Knowledge of genetic predisposition to future illness and disability creates uncertainties that shape and influence life decisions about reproduction, career, health behavior, and the need for care. Current research has not yet identified the meaning of the experience of feeling uncertain among intimate partners of persons who have received genetic information pertaining to future health status. The purpose of this phenomenological study was to understand the meaning of uncertainty as a lived experienced among intimate partners of persons who have tested positive for a mutation in the gene causing Huntington disease (HD) but have not yet been clinically diagnosed with HD. The specific aims were to create a rich, vivid description of uncertainty as experienced by this population and to present these findings within an existential phenomenological perspective. Using van Manen's hermeneutic-phenomenological methodology, experiential descriptions from 10 intimate partners of persons in the prodromal phase of HD were obtained. Thematic aspects of the lived experience of uncertainty were uncovered and isolated; essential themes were determined; and linguistic transformations were composed. The analysis revealed four essential themes, indicating that the meaning of the lived experience of uncertainty was 1) an intangible reality characterized by 2) anticipating with ebbing and flowing disquietude while feeling 3) a weighty pull to dwell upon, towards inner turmoil and 4) a subdued presence with freeing possibilities. The implications of these findings are that nurses need to ensure adequate opportunity is created in which the meaning of the lived experience of uncertainty can be ascertained and explored among persons who are on the cusp of the inevitable but not yet graspable. Continued research is needed to further address the implications of being situated in this potentially fracturing phase of the disease trajectory and to determine appropriate interventions.

This thesis project will explore the landscape site development of fossil fuel steam electric stations as it is presently practiced by electric utility companies, to determine what architectural, engineering, aesthetic, and climatological problems are being created through the engineering requirements acting upon' the site during site development and construction phases of power stations. It will identify typical problem areas that can be resolved by the Landscape Architect through the practical application of landscape architecture principles, the design use and influence of plant material, topography, and the environment. Design criteria will then be formulated for the site development of steam electric stations. The design criteria thus gathered will be applied to a critique of Huntington Canyon Electric Power Plant to determine the effectiveness and degree of success of the criteria.

Les mécanismes sous-tendant la neurodégénérescence aiguë (ischémie cérébrale) et chronique (maladie d'Alzheimer, maladie de Huntington, sclérose latérale amyotrophique), impliqueraient des altérations mitochondriales et des anomalies de transmission glutamatergique (excitotoxicité). La maladie de Huntington (MH) est caractérisée par une neurodégénérescence du striatum. Dans cette structure cérébrale, une diminution de l'activité du complexe II mitochondrial est observée chez les patients. Les mécanismes de la neurodégénérescence induite par l'inhibition du complexe II sont inconnus in vivo et nous les avons caractérisés dans un modèle de rat intoxiqué par l'acide 3-nitropropionique (3-NP). La calpaïne est la protéase majoritairement impliquée dans la mort striatale in vivo en parallèle d'une activation des caspases. De plus, les modèles murins transgéniques de la MH présentent une hyperactivation des récepteurs NMDA (R-NMDA). Les atteintes mitochondriales pourraient de manière synergique, potentialiser les effets toxiques de la dysfonction des R-NMDA. Cependant les mécanismes de cette synergie sont, in vivo, inconnus.<br />Dans la présente étude, nous avons cherché à comprendre comment la mort induite par l'injection intrastriatale de l'acide quinolinique (QA), agoniste des R-NMDA, était potentialisée par le 3-NP, inhibiteur du complexe II mitochondrial.<br />Le 3-NP subtoxique induit une potentialisation de la mort striatale lorsque l'inhibition du complexe II est supérieure à 35%. Le 3-NP seul (sans QA) produit des lésions au-delà de 50% d'inhibition. Entre 35 et 50% d'inhibition, l'utilisation de techniques biochimiques et immunohistochimiques, a permis de démontrer que le 3-NP potentialisait la mort excitotoxique par un facteur 10. Le mécanisme de la potentialisation met en jeu une activation importante de la calpaïne, protéase activée par le Ca2+. L'activation de la calpaïne traduit une élévation délétère de la concentration intracytoplasmique du Ca2+. L'origine du mécanisme calcique de la potentialisation excitotoxique par le 3-NP pouvait sous-tendre l'existence d'une hyperactivation des R-NMDA conduisant à une augmentation de l'influx calcique, et/ou une perturbation de l'homéostasie calcique. Le mécanisme d'augmentation de Ca2+ intracytoplasmique ne semble pas mettre en jeu une hyperactivation des R-NMDA. En effet, le 3-NP ne modifie pas l'entrée de glucose induite par le QA in vivo, ceci traduisant une activation similaire des R-NMDA avec ou sans 3-NP. De plus, l'entrée du 45Ca induite par le QA appliqué sur des cultures primaires de neurones striataux, n'est pas augmentée par le 3-NP, malgré un niveau de calcium intracellulaire augmenté, détecté par imagerie calcique. <br />D'après ces résultats, la potentialisation de mort induite par le QA lorsque le complexe II mitochondrial est inhibé, ne résulterait pas d'une entrée accrue de Ca2+ par les R-NMDA, mais résulterait plus probablement d'une incapacité des neurones à maintenir l'homéostasie calcique. Par ailleurs, la réduction de l'activité du complexe II mitochondrial combinée à l'excitotoxicité pourraient participer à la dégénérescence striatale dans la MH. Ainsi, l'homéostasie calcique constituerait une cible thérapeutique privilégiée.

Polyglutamine-expanded fragments, derived from the human huntingtin protein, are aggregation-prone and toxic in yeast cells, bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline-rich region targets polyglutamine aggregates to the large perinuclear deposit (aggresome). Aggresome targeting ameliorates polyglutamine cytotoxicity in the presence of the prion form of Rnq1 protein, however, aggresome-forming construct remains toxic in the presence of the prion form of translation termination (release) factor Sup35 (eRF3). Disomy by chromosome II partly ameliorates polyglutamine toxicity in the strains containing Sup35 prion. The chromosome II gene, coding for another release factor, and interaction partner of Sup35, named Sup45 (eRF1), is responsible for amelioration of toxicity. Plasmid-mediated overproduction of Sup45, or expression of the Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into prion aggregates, also ameliorate polyglutamine toxicity. Protein analysis indicates that polyglutamines alter aggregation patterns of the Sup35 prion and promote aggregation of Sup45, while excess Sup45 counteracts these effects. In the absence of Sup35 prion, disomy by chromosome II is still able to decrease polyglutamine toxicity. However, SUP45 is no longer the gene responsible for such an effect. Taken together with the finding that the presence of both the Rnq1 prion and the Sup35 prion has an additive effect on polyQ toxicity, one gene or few genes on chromosome II are able to ameliorate polyQ toxicity through a SUP45-independent pathway. The identification of such a gene is currently ongoing. Monosomy by chromosome VIII in diploid heterozygous by AQT (Anti-polyQ Toxicity mutants that are disomic by chromosome II) counteracted the effect of AQT. Similarly, deletion of the arg4 gene in chromosome VIII in AQT haploid was able to eliminate the AQT effect. Moreover, analysis of genes involved in the arginine and polyamine synthesis indicated that loss of genes in later stages of arginine biosynthesis causes increase of polyglutamine toxicity. Deletion of genes arg1, arg4, arg8 (arginine pathway) and spe1 (polyamine pathway) all suppressed the Sup35 prion phenotype expression in the nonsense suppression system. Further analysis regarding the mechanisms behind those effects is needed. Our data uncover the mechanisms by which genetic and epigenetic factors may influence polyglutamine toxicity, and demonstrate that one and the same type of polyglutamine deposits could be cytoprotective or cytotoxic, depending on the prion composition of a eukaryotic cell.

In this dissertation we studied the pharmacological and functional consequences of adenosine A2A receptor interaction with other proteins, as other neurotransmitter receptores localized in the human brain and an important enzyme regulating the extracellular concentration of adenosine, the ecto-ADA (adenosine desaminase). The first aim of this thesis was to study the molecular and functional interaction of A(2A)Rwith ADA. We found out that A(2A)Racted as a membrane anchoring protein of ADA, more exactly, that ADA bound to A2A receptor homomers and induced a strong modification of their quaternary structure in the way it behaved as a positive allosteric ligand. In addition at the functional level, ADA markedly enhanced A2A receptor signalling, increasing the A2A receptor agonist-induced ERK 1/2 phosphorylation. This powerful regulation of A2A function exerted by ADA might have important implications in the physiology and pharmacology of neuronal A2A receptors that are implicated in the striatal motor regulation. The second aim of this thesis was to search for a compound possibly useful in the treatment Huntington´s disease (among other neurological diseases), concretely a more selective antagonist of A2A receptor for presynaptic A1-A2A receptor heteromers versus postsynaptic A2A-D2 receptor heteromers. Applying in vitro and in vivo approaches, we discovered that the A2A receptor antagonists SCH-442416 showed a presynaptically preferential profile and, on the other hand, the KW-6002 behaved as a postsynaptically preferential A(2A)Rantagonist. Other analysed compounds ZM-241385, MSX-2, SCH-420814, and SCH-58261 showed no clear presynaptic or postsynaptic preference, i.e. presented a mixed profiles. The presynaptic preference of SCH-442416 was due to a strong negative cooperativity induced by the physical presence of dopamine D2 receptor in the A2A-D2 receptor heteromer that was detected by the compound SCH-442416. This cooperativity also indicates that A2A-A2A receptor homodimers are present in the A2A-D2 receptor heteromers. In summary, on the basis of their preferential pre- versus postsynaptic actions, SCH-442416 can be used as a lead compound in the development of antidyskinetic drugs in Huntington’s disease, meanwhile KW-6002 confirms to be possibly beneficial in Parkinson’s disease. The third aim of this thesis consisted in investigation of pharmacological and functional properties of A2A receptors in the A2A-CB1 receptor heteromers and determination whether selective A2A receptor antagonists show different selectivity for A2A receptors or A2A-CB1 receptor heteromers. We observed that adenosine A2A receptor changed its G-protein coupling from stimulatory Gs to inhibitory Gi protein when it formed heteromer with CB1 receptor and a synergistic cross-talk in G-protein activation was observed when both receptors were co-activated. At the same time, we saw that CB1 receptor mainly controled the ERK 1/2 signalling under the A2A-CB1 receptor heteromer. The A2A-CB1 receptor heteromers did not show allosteric effects at the ligand binding level. The two specific A2A receptor antagonist, KW-6002 and VER-7835 lost affinity for A2A receptors when expressed in A2A-CB1 receptor heteromers. This all means that A2A-CB1 receptor heteromers constitute a singular unit for adenosine and cannabinoids signalling, introducing diversity in A2A receptor signalling that can be therapeutically relevant in neurological diseases involving striatal neurons. In summary, the results presented in this Thesis show the importance of GPCR heteromers in the brain striatum and their physiological importance for the treatment of neurological diseases. / En esta Tesis hemos estudiado las consecuencias farmacológicas y funcionales de la interacción del receptor A2A de adenosina con otras proteínas, concretamente con otros receptores de neurotransmisores localizados en el cerebro humano y la enzima ecto-adenosina desaminasa. Hemos demostrado que el A2AR actúa como una proteína de anclaje de ADA que se une a los homodímeros de este receptor y a su vez induce una fuerte modificación en su estructura cuarternaria. Esta propiedad hace de ADA un ligando alostérico de los A2AR que modula positivamente la unión de agonistas y antagonistas al sitio ortostérico de este receptor. En segundo lugar, buscamos un antagonista de A2AR potencialmente útil para el tratamiento de la enfermedad de Huntigton, concretamente un antagonista preferencialmente más selectivo para el heterodímero "presináptico" A1R-A2AR versus el heterodímero "postsináptico" A2AR-D2R. Encontramos un compuesto, SCH-442416, que mostró este perfil presináptico, cual fue debido a una fuerte cooperatividad negativa inducida por presencia física del receptor de dopamina D2 en el heterómero A2AR-D2R. Al revés, otro compuesto, KW-6002, mostró un perfil preferencial postsináptico. Por ello, SCH-442416 puede ser utilizado como un compuesto de partida para el desarrollo de fármacos antidiscinéticos para la enfermedad de Huntington, y por su parte KW-6002 comprobó ser posiblemente beneficioso en la enfermedad de Parkinson. En tercer lugar demostramos que el receptor CB1 influye al A2AR cual cambia su acoplamiento de una proteína Gs estimuladora a una Gi inhibidora en el heterodímero A2AR-CB1R y también controla la señalización de ERK 1/2 y que el KW-6002 pierde afinidad por los receptores A2A en este heterómero. En resumen esta Tesis muestra la importancia de heterómeros de receptores acoplados a proteína G en el cerebro y su relevancia fisiológica a la hora de búsqueda de tratamiento para las enfermedades neurológicas.

No description available.

Diss.--Philosophy (Musicology)--Columbia (S.C.)--Univ. of Southern Carolina, 1999. / Bibliogr. p. 99-106.

Thesis (M.A.)--Marshall University, 2009. / Title from document title page. Includes abstract. Document formatted into pages: contains iv, 101 p. Includes bibliographical references p.100-101.

After decades of repression and segregation South Africa managed to break free from the Apartheid era. The year was 1994 when democracy started to prevail in South Africa. That year a truth commission was created in the country to deal with the human rights violations of apartheid. This thesis will analyze the truth commission’s management through three perspectives. These perspectives are the Truth Commission’s, a report by Amnesty International and Human Rights Watch and lastly a theory by Samuel Huntington. The analysis is designed as a case study of the truth commission’s work. This thesis describes the commissions work and the challenges that followed. The purpose of the thesis is to describe and analyze some of the different approaches on South Africa’s process of reconciliation. This has been done to see if there is parallels or possible contradictions between the perspectives and to highlight challenges. The result shows that the perspectives do have split opinions about the commissions work. The Truth Commission aims to bring the country forward in a fast pace, while Amnesty International and Human Rights Watch stands more critical on how the commission chooses to go about. Clear parallels are also shown between Huntingtons theory and the reality of South Africa’s Truth and Reconciliation Commission.

Afin d'analyser le rôle de la plasticité striatale dans la perception temporelle, nous avons réalisé une étude comportementale et électrophysiologique d'un modèle rat transgénique de la maladie de Huntington impliquant la dégénérescence progressive du striatum. Pour ce faire, nous avons élaboré une étude longitudinale (4-15 mois) du suivi de la maladie de Huntington au niveau moteur, motivationnel et temporel, et une étude présymptomatique (4-5 mois) de l'estimation temporelle et électrophysiologique in vivo de la voie préfronto-striatale. Nous avons détecté un dysfonctionnement de la perception temporelle et de la plasticité synaptique de manière présymptomatique, suggérant une corrélation entre ces deux dysfonctionnements. En symptomatique, le comportement temporel discriminatif est plus fortement altéré, corrélat d'une dégénérescence du striatum.