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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
41

Role of p38 and STAT5 Kinase Pathways in the Regulation of Survival of Motor Neuron Gene Expression for Development of Novel Spinal Muscular Atrophy Therapeutics

Farooq, Faraz T 17 July 2012 (has links)
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons from the anterior horn of the spinal cord, resulting in progressive muscle atrophy. The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which can compensate in part for the absence of the functional SMN1 gene. I have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 pathway by the bacterial antibiotic anisomycin which stabilizes and increases SMN mRNA levels in vitro. Activation of the p38 pathway by anisomycin leads to cytoplasmic accumulation of HuR protein which binds to the 3’UTR of SMN transcript resulting in increased SMN levels. This opens up a novel potential therapeutic strategy for SMA. I have also identified and demonstrated a significant induction of SMN protein levels in vitro and in vivo upon treatment with FDA approved drug celecoxib, which also activates the p38 pathway. Celecoxib mitigates disease severity along with increasing the lifespan of SMA mice. Sodium valproate, trichostatin A and aclarubicin, all agents which effectively enhance SMN2 expression, have been recently shown to activate STAT5 in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. Given that prolactin is also known to activate the STAT5 signalling pathway, can cross blood brain barrier and is FDA approved, we elected to assess its impact on SMN levels. In this manner, I have demonstrated a significant induction in SMN mRNA and protein levels in neuronal NT2 and MN-1 cells upon treatment with prolactin. I have also demonstrated that activation of the STAT5 pathway by prolactin is necessary for this transcriptional upregulation of the SMN gene. I have found that prolactin treatment induces SMN expression in brain and spinal cord samples and that it ameliorates the disease phenotype, improving motor neuron function and increasing survival in the SMA mouse model. Presently there is no cure for SMA. This study will help in the identification and characterization of potential therapeutic compounds for the treatment of SMA.
42

Thermomechanical and Transformational Behaviour and Applications of Shape Memory Alloys and their Composites

Tsoi, Kelly Ann January 2003 (has links)
This thesis details an investigation into the properties and applications of shape memory alloy (SMA) composites. SMA-composites are a new material which have the possibility of having a large impact on what the structures as we know today, are constructed with. SMA-composites are adaptive materials which can be used to control the shape and frequencies of vibration of a structure. In order to determine the effectiveness of such a material, research into the functional properties of SMAs and SMA-composites was conducted. As an initial step, the transformation behaviour of constrained SMAs was investigated in order to obtain a better understanding into the recovery stress generation of these wires when embedded into a composite material. It is known that the transformation is based on two types of martensite within the alloy; self accommodating and preferentially oriented martensite. The amounts of each type and how they vary with differing pre-strain were determined through DSC measurements and an explanation for why preferentially oriented martensite is not observed during DSC testing was made. The next step was to investigate the effectiveness of embedding SMA wires into composites and the thermomechanical properties of the SMA wires and the SMA-composites were determined. This was completed using a specially designed tensile testing machine which was capable of having the whole specimen immersed into an oil bath and heated and cooled repeatedly. The stress-strain, strain-temperature, stress-temperature, resistance-strain and cyclic properties of various wires were obtained, giving a better understanding of the behaviour of SMA wires under different test conditions. NiTiCu SMA wires were embedded into kevlar composite materials and the recovery stress generation (stress-temperature), stress-strain, and strain-temperature behaviour was determined. If SMA-composites are to be used as new materials for structural applications, verification that the embedment of pre-strained SMA wires into the material doesn't adversely affect the impact behaviour needs to be carried out. SMA-composite specimens with varying volume fractions of superelastic SMA wires, pre-strain and position through the thickness were made up for impact damage characterisation. These specimens were impacted at three different energy levels. The results showed that by embedding SMA wires into composite materials there is a reasonably low damage accumulation after impact. There is also no adverse impact effect on the structure compared with structures without wires as well as structures with other types of wires such as steel and martensitic SMA wires. The SMA-composites showed good damping and energy absorption capabilities. A novel application of SMA-composites is their use as a SMA patch in order to repair damage in existing cracked metallic structures. An analytical study and finite element modelling showing the closure stresses obtainable for use as patches was made.
43

O modelo intencional de transporte : contribuições da ontologia de bunge para formalização da teoria de comportamento em transporte

Aliaga Medrano, Ronny Marcelo 20 June 2016 (has links)
Tese (doutorado)—Universidade de Brasília, Faculdade de Tecnologia, Departamento de Engenharia Civil e Ambiental, 2016. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-09-12T18:02:03Z No. of bitstreams: 1 2016_RonnyMarceloAliagaMedrano.pdf: 4438580 bytes, checksum: 48dfff8fc0a527132354374e672d2602 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-11-01T11:25:14Z (GMT) No. of bitstreams: 1 2016_RonnyMarceloAliagaMedrano.pdf: 4438580 bytes, checksum: 48dfff8fc0a527132354374e672d2602 (MD5) / Made available in DSpace on 2016-11-01T11:25:14Z (GMT). No. of bitstreams: 1 2016_RonnyMarceloAliagaMedrano.pdf: 4438580 bytes, checksum: 48dfff8fc0a527132354374e672d2602 (MD5) / O interesse na abordagem de Comportamento em Transporte tem aumentado nos últimos anos. As mudanças tecnológicas, culturais e econômicas vigentes levam a explorar novos campos da ciência do transporte relacionados ao comportamento das pessoas. A abordagem Baseada em Viagens não consegue acompanhar essas mudanças, e isso gera gargalos quando os seus conceitos tentam ser aplicados. Outra questão importante é a fixação dos profissionais de transporte na etapa previsão de viagens, que remete a prática do planejamento de transporte basicamente em estimação de fluxos futuros, sem aprofundar no fenômeno transportes, nas interações entre o seu sistema e o ambiente, e no mecanismo que leva a esses resultados observados. Contudo, Comportamento em Transporte ainda carece de uma formalização na teoria e sofre de uma divisão cada vez mais atômica na prática cientifica, que limita a sua viabilidade de ser aplicada pelo profissional do transporte. Diante disso, nessa tese de doutorado buscou-se formalizar e unificar as diferentes teorias de Comportamento em transporte com o intuito de fortalecer e estruturar a abordagem de uma forma robusta, de forma a contribuir com novas soluções aos problemas emergentes e novas formas de consolidar a prática cientifica. Para isso, foi aplicada a Ontologia de Sistemas de Mario Bunge, tal como foi desenvolvida em Magalhães (2010). Primeiramente, apresenta-se uma revisão dos últimos avanços na literatura de Comportamento de Transporte identificando as principais teorias e abordagens utilizadas na prática cientifica. Posteriormente, aplica-se a Ontologia de Sistemas de Bunge para sistematizar essas teorias e abordagens. Uma vez sistematizados e identificados os componentes - o ambiente, a estrutura e o mecanismo - foi encontrado que o Comportamento em Transporte atua em um Sistema de Transporte reduzido. Em função desse Sistema Reduzido, foi construído o modelo teórico intencional de transporte, que constitui-se em um conjunto de processos que descrevem o funcionamento do Sistema de Transporte e o indivíduo. Neste modelo teórico as teorias e as abordagens revisadas foram sistematizadas, resultando na modelização do fenômeno de transporte diferente do que existe atualmente. E também é apresentada uma nova concepção do sujeito de transporte racional limitado, que é diferente do agente racional econômico comum ao fundamento da Abordagem Baseada em Viagens e ao Modelo de Quatro Etapas. Posteriormente, é realizada uma análise de comparação entre o Modelo de Quatro Etapas, o modelo de MATSIM, e modelo intencional. Finalmente, aplica-se uma simulação entre o Modelo de Quatro Etapas e MATSIM com um cenário de Brasília 2016. O resultado permitiu observar os alcances e possiblidades de duas abordagens diferentes na simulação de funcionamento de um sistema de transporte. Além disso, são apresentadas perspectivas para uma futura operacionalização do modelo teórico intencional de transporte desenvolvido. ________________________________________________________________________________________________ ABSTRACT / The interest in the travel behaviour approach has increased in recent years. Technological, cultural and economic changes lead to explore new transport science fields related to the behavior of people. The trip-based approach cannot keep up with these changes, and this creates bottlenecks when their concepts are intended to be applied. Another important issue is the fixing of transport professionals in the travel prediction step, which refers to the practice of transportation planning basically in the estimation of future flows without delving in transport phenomena, the interactions between your system and the environment, and the mechanism which leads to these observed results. However, travel behaviour still lacks a formalized theory and suffers from an increasingly atomic division in scientific practice, which limits its feasibility to be applied by a transport professional. Therefore, this doctoral thesis sought to formalize and unify the different behaviour theories in transport in order to strengthen and structure the approach in a robust manner, in order to contribute new solutions to emerging problems and new ways to consolidate scientific practice. To do this Mario Bunge systems ontology was applied as developed by Magalhães (2010). First, we present a review of recent advances in travel behavior literature identifying the main theories and approaches used in scientific practice. Subsequently, the Bunge systems ontology is applied to systematize these theories and approaches. Once systematized and identified the components, the environment, the structure and the mechanism, it was found that the travel behavior approach operates at a reduced transport system. Due to that, a theoretical model of transport intentional behavior was built, which is in a set of processes that describe the operation of the transport system and the individual. In this theoretical model the theories and revised approaches were systematized, resulting in the modeling of different transport phenomenon than currently exists. And it also presented a new concept of bounded rationality of transport subject, which is different from common rational economic agent of the trip-based approach and the Four Step Model. Subsequently, a comparison analysis between the Four Step Model, MATSIM, and the intentional model is performed. Finally, a simulation of Brasilia 2016 is applied in the Four Step Model and MATSIM. The results allowed us to observe the scope and possibilities of two different approaches to simulate the operation of a transportation system. In addition, they present perspectives for future operationalization of the theoretical model developed of transport intentional behavior.
44

ncRNA-Agents : anotação de RNAs não-codificadores baseada em sistema multiagente

Arruda, Wosley da Costa 10 July 2015 (has links)
Tese (doutorado)—Universidade de Brasília, Instituto de Ciências Exatas, Departamento de Ciência da Computação, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2015-12-17T16:33:56Z No. of bitstreams: 1 2015_WosleydaCostaArruda.pdf: 9296287 bytes, checksum: 948dd92adae694c04c1b0c23076481e6 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2015-12-17T17:05:51Z (GMT) No. of bitstreams: 1 2015_WosleydaCostaArruda.pdf: 9296287 bytes, checksum: 948dd92adae694c04c1b0c23076481e6 (MD5) / Made available in DSpace on 2015-12-17T17:05:51Z (GMT). No. of bitstreams: 1 2015_WosleydaCostaArruda.pdf: 9296287 bytes, checksum: 948dd92adae694c04c1b0c23076481e6 (MD5) / Os RNAs não-codificadores (ncRNAs) constituem um importante subconjunto dos transcritos produzidos nas células dos organismos, pois afetam diversos processos celulares. Embora existam métodos computacionais bastante eficazes para identificar proteínas, a anotação de ncRNAs é hoje objeto de pesquisa intensa, pois suas características e sinais não são ainda completamente conhecidos. Neste contexto, nesta tese, apresentamos uma arquitetura para anotação de ncRNAs baseada no paradigma de Sistema Multiagente. A implementação do sistema, denominado de ncRNA-Agents, usa agentes colaborativos, em que cada agente tem conhecimento e raciocínio (simulando os de biólogos) sobre um aspecto específico de RNA, o que contribui para uma anotação curada de ncRNA, com qualidade associada e explicações baseadas nos resultados das ferramentas usadas pelo sistema para recomendar a anotação. Além disso, foram realizados três estudos de casos com os fungos Saccharomyces cerevisiae, Paracoccidioides brasilienses e Schizosaccharomyces pombe, para avaliar o desempenho do sistema quanto a sua capacidade de anotar ncRNAs conhecidos e de predizer novos ncRNAs. Acesso público a esta ferramenta está em http://www.biomol.unb.br/ncrna-agents. ______________________________________________________________________________________________ ABSTRACT / Non-coding RNAs (ncRNAs) are an important subset of the transcripts produced in the cells of organisms, since they affect many cellular processes. Although there are efficient and fast computational methods to identify proteins, annotation of ncRNAs is now focus of intensive research once their characteristics and signals are not yet entirely known. In this context, in this thesis, we present an architecture for ncRNAs annotation based on the multi-agent system paradigm. The implementation of a system, called ncRNA-Agents, uses collaborative agents, where each agent has knowledge and reasonig (simulating biologists) about a specific aspect of RNA, which contributes to a curated ncRNA annotation, with associated quality and explanations based on the results of the tools used by the system to recommend the annotation. In addition, we performed three case studies with three fungi, Saccharomyces cerevisiae, Schizosaccharomyces pombe and Paracoccidioides brasiliensis, to evaluate the performance of the system and its ability to annotate known ncRNAs and predict new ncRNAs. This tool is publicly available at http://www.biomol.unb.br/ncrna-agents.
45

Otimização de negociação dinâmica para múltiplas áreas restritas de fluxo no programa de opções de trajetórias colaborativo

Cruciol, Leonardo Luiz Barbosa Vieira 03 December 2015 (has links)
Tese (doutorado)—Universidade de Brasília, Instituto de Ciências Exatas, Departamento de Ciência da Computação, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-02-23T11:49:20Z No. of bitstreams: 1 2015_LeonardoLuizBarbosaVieiraCruciol.pdf: 50854244 bytes, checksum: 0070371c612d974e47daebc4365ab3dc (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-02-25T12:37:02Z (GMT) No. of bitstreams: 1 2015_LeonardoLuizBarbosaVieiraCruciol.pdf: 50854244 bytes, checksum: 0070371c612d974e47daebc4365ab3dc (MD5) / Made available in DSpace on 2016-02-25T12:37:02Z (GMT). No. of bitstreams: 1 2015_LeonardoLuizBarbosaVieiraCruciol.pdf: 50854244 bytes, checksum: 0070371c612d974e47daebc4365ab3dc (MD5) / A otimização de recursos no gerenciamento de tráfego aéreo é, por si só, um problema computacionalmente complexo. Durante o último ano, foi colocada em operação nos EUA uma evolução de alguns dos atuais programas de gerenciamento de tráfego aéreo, o Collaborative Trajectory Options Program (CTOP), pela Federal Aviation Administration. Esse programa faz parte da iniciativa Next Generation Air Transportation System e possibilita a melhoria dos resultados de negócio pelas companhias aéreas. Existe uma grande dificuldade pelas companhias aéreas, dada pela incerteza inerente ao complexo processo, na definição de quantas rotas devem ser enviadas para cada voo. O desenvolvimento de uma solução que trate de maneira dinâmica, quando o CTOP é iniciado, se mostrou computacionalmente complexa do ponto de vista da modelagem das informações a serem utilizadas. A utilização de uma estratégia errada pode gerar atrasos diversas vezes maiores. Existe uma solução para este problema, na qual foram utilizados algoritmos de busca greedy para apresentar as rotas com menor atraso para uma determinada companhia aérea envolvida no CTOP, porém esta solução não trata a incerteza envolvida ao serem assumidas premissas não reais. Assim, esta tese apresenta um modelo inovador que utiliza sistemas inteligentes para o tratamento de incertezas ao sugerir ao especialista quantas rotas deverão ser enviadas. O processo de disputa apresentado foi dividido em dois níveis. Primeiro, resolvido pelo modelo computacional Single Games for CTOP (SG-CTOP), como realizar a otimização dinâmica e automática do processo de disputa de slots disponíveis para múltiplas áreas restritas de fluxo durante a primeira rodada de negociações, no qual não existe qualquer conhecimento prévio dos seus concorrentes. Segundo, resolvido pelo modelo computacional Repeated Games for CTOP (RG-CTOP), como a estratégia de cada companhia irá afetar a estratégia da outra e possibilitar o aprendizado de reputações adaptando, assim, as estratégias utilizadas nas negociações anteriores. Os resultados alcançados pelos dois modelos se mostraram promissores para as companhias aéreas. Em dois estudos de caso foram gerados 20.000 negociações em CTOP, assim, retratando os mais diversos casos e estratégias utilizadas dentro do CTOP. O modelo SG-CTOP alcançou um desempenho superior, ou igual, em 97% dos casos, quando comparado com as melhores estratégias atuais, reduzindo em 537 horas de atrasos para uma determinada companhia. Quanto ao modelo RG-CTOP, foi alcançada uma taxa de melhoria aproximada de 21%, para uma determinada companhia aérea, ao se considerar o aprendizado e adaptação de estratégias frente aos seus concorrentes na disputa dos melhores slots. / The optimization of resources in air traffic management is a computationally complex problem. During the last year, the Collaborative Trajectory Options Program (CTOP) had started as an operational evolution of current air traffic management programs by Federal Aviation Administration in USA. This program is part of Next Generation Air Transportation System initiative and makes possible to improve airlines' business results. Airlines have a great issue to decide how many routes might be sent for each flight, because of the uncertainty in this complex process. The development of a solution that handle dynamically, as soon as CTOP has started, it was very complex considering the information modeling to be used. A wrong strategy could achieve delays several times greater. There is a solution for this problem, which used greedy algorithms to find out the routes with minimum delay for a specific airline in CTOP. However, this solution does not handle the uncertainty involved once some unreal assumptions are made. So, this thesis presents an innovation model to suggest how many routes should be sent by intelligent systems to handle uncertainties. The negotiation process was divided into two levels. First, using the computational model Single Games for CTOP (SG-CTOP), how to realize a dynamical and automatic optimization in the dispute process of available slots for multiple flow constrained areas during the first negotiation, which there is no previous knowledge about competitors. Second, using the computational model Repeated Games for CTOP (RG-CTOP), how the competitors' strategy could change the strategy of an airline and makes possible to learn by competitors' reputation, adjusting the past strategies. The achieved results by both computational models are promising for airlines. In the case studies, 20.000 CTOP negotiations were generated. Thus, it was studied several cases and strategies used in CTOP. The SG-CTOP achieved a performance better, or equal, in 97% of CTOP negotiations, when it was compared to others strategies, representing a delay reduction of 537 hours for the airline. The RG-CTOP achieved a rate improvement about 21% for an airline, when it was used a learning process by adapting its strategies against competitors to be allocated in better available slots.
46

MADIK : uma abordagem multiagente para o exame pericial de sistemas computacionais

Hoelz, Bruno Werneck Pinto 08 March 2009 (has links)
Dissertação (mestrado)-Universidade de Brasília, Departamento de Ciência da Computação, 2009. / Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2011-11-07T12:36:39Z No. of bitstreams: 1 2009_BrunoWerneckPintoHoelz.pdf: 4633536 bytes, checksum: 8867267a2ff22f5a79c1af6a9656c13f (MD5) / Approved for entry into archive by Elzi Bittencourt(elzi@bce.unb.br) on 2011-11-29T14:12:39Z (GMT) No. of bitstreams: 1 2009_BrunoWerneckPintoHoelz.pdf: 4633536 bytes, checksum: 8867267a2ff22f5a79c1af6a9656c13f (MD5) / Made available in DSpace on 2011-11-29T14:12:39Z (GMT). No. of bitstreams: 1 2009_BrunoWerneckPintoHoelz.pdf: 4633536 bytes, checksum: 8867267a2ff22f5a79c1af6a9656c13f (MD5) / O exame pericial de sistemas computacionais e evidências digitais é uma tarefa complexa que exige habilidades altamente especializadas para identi car, coletar e analisar vestígios importantes para a investigação de um crime. Muitos são os desa os para a realização de um exame satisfatório, uma vez que os recursos humanos e materiais, bem como o tempo disponível, são na maioria das vezes muito limitados. Com isso, nem sempre é possível realizar um exame tão abrangente e completo quanto o desejado. Este trabalho propõe o desenvolvimento e a utilização de um Sistema Multiagente na realização de exames periciais de sistemas computacionais. O sistema proposto, denominado Multi-Agent Digital Investigation toolKit (MADIK), apresenta uma arquitetura baseada na estrutura hierárquica das organizações, dividida em quatro níveis: estratégico, tático, operacional e especializado. Os agentes localizados em cada um desses níveis trabalham de forma distribuída e cooperativa para examinar as evidências digitais relacionadas a uma investigação. Suas descobertas e recomendações são registradas em uma estrutura compartilhada de blackboard, permitindo ao especialista humano avaliar e revisar os resultados obtidos. A estrutura do blackboard permite também que os agentes realizem a correlação de suas descobertas. Este trabalho apresenta a proposta do Sistema Multiagente (SMA), a implementa ção de um protótipo e os resultados obtidos ao longo de vários experimentos. Os resultados obtidos foram muito positivos, com bons níveis de abrangência da análise do conteúdo das evidências e de correlação de vestígios, e com a redução do tempo total necessário para realização dos exames periciais quando comparados a um examinador humano utilizando as ferramentas forenses atuais em um cenário de recursos materiais e tempo limitados. ______________________________________________________________________________ ABSTRACT / The forensic examination of computational systems is a complex task that demands highly specialized skills to identify, collect, and analyze evidence of interest to the investigation of a crime. Many are the challenges on the way to a satisfactory examination, since the resources, both human and material, as well as the time available, are often limited. So it's not always possible to perform an examination as complete as desired. This work proposes the use of a Multi-Agent System in the performing of forensic examination of computational systems. The proposed Multi-Agent System (MAS), named Multi-Agent Digital Investigation toolKit (MADIK) presents an architecture based on the hierarchical structure of organizations, divided into four layers: strategic, tactical, operational and specialized. The agents in each one of these layers work in a distributed and cooperative manner to examine the digital evidence related to the investigation. Their ndings and recommendations are placed in a blackboard shared structure, that allows the human specialist to evaluate and review the obtained results. The blackboard structure also allows other agents to correlate their ndings with others. This work presents the proposed system, a working prototype and the results obtained after a series of experiments. The obtained results where very positive, with good coverage levels in the digital evidence content analysis and correlation of ndings, as well as reduction in the time required to perform the forensic examination when compared to those obtained by a human examiner using the currently available forensic tools in a scenario of limited time and material resources.
47

Effects of a Novel Right Brain Intervention on Stuttering Frequency in Unfamiliar Speech Tasks

Stewart, Chelsea Beatrice 30 June 2016 (has links)
Developmental stuttering persists in approximately 1% of the United States population. Stuttering has been shown to impact overall quality of life. The present study examines the effects of a Novel Right Brain Intervention on two female participants with persistent developmental stuttering. The aim of the study was to determine whether encouraging greater activation of the right hemisphere, specifically the pre-SMA, via complex left-handed movements, prior to speech production, would lead to a reduced stuttering frequency and severity in people who stutter (PWS). It was hypothesized that each participant would reduce stuttering symptoms and behaviors following the intervention due to the results found in patients with non-fluent aphasia's and neural imaging findings with PWS. Following analysis of speech samples taken from unstructured retell and unfamiliar reading tasks, the results revealed decreases in stuttering and secondary behaviors during the unstructured reading task for Participant 1 and decreases in stuttering and secondary behaviors during the unstructured retell task for Participant 2. The results of this study should be interpreted with caution, as this is a pilot study with multiple limitations. With further research, this method of intervention may become a viable option for those who have not benefited maximally from current intervention methods.
48

Role of p38 and STAT5 Kinase Pathways in the Regulation of Survival of Motor Neuron Gene Expression for Development of Novel Spinal Muscular Atrophy Therapeutics

Farooq, Faraz T January 2012 (has links)
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons from the anterior horn of the spinal cord, resulting in progressive muscle atrophy. The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which can compensate in part for the absence of the functional SMN1 gene. I have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 pathway by the bacterial antibiotic anisomycin which stabilizes and increases SMN mRNA levels in vitro. Activation of the p38 pathway by anisomycin leads to cytoplasmic accumulation of HuR protein which binds to the 3’UTR of SMN transcript resulting in increased SMN levels. This opens up a novel potential therapeutic strategy for SMA. I have also identified and demonstrated a significant induction of SMN protein levels in vitro and in vivo upon treatment with FDA approved drug celecoxib, which also activates the p38 pathway. Celecoxib mitigates disease severity along with increasing the lifespan of SMA mice. Sodium valproate, trichostatin A and aclarubicin, all agents which effectively enhance SMN2 expression, have been recently shown to activate STAT5 in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. Given that prolactin is also known to activate the STAT5 signalling pathway, can cross blood brain barrier and is FDA approved, we elected to assess its impact on SMN levels. In this manner, I have demonstrated a significant induction in SMN mRNA and protein levels in neuronal NT2 and MN-1 cells upon treatment with prolactin. I have also demonstrated that activation of the STAT5 pathway by prolactin is necessary for this transcriptional upregulation of the SMN gene. I have found that prolactin treatment induces SMN expression in brain and spinal cord samples and that it ameliorates the disease phenotype, improving motor neuron function and increasing survival in the SMA mouse model. Presently there is no cure for SMA. This study will help in the identification and characterization of potential therapeutic compounds for the treatment of SMA.
49

Návrh automatizovaného obchodného systému na bázi trendových ukazateľov a oscilátorov / Design of an Automated Trading System Based on Trend Indicators and Oscillators

Kucbel, Jozef January 2016 (has links)
The thesis is concerned with the design and optimization of a trading strategy on currency markets in order to maximize profit on the EURUSD currency pair. The strategy is based on standard technical indicators and is tested in demo account environment. The thesis describes the whole development from initial design to an optimized version of the draft.
50

Identification of Modifiers of Spinal Muscular Atrophy

Ruhno, Corey 20 June 2019 (has links)
No description available.

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