Copan Altar Q: Network of Narratives Depiction of Kings

Located in Honduras, Copan is one of the most studied Maya cities. Copan Altar Q in particular helped Mayanists to understand the lineage of the city\u27s sixteen kings from the lineage\u27s Founder K\u27inich Yax K\u27uk\u27 Mo\u27 to Yax Pasaj Chan Yopaat. This thesis project delves into an assortment of the monuments and depictions of the Classic Period - roughly 426 - 822 - kings to pursue the narrative trends and motifs through their reign. Through the website format, this project allows the user to follow the links between monuments, structures, biographies of kings, and glossaries to put these narratives into conversation with each other. The introductory essay provides an explanation into the process and reasoning behind the website development process before providing a brief overview of content. The Appendix contains a copy of the content pages from the website

Adenovirus Specific T-Cell Responses in Humans Following Natural Infection and Vaccination

The adenovirus (Ad) vector is an attractive candidate for vaccines designed to elicit cellular immunity as studies in animals and humans have proven Ad vectors are capable of inducing large transgene-specific T-cell responses. However, given that natural infection by Ad is prevalent globally, pre-existing Ad immunity is a major impediment to the use of recombinant Ad-based vaccines. Though the prevalence of pre-existing neutralizing antibodies has been well characterized, there is a lack of information on the functionality and phenotype of Ad-specific T-cell responses among heterogeneous human cohorts. The lack of protection and possible increased risk of HIV infection in the Merck Ad5 HIV vaccine STEP trial further highlights the need to understand vector-specific immunity in order to produce safe, effective Ad-based vaccines. We aimed to characterize Ad-specific T-cell responses in humans following natural infection and vaccination. Ad-specific T-cell responses were measured by stimulating peripheral blood mononuclear cells (PBMCs) with whole Ad vector or overlapping Ad hexon peptide pools. PBMCs were obtained from 17 healthy adults to study natural infection and longitudinally from 40 participants in Merck phase I Ad5 HIV vaccine studies, 10 of which were enrolled in the STEP trial precursor study using the same vector, dosing, and schedule used for the STEP study. T-cell phenotype and functionality were measured by polychromatic flow cytometry. We found that both CD4+ and CD8+ Ad5-specific T-cells were universally present in subjects independent of their serostatus. Ad5-specific CD8+ T-cells exhibited an effector phenotype and produced the effector functions MIP1α and perforin whereas Ad5-specific CD4+ T-cells had an effector memory phenotype producing IL-2, IFN-γ and TNFα. Ad5-specific T-cells recognized both conserved and variable hexon epitopes making them highly cross-reactive with chimpanzee serotypes. Upon Ad5-based vaccination, Ad5-specific CD4+ T-cells were only transiently expanded and there were no differences in activation or mucosal homing marker expression between Ad5-seronegative and Ad5-seropositive subjects. These data suggest the increased risk of HIV infection observed in the STEP trial was not a result of Ad5-specific CD4+ T-cells. Ad5-specific CD8+ T-cells were also transiently expanded by Ad5-based vaccination, however, there were no changes in functionality. Together, these data suggest though pre-existing Ad-specific T-cells may reduce vaccine efficacy, they should not represent a safety concern for the use of Ad-based vaccines

Development of novel adenoviral vectors to overcome challenges observed with HAdV-5 based constructs

Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in pre-clinical models and clinical trials over the last two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread pre-existing immunity have been shown to significantly impede the effectiveness of HAdV-5 mediated gene transfer. It is therefore that the in depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

A Regional Weapon of Choice: Forum Choice in International Trade Disputes

What explains a state’s choice to utilize a regional dispute settlement mechanism to resolve a trade dispute with another state instead of the global, multilateral forum of the World Trade Organization (WTO)? I argue that experience in regional dispute settlement mechanisms (DSMs) provides the opportunity for learning about the phases and specifics of the regional dispute resolution process. By learning through previous regional dispute experience, a state is able to generate a more accurate assessment of the expected outcome, costs, and value of bringing a current dispute to a regional forum and, thus, which forum is more preferred. However, I hypothesize that the extent of learning varies. I expect that the effect of previous regional dispute experience on future decisions to utilize a regional forum, given that a multilateral alternative exists at the WTO, is conditioned by a state’s learning capacity. This conditional effect is due to variation in the ability and incentive of a state to learn. Each is measured by a state’s available resources, i.e., its level of development and the economic relationship of the disputing dyad. I posit that the learning that occurs makes these DSMs stumbling blocks toward multilateral trade dispute resolution. I test my expectations using newly-collected original data on the initiation of and rulings issued by the dispute settlement bodies associated with the Andean Community (CAN), Central American Common Market (CACM), Common Market of the South (CACM), North American Free Trade Agreement (NAFTA), and the World Trade Organization (WTO) between 1995 and 2010. I find that previous regional dispute experience increases the likelihood of initiating a current regional dispute in a particular subject area, relative to initiating a WTO dispute. In line with my expectations, I also find that the effects of previous experience vary. The effects of previous experience are conditioned by a state’s learning capacity and the amount of previous experience. These results are robust to different conceptualizations of previous experiences and model specifications. The findings of this project demonstrate that the regional dispute settlement mechanisms act as a stumbling block toward multilateral trade dispute resolution

The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice

DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability. Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation. Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity. We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation-sensitive germline genome-defence genes: Tex19.1. Tex19.1 appears to play an important role in placenta function as Tex19.1(−/−) mouse embryos exhibit intra-uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells. Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19.1(−/−) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19.1. This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease

Vaccination with Ad5 Vectors Expands Ad5-Specific CD8+ T Cells without Altering Memory Phenotype or Functionality

Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8(+) T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8(+) T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8(+) T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8(+) T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8(+) T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8(+) T-cells.These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8(+) T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].ClinicalTrials.gov NCT00849680[http://www.clinicaltrials.gov/show/NCT00849680]