHMP2Bintron5 toxicity. I found that partial loss of Pumilio, a translation repressor, mitigates CHMP2Bintron5 induced toxicity in the fly eyes. Western blot analysis showed that down regulation of Pumilio does not significantly decrease CHMP2Bintron5 protein level, indicating indirect regulation involved in suppression of the phenotype. The molecular targets regulated by Pumilio and the mechanism underlying CHMP2Bintron5 toxicity suppression by Pumilio down-regulation requires further investigation.

Purpose: Assess the effectiveness of an online intervention to encourage self-management in adolescents with cerebral palsy (CP). Specific Aims: (a) assess effectiveness of an online intervention to promote readiness for self-management in adolescents with CP, (b) describe health literacy and associations with readiness to assume self-management, and (c) evaluate adolescents’ exposure to the online intervention. Hypotheses: (a) intervention subjects would demonstrate improvement in self-management, and (b) subjects with higher health literacy would demonstrate higher self-management capabilities. Framework: Transtheoretical Model of Health Behavior Change Design: Randomized control trial, performed in a multidisciplinary CP clinic at a university based children’s hospital. Instruments used: (a) Transition Readiness Assessment Questionnaire (TRAQ) and (b) the Health Literacy Skills Instrument-SF (HLSI). Due to low engagement, the study terminated early. Intervention subjects were interviewed to assess their limited engagement. Results: Seventy-five percent of subjects demonstrated inadequate HL. Mean baseline TRAQ score (n=24) was 2.71 (SE = .24). Positive associations were found between TRAQ and age (.47, p = .00) and TRAQ and HL (.48, p = .00). Conclusion: Failure to engage with the intervention appeared to be related to: (a) low HL, (b) low TRAQ scores (indicating subjects in contemplation stage) (c) inconsistency between subjects’ preference for learning and delivery of information, and (d) low motivation for self directed learning. Online interventions should be easy to use and include learning preferences. Lessons learned will inform future development of interventions for this population.

Orientador: Dionei Ramos / Resumo: Estudos vem investigando a relação do nível da atividade física com a melhora da qualidade do sono de tabagistas, além da utilização do exercício físico para aumentar o sucesso da cessação do tabagismo. No entanto, faz-se necessário investigar a relação da qualidade do sono e sistema nervoso autônomo (SNA) de acordo com o nível de atividade física habitual de tabagistas, para promover a identificação de possíveis mecanismos responsáveis pelos distúrbios do sono desta população, além disso os efeitos do exercício físico no sucesso da cessação do tabagismo ainda é pouco compreendida indicando pequenas taxas de adesão e abstinência ao final do tratamento. Objetivos: Identificar a relação entre a qualidade do sono de tabagistas com o nível de atividade física habitual e modulação do SNA. Além disso, comparar dois tipos de exercícios associados à terapia cognitivo-comportamental (TCC) no sucesso da cessação do tabagismo. Métodos: Trata-se de dois estudos, sendo o primeiro transversal realizado com 42 tabagistas divididos em dois grupos de acordo com o percentil 50% do nível de atividade física de moderada à vigorosa (AFMV) avaliada por meio da acelerometria; onde a qualidade do sono foi avaliada por meio do questionário Mini-Sleep e a modulação do SNA por meio de índices da variabilidade da frequência cardíaca (VFC). Para as análises dos dados foi utilizado análise de covariância (ANCOVA) ajustado para idade, sexo, composição corporal, anosmaço, medicamentos beta-bloqueadores, ans... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Studies has been investigating the relationship of habitual physical activity with improved of sleep quality in smokers, in addition to using exercise to increase the success of smoking cessation. However, it is necessary to investigate the relationship between sleep quality and autonomic nervous system (ANS) according to the level of habitual physical activity of smokers, to promote the identification of possible mechanisms responsible for sleep disorders in this population. The effects of physical exercise on smoking cessation success, it is still poorly understood, indicating low adherence and abstinence rates at the end of treatment. Objectives: To identify changes in the sleep quality of smokers and its relation with habitual physical activity level and ANS modulation. Also, compare two types of exercise associated with cognitive behavior therapy (CBT) in successful smoking cessation. Methods: These are two studies, the first cross-sectional study conducted with 42 smokers divided into two groups according to the 50th percentile of the moderate-to-vigorous physical activity (MVPA) assessed by accelerometry; where the sleep quality was assessed using the Mini-sleep Questionnaire and the ANS modulation was assessed by indices of heart rate variability (HRV). For the analysis of possible mean differences analysis of covariance (ANCOVA) was used adjusting for age, sex, body composition, pack-years, beta-blockers, anxiety, and depression in log base 10. Correlations were made... (Complete abstract click electronic access below) / Doutor

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene, which encodes a protein serving, at least in part, to accelerate the intrinsic hydrolysis of active Ras-GTP to inactive Ras-GDP. A second-hit NF1 mutation precedes predominant NF1 neoplasms, including juvenile myelomoncytic leukemia (JMML) and plexiform neurofibroma formation, potentially fatal conditions with no medical therapy. While NF1 loss of heterozygosity (LOH) in myeloid progenitor cells sufficiently engenders leukemogenesis, plexiform neurofibroma formation depends on LOH in Schwann cells and Nf1 heterozygosity in the hematopoietic system. Specifically, recruited Nf1+/- mast cells accelerate tumorigenesis through secreted cytokines and growth factors. Nf1+/- mast cells depend upon deregulated signaling in c-kit pathways, a receptor system conserved in hematopoietic stem cells (HSCs). Accordingly, Nf1-/- myeloid progenitor cells, which can induce a JMML-like disease in mice, also demonstrate deregulated c-kit receptor signaling. C-kit-activated Nf1+/- mast cells and Nf1-/- myeloid progenitors both show increased latency and potency of active Erk1 and Erk2, the principal cytosolic-to-nuclear effectors of canonical Ras-Raf-Mek signaling. Thus, Erk represents a potential regulator of leukemogenesis and tumor-associated inflammation. However, single and combined Erk1 and Erk2 roles in HSC function, myelopoiesis, and mature mast cell physiology remain unknown, and recent hematopoietic studies relying on chemical Mek-Erk inhibitors have produced conflicting results. Here, we show that hematopoietic stability, myelopoiesis, and mast cell generation require Erk1 or Erk2, but individual isoforms are largely dispensable. Principally, Erk-disrupted hematopoietic stem cells incorporate BrdU but are incapable of dividing, a novel and cell type-specific Erk function. Similarly, mast cell proliferation requires Erk but cytokine production proceeds through other pathways, elucidating molecule-specific functions within the c-kit cascade. Based on these findings, we have reduced tumor mast cell infiltration by treating genetically-engineered tumor model mice with PD0325901, a preclinical Mek-Erk inhibitor. Moreover, we have devised a quadruple transgenic HSC transplantation model to examine dual Erk disruption in the context of Nf1 nullizygosity, testing whether diseased hematopoiesis requires Erk. These insights illuminate cell-specific Erk functions in normal and Nf1-deficient hematopoiesis, informing the feasibility of targeting Mek-Erk in NF1-associated disease.

PURPOSE: To review the role of excitatory neurotransmitters in normal mammalian brain function, the concept of excitotoxic neuronal death as an important final common path in a variety of diseases, and modification of excitatory synaptic transmission as an important new pharmacological principle. These principles are discussed, with special emphasis on diseases of importance to older adults. DATA SOURCES: A MEDLINE search from 1966 to May 1995 was undertaken, as well as a manual search of current issues of clinical and basic neuroscience journals, for articles that addressed glutamate N-methyl-D-aspartate and/or excitotoxicity. STUDY SELECTION: A total of 5398 original and 68 review articles were identified that addressed animal and human experimentation relevant to excitotoxic neuronal death. There were 364 articles with potential significance for clinical application identified; 132 of the most recent references are provided. DATA EXTRACTION: All articles were classified into three categories: general receptor, biology pathogenesis of disease, and pharmacotherapy. RESULTS: Glutamic and aspartic acids are the physiological mediators of most excitatory synaptic transmission. This is critical to several normal nervous system functions, including memory and long-term modification of synaptic transmission and nociception. Activation of the inotropic NMDA and non-NMDA receptors increases transmembrane calcium and sodium fluxes, and the metabotropic glutamate receptor activation results in generation of inositol triphosphate and inhibition of adenylate cyclase. Numerous modulatory sites exist, especially on the NMDA receptor. Nitric oxide, arachidonic acid, superoxide, and intracellular calcium overload are the ultimate mediators of neuronal death. Glutamate re-uptake transporters belong to a unique family of amino acid transport systems, the malfunction of which is intricately involved in disease pathogenesis. Ischemic stroke, hypoglycemia, Parkinson's disease, alcohol intoxication and withdrawal, Alzheimer's disease, epilepsy, and chronic pain syndromes are only some of the important clinical neurological disorders with a major pathogenic role for the excitatory amino acids. CONCLUSIONS: Pharmacological manipulation of the excitatory amino acid receptors is likely to be of benefit in important and common diseases of the nervous system. Only a few of the currently available drugs that modify excitatory neurotransmission, such as remacemide, lamotrigine, and tizanidine, have an acceptable therapeutic index. The identification of numerous receptor subtypes, topographic variabilities of distribution, and multiple modulatory sites will provide a true challenge to the neuropharmacologist.

As more studies accumulate on the impact of diabetes mellitus on the central nervous system, they resound with the same conclusion - diabetes has a detrimental effect on cognition regardless of the presence of comorbidities. Less consistent however, are the specific mental processes wherein these declines are noticeable, and the structural changes that accompany these reductions in mental capacity. From global atrophy to changes in the volume of gray and white matter, to conflicting results regarding the effects of hypo- and hyperglycemic states on the development of the hippocampus, the studies display a variety of results. The goal of this research is to link the structural and compositional changes occurring in the diabetic brain with the clinical and behavioral findings highlighted in the literature, as well as to explore the potential mechanisms behind the pathologic brain state of diabetic encephalopathy. Using diabetic (OVE26) and non-diabetic wild type (FVB) mice as models, differences in the number of hippocampal neurons in the dentate gyrus, and cornu ammonis areas 1,2, and 3 were investigated through Nissl staining. Neurodegeneration was confirmed in those cells determined to be hyperchromatic in the diabetic model through staining with Fluoro-Jade C. Finally, the presence of progenitor cells in the hippocampus was compared in the diabetic and non-diabetic models using Musashi-1 antibodies, to determine whether neurogenesis in these areas is affected by diabetes. These experiments were performed to better understand the effect of DM on learning and memory, and could potentially explain the linkage between diabetes mellitus and the increased prevalence of Alzheimer’s disease, vascular dementia, and depression in this subset of the population.

<p>It is well established that physical activity can improve aspects of physical fitness in individuals with spinal cord injury (SCI). Despite reports of declining health and fitness post-discharge from rehabilitation, there is a limited amount of research exploring exercise status or interventions during this period. The purpose of this dissertation was to investigate the integration of structured exercise into the rehabilitation process following SCI, and to optimize the exercise prescription in the community setting. Findings from the first study indicated that exercise is well tolerated among individuals with sub-acute SCI; performance of a peak exercise test on an arm ergometer was feasible for all injury types. At this stage post-injury, interventions should be mindful of the greater risk of orthostatic intolerance in individuals with complete tetraplegia and focus on building task specific self-efficacy. The second study involved a direct referral and physical activity counselling intervention post-discharge. Adherence rates were excellent among those participants who received the intervention suggesting that this model of care can facilitate adherence to community exercise after discharge.</p> <p>The final two studies took place in the community. Several modes of adapted exercise were compared and findings indicated that while there were no differences in measures of physiological intensity or enjoyment between the different modes, arm-only exercise was perceived as safer than passive hybrid (arm and leg) exercise. Further, the validity of using ratings of perceived exertion (RPE) to attain prescribed exercise intensity was established. The efficacy of the physical activity guidelines for improving fitness in adults with SCI were evaluated in a community-based randomized controlled trial and the results revealed that the guidelines were effective in improving both aerobic capacity and muscle strength. Taken together, this series of studies describes a model of care that links rehabilitation with community exercise and suggests options for sustained engagement.</p> / Doctor of Philosophy (PhD)

<p>Parkinson’s disease (PD) is a complex neurodegenerative movement disorder involving protein misfolding, mitochondrial dysfunction, and oxidative stress. The current dissertation, motivated by a lack of valid biomarkers and sustainable therapies, examined the potential application of a novel target for therapeutics and diagnostics of PD — the multifunctional, heat-shock like protein Catecholamine-Regulated Protein 40 (CRP40). The goal of this program of research was to elucidate further the implications of CRP40 in PD using a variety of molecular biology, bioinformatics, and clinical approaches through integrative collaborations with academia, government, and industry partners to translate scientific findings into real world solutions. Chapters 2 and 3 explored the potential therapeutic use and structure-function relationships of CRP40 through elucidating the smallest functional piece of this protein that was six times smaller, and validating a negative control for these experiments (Heat-Shock Protein 47). These initiatives could eventually lead to a small drug that could cross the blood-brain barrier and be targeted to the specific brain regions affected in PD. Chapter 4 examined the potential mechanisms of CRP40, and suggested that this protein may protect neurons from oxidative stress, maintain energy levels, and mitochondrial homeostasis, with important future implications for a variety of disorders. Finally, Chapter 5 presented compelling evidence for the potential use of CRP40 as a valid biomarker for early detection of PD and monitoring of disease progression. Overall, findings suggest that CRP40 may be a critical target for future breakthroughs in the diagnosis and treatment of PD.</p> / Doctor of Science (PhD)

No / Starting from the premise that people are essentially narrative beings, I argue that the onset of severe mental illness compromises the narrative enterprise of being able to construct one's Self and one's relationships inmeaningful and coherent ways. This is due to both the curtailment of opportunities for narrative engagement and the dispossession of those whose narratives do not conform to the current conceptualization of narrative and narrativity. In these circumstances, supporting the narrative enterprise is an ethical endeavour that requires that we examine not only which narratives we construct, but also how we construct them. This requires a re-thinking of what might constitute narrative and how we might facilitate or enhance the narrativity of people with severe mental illness. Following this, I suggest four means to support the narrativity of people with severe mental illness: through maintaining narrative continuity, maintaining narrative agency, countering master narratives and attention to small stories.

T cells infiltrate the degenerating brain and influence central nervous system (CNS) inflammation and neuronal health. In mice, the choroid plexus and the meninges have been implicated in regulating T cell entry and egress from the CNS, respectively. Further, antigen presenting cells in the mouse meninges present CNS-derived antigens to T cells and may represent a method for the peripheral immune system to sense and respond to CNS immune triggers. However, whether these processes occur in the human choroid plexus and meninges has not been comprehensively studied. Further, the antigens towards which T cells in the degenerating human brain and its borders respond remain unknown. Therefore, I implemented a multi-omics approach using fresh postmortem tissue from patients diagnosed with amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and non-neurodegenerative controls to identify not only the T cell-associated changes that occur in the degenerating human CNS and surrounding tissues but also identified a library of putative antigen targets for disease-associated T cell populations. Specifically, using single cell RNA and TCR sequencing information from paired postmortem choroid plexus, leptomeninges, and brain I lineage traced T cells using their TCR information and found that T cell access to leptomeninges and brain is likely limited and controlled by anti-inflammatory macrophage activity at the blood/CSF barrier (BCSFB). Once past the BCSFB, I present evidence that T cells access the CNS where they interact with MHC expressed by microglia. T cells also accumulate in the leptomeninges where they become tissue resident memory T cells. These tissue resident memory T cells likely serve as a reservoir for a rapid antigen-driven immune response to future CNS inflammatory insults. Finally, by performing immunopeptidomics to identify peptides presented by MHC in the same patients’ CNS and border tissues, I identified a library of putative antigenic triggers that may drive high levels of T cell clonal expansion in the brain and surrounding tissues. Altogether, this thesis serves as a resource for understanding the trajectory of T cells as they travel into the degenerating human brain and as a foundation for the development of antigen-specific precision medicines to treat neurodegeneration.