Browsing by Subject "Primates"
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Item Clonotypic Analysis of CMV-Specific CD4+ T Cells in Human and Nonhuman Primates(2005-05-04) Bitmansour, Arlene Diana; Picker, Louis J.Cytomegalovirus (CMV) is a complex pathogen with the ability to persist in a host via mechanisms of immune evasion. CD4+ T cells are known to play a role in maintaining life-long immunity against CMV; however, the cellular requirements for establishing and maintaining protection against CMV disease have not been characterized. The objective of this work was to understand the nature of a protective CD4+ T cell memory response in primates using CMV as a model viral pathogen. First, we characterized the clonotypic hierarchy of an established CMV-specific CD4+ memory T cell response in human subjects and Rhesus macaques (RM). In both we found that long-term CD4+ memory responses to CMV are characterized by highly skewed clonotypic hierarchies, and these hierarchies remained stable over the months examined. We then used the RM model to elucidate the evolution of the CMV-specific CD4+ clonotypic hierarchy during and after primary infection. The clonotypic composition of an emerging CMV-specific response during a primary infection was strikingly diverse. Third, we reinfected the RM and found that reinfection with CMV recruited new clonotypes into the response, further increasing clonotypic complexity. Taken together, these data indicate the CMV-specific CD4+ T cell response undergoes an evolution during primary and secondary infection and includes the generation of a large initial repertoire, followed by selection of a few dominant clonotypes. In chronic infection, stable oligoclonal hierarchies predominate, suggesting that long-term surveillance for CMV reactivation or reinfection is mediated by a small number of clones, which are maintained at higher frequency. Having found these large single clonotype responses to CMV, we examined T cell receptor (TCR) activation requirements at the level of single clonotypes. We found that single clonotypes have heterogeneous activation thresholds and the activation thresholds for elaborating IL-2 and IFN-gamma differed. Finally, we found that the threshold heterogeneity within a clonotype was independent of CD27 expression.Item A simulation approach to studying the relationship between landscape features and social system on the genetic structure of a tamarin primate population(2013-05) Valencia Rodriguez, Lina Maria; Di Fiore, Anthony, Ph. D.Landscape genetics is an emerging field that seeks to understand how specific landscape features and microevolutionary processes such as gene flow, genetic drift, and selection interact to shape the amount and spatial distribution of genetic variation. This study explores, through agent based simulations, how the specific mating and social system of tamarin primates (genus Saguinus) influences population genetic structure and patterns of relatedness within and among groups of this primate species, which might affect the ability of landscape genetic studies to detect the effects of fragmentation on gene flow. I use a spatially-explicit agent-based population genetics simulation model (GENESYS) configured to reflect the particular social system of tamarin monkeys (i.e. small group size, limited numbers of breeders per group, frequent twin births, and short dispersal distances) to assess whether the isolation by distance model of genetic differentiation expected in an unfragmented landscape can be distinguished from the isolation by barrier model expected in a fragmented landscape. GENESYS allows a user to explore the effects of social structure and landscape features on the population genetic structure of social animals, such as primates. I simulated two different landscapes containing an otherwise equivalent population of tamarins. In the first setup I simulated a homogeneous landscape unconstrained by any barriers to gene flow, while for the second setup, a barrier to gene flow restricted dispersal from one half of the landscape to the other. I found that the particular mating system of tamarin results in the rapid genetic differentiation of its social groups and consequently its populations. Social groups in the continuous landscape indeed revealed an isolation by distance pattern, while social groups on the fragmented landscape yielded instead an isolation by barrier model, where the barrier rather than geographic distance per se influenced the spatial genetic structure of the population. The results from this study suggest that features of the tamarin social system influence population genetic structure, which could affect the ability of landscape genetic studies to detect the effects of fragmentation on gene flow. To more fully address that issue, future studies should focus on a range of different primate social systems.Item Strategies for deciphering the genome(2014-12) Lou, Dianne In-Hye; Sawyer, Sara L.; Press, William H; Paull, Tanya T; Sullivan, Christopher S; Ehrlich, Lauren IR; Miller, Kyle MThe development of highly sophisticated technologies has ushered in the era of the genome. Most importantly, high-throughput sequencing technologies has vastly expanded the number of available genome projects of many different organisms. One of challenges that we now face is in understanding the information encoded within these genomes. Within each chapter of this dissertation, information from existing genome projects are used to answer fundamental biological questions related to human disease and an attempt to further advance new technologies is made. In chapter 2, I describe a novel method that decreases the error rates associated with next-generation sequencing technologies, allowing for the investigation of more complex and heterogenous samples relevant to many biological systems. In chapter 3, I use available primate genome projects to understand the evolutionary trajectory of two DNA repair genes, whose defect increases the development of breast and ovarian cancers. Finally, in chapter 4, wild-type primate alleles are used as tools to uncover novel mechanisms in the lifecycle of viruses. Although seemingly non-overlapping, each of these studies is centered around using the sea of information that is now readily available in order to decipher the many secrets encoded by genome.Item The structure and function of trabecular bone in the femoral head of strepsirhine primates(2001-05) Ryan, Timothy Michael; Kappelman, John W.It has been hypothesized for over a hundred years that trabecular bone plays an important structural role in the musculoskeletal system of animals and that it dynamically responds to applied loads through growth. The objectives of this project are to quantify the three-dimensional structure of femoral head trabecular bone in a sample of extant strepsirhines, to test the functional significance of structural variation, and to assess the utility of femoral head trabecular structure for reconstructing the locomotor behavior of extinct primates. The bone volume fraction and fabric anisotropy of trabecular bone in the femoral heads of Cheirogaleus major, Avahi laniger, Galago senegalensis, Galago alleni, Loris tardigradus, Otolemur crassicaudatus, and Perodicticus potto were quantified in three dimensions using serial high-resolution x-ray computed tomography scan data. Significant structural differences were found between the predominantly leaping galagines and indriids and the non-leaping lorisines and cheirogaleids. The leapers in general have relatively anisotropic trabecular bone and the galagines display a unique pattern of increasing anisotropy and decreasing bone volume moving from the superior to the inferior half of the femoral head. By contrast, the non-leaping taxa possess relatively uniform and isotropic bone throughout the femoral head. To test the functional significance of structural differences between the leaping and non-leaping taxa, finite element models of the femoral head trabecular bone in Loris and Galago were constructed. Tissue stresses and strains in the Galago increased as the loading direction shifted from a more superior to a more ventral position, suggesting that the relatively anisotropic bone in this taxon is not optimally designed for significant loads varying off of a generally superoinferior axis. Stress and strain values were higher for both taxa in models with significantly decreased bone volume and connectivity among trabeculae, corroborating the hypothesized structural importance of trabecular bone. Analyses of two Eocene primate taxa – Omomys carteri and Shoshonius cooperi – demonstrate the utility of trabecular bone analyses for determining the possible locomotor behaviors of extinct taxa. Omomys has trabecular bone most similar to modern generalized quadrupedal forms like P. potto while Shoshonius has trabecular bone most like that of the leaping galagos.