This research investigated two groups of patients diagnosed with dementia before the age of sixty-five. The patients were diagnosed with Alzheimer’s Disease (AD, n = 25) and Frontotemporal Dementia (FTD, n = 37). Patients were assessed for approximately 3 years. The study found that FTD is a valid and useful diagnostic category, and can be reliably differentiated from AD. A combination of behavioural, neurological, and neuropsychological assessments were found to be complementary in the early and accurate diagnosis of early-onset dementia, and the differential diagnosis of FTD from AD. FTD patients were found to have relatively preserved visuo-spatial abilities compared to the AD patients. Problems associated with administering neuropsychological tests to early-onset dementia patients were highlighted. FTD patients were found to deteriorate more rapidly than AD patients, and to have significantly increased behavioural disturbances throughout the course of the illness in comparison with the AD patients. Practical guidelines to assist with care and management of early-onset dementia patients were presented. A strengths-based model of care was outlined. Individualised assessments and care plans were recommended for the development and provision of humane services to early-onset dementia patients. Issues surrounding providing palliative care were discussed.

The hexanucleotide repeat expansion GGGGCCn (also known as G4C2n) localizes in the first intron of the C9ORF72 gene and is the most common genetic cause of ALS and FTD (C9ALS/FTD). The pathomechanisms proposed for C9ALS/FTD suggest that from sense (G4C2)n- and anti-sense (C4G2)n-containing transcripts originate two different mechanisms of toxicity: i) by the alteration of RNA processing due to binding and sequestration of RNA-binding proteins, thereby leading to impairment of RNA metabolism; and ii) by their unconventional Repeat-associated non AUG (RAN) translation into five different dipeptide-repeats (DPRs). In addition, pathological expansion of (G4C2)n reduces the C9orf72 transcription causing loss of function of the C9ORF72 protein. The toxicity of some of these DPRs has been showed in several cell lines, in iPSC-derived neurons, in Drosophila and in mouse models. An impairment of the ubiquitin-proteasome system (UPS) due to aggregation of toxic proteins is largely demonstrated in neurodegenerative disorders and among the mechanisms of DPR-related toxicity. RAN translation of (G4C2)n-RNAs has been recently shown to require a near-cognate start codon upstream of the repeat in frame +1 and to be triggered by stress conditions in a cap-dependent or cap-independent way. However, the mechanism regulating RAN translation is still largely unknown. Importantly, no small molecules are known to selectively modulate RAN translation, even if antisense oligonucleotides (ASOs) and small molecules binding the r(GGGGCC)n have been proposed as therapeutics for C9ALS/FTD. In addition, no effective pharmacological approach to reduce the pathological load of DPRs is currently available. Here, I developed a high-throughput drug-screening assay to identify small molecules and relative molecular targets that can modulate the DPR level. Among the identified hits, two hits reduced DPRs expression levels triggering the protein clearance system in vitro. Moreover, the screening identified compounds having the same target that increased DPRs expression levels indicating the targeted pathway as a crucial modulator of the translation process of the C9orf72 repeat-containing mRNAs. Conversely, I showed that pharmacological inhibition of the pathway reduced DPRs expression levels in vitro, while in vivo it rescued climbing ability and increased life span of Drosophila flies carrying G4C2X36 repeats. Moreover, genetic ablation of the target reduced DPRs expression levels by decreasing their translation efficiency in vitro and rescued the pathological phenotype in vivo. Together, the results show the identification of new pathways as new drug targets for C9ALS/FTD.

These times the third generation cellular networks are getting in use increasingly and they dramatically exceed the parameters of second generation networks. Third generation networks are in contrast to older generations data-oriented, providing better maintenance in data and multimedia services. The most widespread third generation network is the UMTS, designed as succesor of GSM network. Master’s thesis is focused on parameters and communication protocols of radio interface of UMTS network. Parameters of radio interface affect the behaviour of mobile terminal through utilization of network services. This thesis describes individual protocols of radio interface and individual procedures, which the mobile terminal have to perform through its staying in the cell. Theoretical part of this thesis considers description of the UMTS network and individual procedures and parameters. Practical part is focused on measuring the radio interface and individual procedures in real UMTS networks. Some procedures are simulated in network simulation software. This thesis includes a lab task focused on this thema.

More than 40 neurological diseases are known to be caused by large expansions oftandem repeat sequences scattered throughout the human genome in introns, exons and untranslated regions. The GGGGCC (G4C2) repeat expansion located in the first intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In C9 FTD/ALS, expanded transcripts are known to aggregate and accumulate in the cell nucleus, sequestering RNA binding proteins. Other expanded RNA species are exported to the cytoplasm to undergo a non-canonical form of translation termed ‘repeat-associated non-AUG (RAN) translation’. RAN translation leads to the production of toxic polydipeptide repeat proteins in the absence of a canonical AUG start codon. This dissertation will highlight new mechanistic features of translation across the G4C2 repeat expansion, identify a potential therapeutic for C9 FTD/ALS using RNAi and develop a cellular system to explore the G4C2 repeat RNA lifecycle. First, we demonstrate that increasing G4C2 repeat expansion size results in suppression of translation from both canonical and non-canonical start codons, suggesting that large polydipeptide repeats are rarely fully translated. We further find that initiation does not occur from within the repeat expansion, relying on upstream sequence for initiation. However, some reading frames are prone to substantial frameshifting, such as poly-GA. We also show that a bias in ii codon usage efficiency contributes to previously observed variations in the levels of each polydipeptide. Our results support and extend previous studies by identifying two new mechanisms that bias production of poly-dipeptides toward poly-GA in C9 FTD/ALS. Further, we generated central mismatch-containing short hairpin RNAs (shRNAs) targeting the G4C2 repeat expansion to reduce aggregation or block translation of repeatcontaining transcripts. Iterative design was able to improve shRNA processing efficiency and cellular abundance, yet they were unable to reduce nuclear RNA foci in patient-derived cells. Despite this, we show preliminary data suggesting that these shRNAs are able to target cytoplasmic repeat-containing transcripts and resulting in a reduced translation of poly-GP. Finally, we optimized the previously published RNA-protein interaction detection (RaPID) technique, which uses proximity dependent labelling by a mutant biotin ligase and mass spectrometry for protein identification in living cells, to identify proteins interacting with the G4C2 repeat expansion. We embedded the box B RNA hairpin between G4C2 repeats and tested the ability for λN fused to a biotin ligase mutant, BASU, to specifically bind the box B hairpin in vitro. We show that 6 repeats each side of the hairpin combined with an extended hairpin stem promotes specific binding of the λN-BASU fusion protein and is likely to be successful in cells. C9 FTD/ALS is a currently incurable neurodegenerative disorder largely due to the limited understanding of disease mechanism. This dissertation demonstrates new mechanisms of translation across the G4C2 repeat expansion that results in toxic DPR production while also developing a nucleic acid therapeutic for long-term treatment of C9 FTD/ALS and further developing systems to explore RNA-mediated toxicity in cells.

La Sclérose Latérale Amyotrophique (SLA) et la Démence Frontotemporale (DFT) sont deux maladies neurodégénératives formant un continuum clinique, génétique et histopathologique. Des mutations dans le gène CHMP2B sont associées à la fois à des cas de SLA et de DFT. Le but de cette thèse a été de caractériser un nouveau modèle de souris transgéniques basé sur l'expression neuronale de la mutation humaine CHMP2Bintron5.Ces souris présentent une faiblesse musculaire progressive et des défauts de coordination motrice. Les motoneurones présentent des altérations au niveau distal. Les souris transgéniques développent des modifications du comportement alimentaire, un désintérêt social et des stéréotypies, tandis que les fonctions mnésiques sont préservées. Nous avons observé une accumulation d'agrégats protéiques dans les neurones ainsi qu'une astrocytose, reflétant le profil histopathologique des patients.Ainsi, l'expression neuronale de CHMP2Bintron5 induit chez les souris des symptômes caractéristiques de la SLA et de la DFT ainsi que l'apparition des marqueurs histopathologiques de ce syndrome. Cette lignée permettra l'étude des mécanismes communs impliqués dans le syndrome SLA-DFT. / The neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) form a clinical, genetic and histopathological continuum. Mutations in CHMP2B can cause ALS or DFT. The aim of this study was to characterize a new transgenic mouse model based on the neuronal expression of the human mutation CHMP2Bintron5.The mice develop a progressive muscle weakness and motor coordination defects, associated with a distal alteration of the motoneurons. Moreover, their feeding behavior is altered and they develop social disinterest and stereotypies, while mnesic functions are spared. We observed protein aggregates in neurons and an astrocytosis, mirroring the histopathological profile of patients.The neuronal expression of the mutant CHMP2Bintron5 triggers a motor phenotype associated with dementia symptoms and histopathological hallmarks of ALS and FTD. This transgenic line willallow the study of the common mechanisms implicated in the ALS-FTD syndrom.

Frontotemporal dementia is a neurodegenerative disorder with high heterogeneity on the genetic, pathological and clinical level. The familial form of the disease is mainly caused by pathogenic variants of three genes: C9orf72, MAPT and GRN. As there is no clear correlation between the mutation and the clinical phenotype, symptom severity or age of onset, the demand for predictive biomarkers is high. While there is no fluid biomarker for frontotemporal dementia in use yet, there is strong hope that changes of protein concentrations in the blood or cerebrospinal fluid can aid prognostics many years before symptoms develop. Increasing amounts of data are becoming available because of long-term studies of families affected by familial frontotemporal dementia, but its analysis is time-consuming and work intensive. In the scope of this project a pipeline was built for the automated analysis of proteomics data. Specifically, it aims to identify proteins useful for differentiation between two groups by using random forest, a supervised machine learning method. The analysis results of the pipeline for a data set containing blood plasma protein concentration of healthy controls and participants affected by frontotemporal dementia were promising and the generalized functioning of the pipeline was proven with an independent breast cancer proteomics data set.

No description available.

Les troubles neurodégénératifs, tels que la sclérose latérale amyotrophique (SLA) et la démence frontotemporale (DFT), ont été associés aux protéines de liaison à l'ARN (RBP). Les principales caractéristiques de la SLA sont l'agrégation d'une protéine de liaison à l'ARN appelée protéine de liaison TAR (TDP-43). Il a été démontré que TDP-43 se lie à G3BP1, un facteur de nucléation pour l'assemblage des granules de stress, pour le stabiliser. Les granules de stress sont des structures séparées par phases qui se forment dans des conditions stressantes et favorisent la survie cellulaire. Une altération de l’assemblage des granules de stress et une réduction du G3BP1 sont signalées dans la SLA. Cette réduction est due à un défaut dans les transcriptions codantes pour G3BP1 stabilisant TDP-43. Par conséquent, une réponse défaillante des granules de stress pourrait jouer un rôle majeur dans la maladie. Ainsi, ce projet de recherche se concentre sur la restauration de G3BP1, dont la déplétion est liée à la perte de fonction de TDP-43. En utilisant des composés de petites molécules identifiés lors d'une campagne de dépistage de médicaments, nous cherchons à augmenter l'expression de G3BP1, rétablissant ainsi le mécanisme SG endogène et favorisant la survie neuronale. La découverte de candidats principaux (NPX-047, NPX-000-115 et NPX-001-280) qui sauvent efficacement l'expression et la fonction de G3BP1 est prometteuse pour des thérapies potentielles contre la SLA. Ces composés ont été testés sur des cellules SHSY5Y traitées avec du si-TDP, mais aucune récupération de l'ARNm de G3BP1 n'a été observée malgré des niveaux plus élevés de signaux de luciférase. Ainsi, une enquête approfondie sur les divergences dans nos résultats constitue notre prochaine étape, ce qui n’a pas été possible pendant la durée limitée de cette mémoire. De plus, les cibles non ciblées de ces composés seront étudiées à l’aide du séquençage Bru Chase. Dans l’ensemble, cette étude explore de nouvelles stratégies pour restaurer l’expression de G3BP1, offrant ainsi une voie potentielle d’intervention thérapeutique dans la SLA. / Neurodegenerative disorders, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), have been associated with RNA-binding proteins (RBPs). Major hallmark of ALS is aggregation of an RNA-binding protein called TAR binding protein (TDP-43). TDP-43 has shown to bind to G3BP1, a nucleating factor for stress granule assembly, to stabilize it. Stress granules (SGs) are phase separated structures that form under stressful conditions and promote cell survival. Impaired stress granules assembly and reduced G3BP1 is reported in ALS. This reduction is due to a defect in TDP-43 stabilizing G3BP1 encoding transcripts; thus, a failed stress granule response could have a major role in the disease. Thus, this research focuses on restoring G3BP1, whose depletion is linked to TDP-43 loss of function. By utilizing small-molecule compounds identified through a drug screening campaign, we seek to increase G3BP1 expression, consequently reinstating the endogenous SG mechanism and promoting neuronal survival. The discovery of lead candidates (NPX-047, NPX-000-115, and NPX-001-280) that effectively rescue G3BP1 expression and function offers promise for potential ALS therapies. These compounds were tested on SH-SY5Y cells treated with si-TDP however no rescue of G3BP1 mRNA was observed despite higher levels of luciferase signals. Thus, in-depth investigation of discrepancies in our results is our next step which was not possible during the limited timeline of this thesis. In addition, off-targets of these compounds will be investigated using BruChase-sequencing. Overall, this study explores novel strategies to restore G3BP1 expression, providing a potential avenue for therapeutic intervention in ALS.

Orientador: Maria Angela Miorim / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Educação / Made available in DSpace on 2018-08-11T01:44:35Z (GMT). No. of bitstreams: 1 Barone_Jessica_M.pdf: 4058474 bytes, checksum: 11d44a6d13368c7d92320962629227ab (MD5) Previous issue date: 2008 / Resumo: O presente trabalho tem como objetivo específico descrever e analisar, através da História da Educação Matemática, do Livro no Brasil e da História Geral da Educação, como os livros didáticos de matemática, em sua materialidade, especialmente os da editora FTD, se enquadram no contexto editorial e cultural desse período e como essa relação se estabeleceu economicamente, politicamente e socialmente, através de uma comunidade religiosa católica: a Sociedade dos Irmãos Maristas. Este estudo vai desde o estabelecimento da editora no Brasil em 1902 até o ano de 1930, quando entra em vigor a Reforma Francisco Campos, época em que as mudanças educacionais atingem proporções maiores e provocam mudanças observáveis nos livros didáticos / Abstract: The present study historical research has as specific objective to describe and to analyze through the History of the Mathematical Education, the history of text books in Brazil and the General History of the Education, how text books of mathematics, in its materiality, especially of publishing company FTD, fit in the publishing and cultural context of this period and how this relation established economically, politically and socially, through a religious community catholic: the Society of the Maristas Brothers. This study goes since the establishment of the publishing company in Brazil in 1902 until the year of 1930 when the Reformation enters in vigor Francisco Fields, time where the educational changes reach bigger ratios and provoke changes you observed in didactic books / Mestrado / Educação Matematica / Mestre em Educação

The thesis investigates the elements of a consistent strategy for favorable acquisition and utilization of Flight Simulation Training Devices (FSTD), thus Full Flight Simulators (FFS) and Flight Training Devices (FTD). The primary purpose is to determine a knowledge-based strategy for the end-user, acquisition professional, aviation firms and institutions. Hence, it could be possible to shed a light for cooperative groups and main institutions of national innovation system involved in entrepreneurial and innovative efforts regarding complex technologies like FSTD. In the sample study, 114 pilots from varied sources were administered a questionnaire and their FFS and FTD perceptions were statistically tested regarding each &ldquo / technology&rsquo / s usefulness&rdquo / in four types of training. Another variable, each &ldquo / technology&rsquo / s ease of operation and use&rdquo / was also tested additionally via agent-based model whether it had any effect on technologies&rsquo / selection processes. It could be inferred that that aviation institutions and firms could acquire and utilize FTD as a complementary to both aircraft and FFS within a range of 30-60% depending upon type of the training. Moreover, FTD could be acquired and utilized as a substitute to FFS for Instrument Flight Training (IFT). The FTD&rsquo / s usefulness for IFT was rated as 67% by the military pilots. The research also asserts that the aviation institutions and firms as well as cooperative groups and organizations could favor the established strategy and policy during their FSTD related efforts at &ldquo / micro and meso-level&rdquo / . The final aim is to create a collaborative medium and a synergy for those agents.