6 research outputs found
Investigating the effect of emetic and aversive compounds on Dictyostelium identifies a novel non-sentient model for bitter tastant research
No full textNausea and vomiting are common but serious side effects associated with many therapeutic drugs. Whilst the physiological mechanisms behind the generation of the vomiting response are well characterised, the range of emetic stimuli that can generate the response are poorly understood. The potential of using Dictyostelium discoideum, a eukaryotic amoeba, as a model for predicting emetic liability was examined in this thesis. The effects of a range of known emetic and aversive compounds on Dictyostelium cell behaviour was investigated, resulting in the identification of a small number that strongly inhibited cell migration in a concentration-dependent and reversible manner. These active compounds included a range of bitter compounds and the pungent taslant, capsaicin. A Dictyostelium mutagenesis screen was then used to identify genes controlling sensitivity to bitter tastants. This screen identified a mutant containing a disrupted grlJ gene as showing partial resistance to phenylthiourea in growth and behavioural changes in movement. GrlJ is a Gprotein coupled receptor that regulates a phenylthiourea-dependent effect by inhibition of a phosphatidylinositol (PIP3) signalling pathway. A search for proteins sharing homology to GrlJ identified an uncharacterised GABAB-like receptor, QaNHA5, involved in the detection of phenylthiourea in Dictyostelium. This thesis has therefore identified Dictyostelium as a potentially useful model for the identification of bitter and pungent tastants. In addition, this thesis has identified the Dictyostelium protein, GrIJ, as well as an uncharacterised human protein, Q8NHA5, involved in the detection of the bitter tastant, phenylthiourea.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Summary Report: Regional Assessment of the Ground-water Resources in Eastern Kankakee and Northern Iroquois Counties
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Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
No full textInvestigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research.
No full textNovel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds--denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers--capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9 ± 4.0 µM) > quinine hydrochloride (IC(50) = 44.3 ± 6.8 µM) > denatonium benzoate (IC(50) = 129 ± 4 µM) > phenylthiourea (IC(50) = 366 ± 5 µM) > copper sulphate (IC(50) = 1433 ± 3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general
A novel human receptor involved in bitter tastant detection identified using dictyostelium discoideum
No full textDetection of substances tasting bitter to humans occurs in diverse organisms including the social amoeba Dictyostelium discoideum. To establish a molecular mechanism for bitter tastant detection in Dictyostelium, we screened a mutant library for resistance to a commonly used bitter standard, phenylthiourea. This approach identified a G-protein-coupled receptor mutant, grlJ−, which showed a significantly increased tolerance to phenylthiourea in growth, survival and movement. This mutant was not resistant to a structurally dissimilar potent bitter tastant, denatonium benzoate, suggesting it is not a target for at least one other bitter tastant. Analysis of the cell-signalling pathway involved in the detection of phenylthiourea showed dependence upon heterotrimeric G protein and phosphatidylinositol 3-kinase activity, suggesting that this signalling pathway is responsible for the cellular effects of phenylthiourea. This is further supported by a phenylthiourea-dependent block in the transient cAMP-induced production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in wild-type but not grlJ− cells. Finally, we have identified an uncharacterized human protein γ-aminobutyric acid (GABA) type B receptor subunit 1 isoform with weak homology to GrlJ that restored grlJ− sensitivity to phenylthiourea in cell movement and PIP3 regulation. Our results thus identify a novel pathway for the detection of the standard bitter tastant phenylthiourea in Dictyostelium and implicate a poorly characterized human protein in phenylthiourea-dependent cell responses
Modelo de implantação de informática na educação segundo uma visão sistêmica apoiada na gestão de mudanças
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia de Produção.O CGI (Comitê Gestor da Internet no Brasil) (2006), PNAD (Pesquisa Nacional por Amostras de Domicílios) (2005) e Censo Escolar (2005) apontam para uma realidade onde, apesar dos recentes esforços de vários governos, aproximadamente, 54% da população brasileira nunca usou um computador e 67% nunca navegou na Internet. Apenas 19% dos domicílios possuem computador e somente 25% das escolas básicas possuem computadores ligados à Internet. A situação é ainda mais grave quando se identifica que, mesmo nas escolas com conexão e computadores, muitas das salas de informática ficam trancadas e tornam-se alvo de sucateamento e furto de equipamentos, em geral, pela falta de formação dos professores ou pela ausência de uma política educacional que pressuponha as tecnologias de informação e comunicação (TIC ) como instrumento pedagógico. A democratização do acesso aos produtos tecnológicos e a inclusão digital é um desafio para a sociedade atual e requer esforços e mudanças na área educacional. Este trabalho visa o desenvolvimento e experimentação de um modelo sistêmico de informatização educacional de escolas, que enfatize a implantação da informática educacional em uma abordagem de gestão de mudança, através de ações voltadas ao contexto especifico do ambiente de atuação, de maneira a gerir e integrar aspectos sociais, gerenciais e tecnológicos que contribuam, direta e indiretamente, para a mudança desejada. Nesse processo de integração, a estratégia de incorporação tecnológica leva em conta a visão social da organização, evidenciando o entendimento da escola como um sistema sócio-técnico. Nesta visão, é através da integração dos elementos da comunidade escolar que se viabiliza que as TIC consigam adquirir um estatuto de instrumento educacional, sendo internalizadas pelos atores do processo ensino-aprendizagem. Neste modelo, o enfoque sistêmico, pressupõe uma constante validação e atualização (auto-regulação), onde é possível recuperar defasagens oriundas de momentos anteriores do processo através de um constante feedback. O modelo e as nuances permitem balizar decisões no momento de definição, implantação, acompanhamento e repetição do processo. The CGI (Brazil Internet Management Committee) (2006), PNAD (National Research for Sample Home) (2005) e School Census (2005) point to a reality where, although the recent efforts of some governments, 54% of Brazilian people never used a computer and 67% never accessed the Internet. Only 19% of the homes have a computer and only 25% of the basic schools have computer with access to the Internet. The situation is even more serious when is identified that even in the schools with connection and computers, many of the computer rooms are locked and become target of trashing and equipment robery, usually, because the lack of formation of the teachers or the absence of educational politics that understand the technologies of computer science and communication as a pedagogical instrument. The democratization of the access to the technological products and the digital inclusion are a challenge to the current society and require efforts and changes in the educational area. This work aims at the development and experimentation of a systemic model of educational computerization of schools, that emphasizes the implantation of educational computer science in focus of change management, through actions faced to the specific context of the working environment, in way to manage and integrate social aspects, managemental and technological, that contribute direct and indirect ways, to the desired change. In this process of integration, the strategy of technological incorporation care about the social vision of the organization, evidencing the understanding of the school as a system partner-technician. In this vision, it is through the integration of the elements of the school community that makes possible that the technologies of computer science and communication achieve a statute of educational instrument, being internalized for the actors of the process teach-learning. In this model, the systemic approach, estimates a constant validation and update (self-regulation), where is possible to recover from imbalance derived from previous moments of the process through a constant feedback. The model and its variables allow to demarcate decisions in the definition moment, implantation, accompaniment and repetition of the process
