Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Additional advisors: Frank Amthor, Claudio Busettini, James Cox, Rosalyn Weller. Description based on contents viewed July 27, 2009; title from PDF t.p. Includes bibliographical references (p. 104-113).

Thesis (M.S.)--University of Wisconsin-Madison, 1962. / Includes bibliographical references (leaves 22-23).

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia Química / Made available in DSpace on 2012-10-23T03:11:35Z (GMT). No. of bitstreams: 1 247605.pdf: 3533548 bytes, checksum: f52fb43b7970aacdfbccf7b62930e6a6 (MD5) / O processamento da informação pelo cérebro é uma das principais questões científicas da nossa época. Ele é um tema complexo que exige avanços em vários níveis de conhecimento. Em um destes níveis, o da neurociência sistêmica, é estudado o comportamento de sistemas de neurônios. Duas das principais dificuldades neste estudo são a concepção da topologia da rede e a seleção das propriedades fisiológicas que influenciam a sua dinâmica. Ambos compõem o objetivo deste trabalho. É proposta uma rede neuronal fisiologicamente plausível, RNFP, na qual a estrutura e a dinâmica reproduzem um conjunto de dados fisiológicos considerados significativos. A rede é aplicada ao sistema visual primário do macaco rhesus, via reconhecimento da forma dos objetos. A estrutura da rede reproduz a complexidade das ligações entre as camadas do V1 e leva em conta a posição espacial relativa de cada uma das sinapses. As dimensões das árvores dendríticas e axônicas e as velocidades do sinal em cada uma delas são usadas para a discretização temporal no programa computacional. Entre as propriedades que influenciam a sua dinâmica estão o potencial excitatório pós-sináptico, a constante espacial da membrana, e o período refratário. A estrutura computacional é construída de maneira a atender às necessidades de memória e à capacidade de processamento dos computadores disponíveis. Os estímulos aplicados na retina se refletem no sistema visual primário na forma de avalanches e ondas de atividade. Os padrões de resposta são semelhantes aos obtidos experimentalmente com sistemas de neurônios excitatórios e mostram que a rede funciona na região crítica.

Esta dissertação apresenta um estudo seguido de tradução da tragédia Reso, tradicionalmente atribuída a Eurípides. No estudo, busca-se comparar o tratamento dado na peça ao mito de Reso e ao tema da astúcia (mêtis) com aquele presente em Ilíada X, tomando-se Odisseu como figura central: a partir dele, são abordados, por semelhança e dessemelhança, as demais personagens da peça e a visão de mêtis que cada uma tem ao longo da trama, além da estrutura da tragédia e as relações existentes entre os planos humano e divino. O objetivo principal é mostrar que os dois textos estão bem inseridos nos seus respectivos períodos e ilustram certa transformação no status do conceito estudado. / This research presents a study followed by a translation of Rhesus, a tragedy traditionally attributed to Euripides. In the study, we aim at comparing the treatment the play gives to Rhesuss myth and the theme of cunning intelligence (mêtis) with that presented by Iliad X. Taking Odysseus as the central figure, we make an approach (through similitude and dissimilitude) of the other characters of the play, as well as of the view concerning mêtis that each of them expresses in the action, the structure of the play and the relationship between men and gods. Our main purpose is to show that both texts are well inserted in their respective periods and illustrate some change in the status of the concept of mêtis.

L’hallux de l’humain (plus couramment appelé gros orteil) est aujourd’hui aligné avec les autres orteils ce qui rend son opposition aux autres orteils impossible. Il a été proposé que la perte de l’opposabilité de l’hallux, chez les premiers hominines, aurait mené à une augmentation des coûts liés à la maternité, due à l’obligation de transporter activement les juvéniles lors de longs trajets (Tanner & Zihlman 1976 ; Wall-Sheffler 2007 ; Watson et al. 2008). Cela suggère que l’Australopithecus afarensis devait transporter activement son juvénile car il ne pouvait pas se maintenir par lui-même lors des transports. Mon étude propose de vérifier cette hypothèse en déterminant si un primate juvénile a besoin de son hallux pour s’accrocher au poil de sa mère. Les deux hypothèses de ce travail sont donc les suivantes : L’abduction de l’hallux est nécessaire à la préhension du poil d’un porteur (généralement la mère) par les jeunes macaques et l’abduction de l’hallux n’est pas nécessaire à la préhension du poil d’un porteur (généralement la mère) par les jeunes macaques lors des transports. L’observation de vidéos de dyades mère/enfant de macaques rhésus vivant en liberté à Cayo Santiago (Costa Rica) filmées sur une période de cinq mois, tend à supporter mon hypothèse. En effet, les résultats de mon étude montrent que les macaques rhésus sont capables de s’accrocher, et se maintenir, par eux-mêmes à leur mère durant les transports sans se servir de leur hallux. Il serait cependant nécessaire de compléter cette étude par des recherches supplémentaires pour inférer avec plus de confiance ce type de comportement à l’A. afarensis. / The human hallux (more commonly called big toe) is now aligned with the other toes, which makes its opposition to other toes impossible. It has been proposed that the loss of opposability of the hallux in early hominins would have led to increase the energetic costs related to maternity, due to the obligation to carry juveniles actively (Tanner & Zihlman 1976; Wall-Sheffler 2007, Watson et al. 2008). This implies that Australopithecus afarensis juveniles had to be actively transported instead of grasping their mother's hair. My study proposes to test whether a juvenile primate needs its hallux to cling to the hair of its mother. The two hypotheses of this work are as follows: The abduction of the hallux is essential for the grasping of the hair of a carrier (usually the mother) by the young macaques and the abduction of the hallux is not necessary for the grasp of the hair of a carrier (usually the mother) by young macaques during transport. Videos of mother/child dyads of rhesus macaques are used in this study to evaluate the use of the hallux in juveniles being carried. The macaques are from a free-range colony in Cayo Santiago, Costa Rica, and they were filmed over a 5-month period. Results tend to support my hypothesis. Indeed, rhesus macaques are able to cling and maintain themselves on their mother during transport without using their hallux. It would, however, be necessary to supplement this study with further research in order to infer this type of behavior in A. afarensis.

In contrast to most teleost fish that are ammoniotelic, the gulf toadfish (Opsanus beta) is both facultatively ureogenic and ureotelic. In vivo pharmacological manipulations were used to show that lowering circulating cortisol levels or blocking glucocorticoid receptors (GR) enhanced both urea excretion and urea pulse size. These findings demonstrated that changes in pulsatile urea excretion in the toadfish are mediated by the permissive action of cortisol through GRs. Measurement of urea transport across isolated basolateral gill membranes revealed a cortisol-sensitive carrier mechanism. Cortisol infusion in vivo significantly reduced urea transport capacity, suggesting that cortisol inhibits the recruitment of urea transport proteins (UT) to the basolateral membrane to ultimately decrease the size of the urea pulse in toadfish. A 1.2 kb fragment of the upstream transcription start site for the toadfish urea transporter (tUT) gene was isolated and in silico analysis revealed the presence of several putative glucocorticoid response element (GRE) half sites. Toadfish provided with this regulatory sequence in a reporter gene construct showed increased reporter gene transcription driven by cortisol. The data indicated that cortisol-mediated upregulation of tUT mRNA by GREs may be necessary to maintain tUT activity. Four Rhesus (Rh) glycoproteins (Rhag, Rhbg, Rhcg1, Rhcg2) were isolated from toadfish; these sequences grouped with those of other vertebrates coding for membrane channels that transport ammonia. In vivo increases in circulating cortisol reduced branchial Rh glycoprotein expression and decreased ammonia excretion. These changes were accompanied by cortisol-induced increases in glutamine synthetase activity, an enzyme that captures ammonia for urea synthesis. Taken together, the data indicated that cortisol reduces the loss by branchial excretion of ammonia, instead favouring biochemical pathways that convert ammonia to urea. This thesis confirms that nitrogen excretion in toadfish is controlled and regulated in fashions unlike those in other teleosts. The results demonstrate the importance of the GR signaling pathway in mediating changes in both urea and ammonia transport through molecular mechanisms. As a whole, the data provide a new understanding of branchial nitrogen excretion in the gulf toadfish and enhance our evolutionary perspective of the integrated biological systems involved in nitrogen excretion in fish.

Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus monkeys with three aims. One aim determined the utility of N-methyl D-aspartate (NMDA) receptor antagonists to selectively enhance MOR agonist antinociception. A second identified the pharmacological determinants of antinociceptive interactions between a nociceptin opioid peptide (NOP) receptor agonist and MOR agonists. A third aim investigated the potential for fixed-proportion mixtures of a competitive MOR antagonist and MOR agonist to manipulate antinociceptive efficacy. Experimental results did not support the utility of NMDA antagonists as adjuncts to selectively enhance MOR agonist antinociception. Furthermore, the antinociceptive interactions between a NOP agonist and MOR agonists were modest and occurred under a narrow range of conditions. Finally, fixed proportion MOR antagonist-agonist mixtures were effective in manipulating antinociceptive in vivo efficacy. In conclusion, this dissertation does not provide strong empirical evidence that a combination therapy approach will result in clinically effective and selective enhancement of MOR agonist analgesia. The dissertation concludes with proposed strategies and novel preclinical methods to enhance preclinical-to-clinical translation of effective candidate analgesics.

BACKGROUND: Natural killer (NK) cells are traditionally considered part of the innate immune system but have recently been shown to possess adaptive qualities similar to T cells in response to an infection with a pathogen. In addition to possessing adaptive features, NK cells have also been found to reside in different organs such as the liver, spleen, and lymph nodes and differ based on phenotypic markers and their responses to different cytokines. Utilizing these findings, several groups have isolated and identified CD49a as a marker for tissue-resident NK cells. In the liver, CD49a has also been shown to be a positive indicator for NK cell memory-like responses in murine models. Building off work that demonstrated antigen-specific responses in rhesus macaques, this project focuses on characterizing the phenotypic markers and functional profile of CD49a+ NK cells in non-human primates. To better understand the role of CD49a in memory-like NK cells outside of the liver, this project utilized spleen samples from rhesus macaques infected with SIV/SHIV. This work aims to help us better understand the dysfunction NK cells experience as a result of HIV-1 infection in humans and also to demonstrate the changes NK cells experience as the disease progresses. A thorough understanding of the adaptive capabilities of NK cells can pave the way for targeted therapies to increase NK cell antiviral activity in HIV and other infections. METHODS: To characterize the functional and phenotypic profiles of CD49a+ NK cells by multiparameter flow cytometry, thirteen samples of spleen from rhesus macaques were thawed and then stained with two different protocols. A phenotyping protocol involved staining with antibodies against surface markers as well as intracellular markers T-Bet and Eomes. For the functional characterization protocol, the same thirteen samples were stained intracellularly after being stimulated with a cocktail of PMA and ionomyocin. The antibodies used in this were for functional markers. Of the thirteen samples used, six were infected with SHIVSF162P3, two were infected with SIVmac239X, and the remaining five were uninfected. After staining, these samples were analyzed on an BD LSRII from BD Biosciences. The data obtained were then analyzed using FlowJo software to study NK cells, which were characterized as CD45+CD14-CD20-CD3-CD159+. RESULTS: The analysis compared NK cells with T cells, B cells, and NKB cells. Some increases were seen among CD49a+ NK cells in the frequency of CD336+ (NCR2/NKp44), CD337+ (NKp30), and CD366+ (Tim-3) after infection. Although there were some mild increases in CD107a and TNF- in infected samples compared to uninfected, a significant increase was observed in the frequency of IFN-ɣ among infected CD49a+ NK cells compared to uninfected. CONCLUSION: When comparing samples that were infected vs uninfected, it appears there were some mild decreases after infection in the ratio of NK cells to other lymphocytes. In addition, there did not appear to be a significant increase in the frequency of CD49a+ among these NK cells as a result of the infection. However, among the CD49a+ subpopulation, there were some observed non-significant decreases in CD56-CD16+ cells. Furthermore, there was found to be an almost significant increase in TNF- (p = 0.06) among CD49a+ cells after infection. These findings demonstrate an increase in cytotoxic activity in splenic NK cells associated with an adaptation to the virus. Although there does not appear to be significant changes in the ratio of NK cell populations in the spleen, the changes observed in phenotypic and functional markers associated with CD49a+ demonstrate an increase in the cytotoxic activity of NK cells as a result of infection with SIV/SHIV. However, it remains to be seen if CD49a is a direct indicator of this type of infection. Future work geared toward memory-like NK cells in non-human primate splenic tissue could look at the contrast in CD49a+ NK cells from different states of infection with HIV-1 and/or SIV (acute vs chronic) to better understand the integrin’s role in adaptation.

Cognitive decline is one of the most common symptoms from neuropathology as well as a part of natural aging. While there may be a number of factors that contribute to age-related cognitive decline, previous research has shed a light on the role of chronic hypertension. The effect of hypertension on cognitive decline through small vessel disease is referred to as Vascular Cognitive Impairment and Dementia (VCID). However, the exact molecular pathology behind VCID is not very well understood. Using a non-human primate model of hypertensive aging with the Macaca mulatta, (more commonly known as the Rhesus Macaque) this project builds on previous research implicating collagen IV as part of the cascade of molecular changes that occur in VCID. This project evaluated collagen IV thickness around blood vessels in the corpus callosum and cingulum bundle of normotensive and hypertensive monkeys. as well as determined vessel properties such as total vessel area and perimeter length to evaluate the relationship to scores from the subjects cognitive testing batteries. The results from this project will allow for an examination of the effects on hypertension on vascular properties and possible mechanisms for the development of cognitive impairments. Data collected from this research shows significant differences of collagen IV thickness in the Corpus Callosum between hypertensive and normotensive groups. Similarly, in the cingulum bundle we see that the difference between these groups in collagen IV thickness is trending towards significance. The relationship between average collagen IV densities, blood pressure at perfusion, and cognitive testing scores also showed trending relationships in both the cingulum bundle and the corpus callosum. These results demonstrate how prolonged hypertension can negatively influence cognitive abilities and implicates increases in collagen IV around small vessels in white matter as a significant factor in the molecular cascade which results in cognitive impairment.

Evidence suggests that certain genotypic variants associated with novelty-seeking and aggressiveness, such as the 7-repeat dopamine D4 receptor variant (DRD4-7R), short (s) allele of the serotonin transporter (5-HTT), and the low-activity variant of the MAOa promoter (MAOa-L), are more prevalent in human groups that radiated out of Africa than human groups that remained in Africa. Rhesus macaques (Macaca mulatta), like humans, are a widespread species of primates that needed to adapt to different regional environments with one group, Indian-derived rhesus macaques, largely occupying predictable and resource-rich environments, while the other group, the Chinese-derived rhesus macaques, has come to occupy less predictable and resource-abundant environments. Rhesus macaques possess orthologues of these trait-related genes, making it possible to compare the frequency of genotypes associated with these traits between members of two strains. DNA was obtained from N=212 rhesus macaques (n=54 Chinese-derived, n=158 Indian-derived) and genotyped for DRD4 (n=98), 5-HTT (n=190), and MAOA (n=97). Analyses showed that Chinese-derived subjects exhibited higher frequencies of the DRD4-7R and 5-HTT-s-allele when compared to Indian-derived subjects. There were no strain differences in MAOA-L genotype groupings, but the Chinese-derived subjects exhibited a more frequent high-activity (MAOA-H-6R) allele when compared to the Indian-derived subjects. The results suggest that the Chinese-derived rhesus macaques possess a higher frequency of alleles associated with novelty-seeking, impulsivity, and aggressiveness compared to their Indian-derived peers and that those genotypically-mediated traits may have beneficial to both humans and rhesus macaques as they spread into novel and unfamiliar environments.