No description available.

<p> We look for time-dependent solutions to a general class of supergravity models in an arbitrary amount of dimensions. Previously, many static solutions of these models have been found and studied, of which a subclass of these solutions support membrane-like configurations. While many properties of these solutions are known, their dynamics - and therefore stability - are not. We follow this motivation, and investigate the possibility of time dependent solutions that will also support this membrane configuration. Under various conditions, it turns out this is the case, bringing a better understanding to the stability of these branes. In addition, the form of the time dependence found suggest possible applications of supergravity to cosmological models.</p> / Thesis / Master of Science (MSc)

No description available.

No description available.

When unreplicated or damaged DNA is present, cell cycle checkpoint pathways cause cell cycle arrest by inhibiting cyclin-dependent kinases (Cdks). In Xenopus laevis, early embryonic development consists of twelve rapid cleavage cycles between DNA replication (S) and mitosis (M) without checkpoints or gap phases. However, checkpoints are engaged in Xenopus once the embryo reaches the midblastula transition (MBT). At this point, the embryo initiates transcription, acquires gap phases between S and M phases, and establishes a functional apoptotic program. During the cell cycle, there are two main checkpoints that regulate entrance into S and M phases. The focus of this study is the role of protein kinase Chk1 and the phosphatase Cdc25A in the DNA replication checkpoint. In the absence of active Chk1, Cdc25A activates cyclin dependent kinases (Cdks) allowing the cell to progress into S or M phase. Chk1 regulates cell cycle arrest in the presence of unreplicated DNA in somatic cells by phosphorylating Cdc25A and leading to its degradation. Chk1 is also transiently activated at the MBT in Xenopus laevis embryos, even when there is no block to DNA replication or damaged DNA. One goal of this work is to understand the developmental role and regulation of checkpoint signaling pathways due to its monitoring of DNA integrity within the cell. Chk1 plays a critical but not fully understood role in cell cycle remodeling and early embryonic development. In order to understand the function and regulation of Chk1 in checkpoints, the features of the MBT that activate Chk1 must be identified. The activation of Chk1 by two time-dependent events in the cell cycle, the critical nuclear to cytoplasmic (N/C) ratio and the cyclin E/Cdk2 maternal timer are explored in this study. Embryos treated with aphidicolin, resulting in a halted replication fork and therefore a reduced DNA concentration, were tested for Chk1 activation and Cdc25A degradation. Chk1 and Cdc25A were observed to undergo activation and degradation, respectively, in embryos with a reduced DNA concentration. In addition, embryos were injected with Δ34Xic cyclin E/Cdk2 inhibitor, in order to disturb the maternal timer and tested for Chk1 activation and Cdc25A degradation. Both Chk1 and Cdc25A were unaffected by the disruption of the cyclin E/Cdk2 maternal time in the embryo. Therefore, the N/C ratio and the cyclin E/Cdk2 maternal timer do not affect Chk1 activation and therefore Cdc25A degradation. Another means of characterizing the unreplicated DNA checkpoint is through the use of mathematical modeling of the checkpoint-signaling cascade of the cell cycle. Mathematical modeling is the translating of biological pathways into mathematical equations that can simulate interactions without performing laboratory experiments. The Novák-Tyson checkpoint model made important predictions of hysteresis and bistability in the frog egg checkpoint model, predictions that were later confirmed experimentally. The model was updated with additional interactions, such as those including Myt1, a second inhibitor kinase, and lamin proteins, which become phosphorylated at the onset of nuclear envelope breakdown (NEB) at entry into mitosis. Also, experimental data was fit into the model while maintaining hysteresis and bistability. Therefore, the unreplicated DNA checkpoint model was updated with new interactions and experimental data while still preserving previously identified dynamic characteristics of the system. As described, Cdc25A regulation is dynamic in the embryo. The checkpoint original model represents the activity of Cdc25 phosphatase on the mitosis promoting factor (MPF) that leads the cell into mitosis. In the checkpoint model, Cdc25C is the phosphatase activating MPF. However, the model does not include Cdc25A, which is an integral part of the checkpoint-signaling pathway due to its role in activating the cyclin/Cdk complex allowing entry into S and possibly M phase. Experimental studies were performed in which Cdc25A levels were reduced in embryos and extracts using Cdc25A morpholinos. Embryos and extracts showed delayed cell cycle and mitotic entry, demonstrating the importance of Cdc25A plays in the cell cycle. Based upon experimental data, the mathematical model of the DNA replication checkpoint was expanded to include Cdc25A. The expanded model should more accurately demonstrate how checkpoints affect the core cell cycle machinery. Cdc25A was incorporated into the model by gathering experimental data and designing a signaling cascade, which was translated into differential equations. The updated model was then used to simulate the effect of synthesis and degradation rates of Cdc25A on the entry into mitosis dynamics. Therefore, using mathematical modeling and experimental design, we can further understand the role that Cdc25A plays in cell cycle progression during development. Understanding the regulation of Chk1 activity at the MBT and the role of Cdc25A in checkpoint signaling will help us further characterize the dynamics of early embryonic development. The use of mathematical modeling and experimental tools both contribute to further our understanding of controls of the checkpoint signaling pathway and therefore leading us one step closer to truly being able to model a pathway and make predictions as to the behavior of the cell during early embryonic development. / Ph. D.

The budding yeast cell cycle has attracted attention from many experimentalists over the years for its simplicity and amenability to genetic manipulation. Moreover, the regulatory components described in budding yeast, Saccharomyces cerevisiae, are conserved in higher eukaryotes. The budding yeast cell cycle is governed by a complex network of chemical reactions controlling the activity of the cyclin-dependent kinases (CDKs), proteins that drive the major events of the cell cycle. The presence of these proteins is required for the transition from G1 to S phase (Start) whereas their absence permits the transition from S/M to G1 phase (Finish). The cell cycle of budding yeast is based on alternation between these two states. To test the accuracy of this theory against experiments, we built a hypothetical molecular mechanism of the budding yeast cell cycle and transcribed it into differential equations. With a proper choice of kinetic parameters, the differential equations reproduce the main events of the cell cycle such as: the synthesis of cyclins (Cln1,2; Cln3; Clb1,2; Clb5,6) by their transcription factors (SBF, Mcm1, MBF); their association with stoichiometric inhibitors (Sic1, Cdc6); their degradation by SCF and adaptors of the APC (Cdc20, Cdh1). The emphasis was put on mechanisms responsible for the release of Cdc14 from the RENT complex, Cdc14 being a major player in exit from mitosis. Simulations of the wild type strain and more than 100 mutants showed phenotypes in accordance with experimental observations. Some mutants defective in the Start and Finish transitions and the different ways to rescue them will be presented. / Ph. D.

DNA is a potential component in molecular electronics. To explore this end, there has been an incredible amount of research on how well DNA conducts and by what mechanism. There has also been a tremendous amount of research to find new uses for it in nanoscale electronics. DNA's self-assembly and recognition properties have found a unique place in this area. We predict, using a tight-binding model, that spin-dependent transport can be observed in short DNA molecules sandwiched between ferromagnetic contacts. In particular, we show that a DNA spin-valve can be realized with magnetoresistance values of as much as 26% for Ni and 16% for Fe contacts. Spin-dependent transport can broaden the possible applications of DNA as a component in molecular electronics and shed new light into the transport properties of this important biological molecule. / Master of Science

The Wingless (Wnt) signaling pathway is one of the critical developmental pathways for control of cell differentiation, proliferation, and cell growth. The DEP domain, located on the C-terminus of Dishevelled (Dvl), plays a role in cytoplasm-membrane association, which branches the canonical and non-canonical Wnt signaling pathway within the cell. It has been suggested that the DEP domain requires the recruitment of ionic lipids, such as phosphatidic acid, to regulate its localization to the plasma membrane and association to the frizzle receptor. However, the physical mechanism for DEP association to the plasma membrane is still unknown. We show that mDvl2-DEP interacts with phosphatidic acid at a distinct patch on the surface formed by a positively charged surface area by NMR spectroscopy. The binding of this interaction was also found at physiologically relevant concentration using fluorescence spectroscopy. We also determined that the interaction is pH-dependent and regulated through a 'histidine switch' mechanism at His464 and His465 where there is increased association of mDvl2-DEP to the plasma membrane at higher pH values (7.5). This association is based on tertiary structure conformational changes with rearrangement of the loop regions by a change in local pH, not its interaction with phosphatidic acid. Overall, our work will contribute to elucidate how cells regulate their developmental pathways through localized molecular interactions. / Master of Science

In recent years, dengue viral infection has become one of the most widely-spread mosquito-borne diseases in the world, with an estimated 50-100 million cases annually, resulting in 500,000 hospitalizations. Due to the nature of the immune response to each of the four serotypes of dengue virus, secondary infections of dengue put patients at higher risk for more severe infection as opposed to primary infections. The current hypothesis for this phenomenon is antibody-dependent enhancement, where strain-specific antibodies from the primary infection enhance infection by a heterologous serotype. To determine the mechanisms responsible for the increase in disease severity, we develop mathematical models of within-host virus-cell interaction, epidemiological models of virus transmission, and a combination of the within-host and between-host models. The main results of this thesis focus on the within-host model. We model the effects of antibody responses against primary and secondary virus strains. We find that secondary infections lead to a reduction of virus removal. This is slightly different than the current antibody-dependent enhancement hypothesis, which suggests that the rate of virus infectivity is higher during secondary infections due to antibody failure to neutralize the virus. We use the results from the within-host model in an epidemiological multi-scale model. We start by constructing a two-strain SIR model and vary the parameters to account for the effect of antibody-dependent enhancement. / Master of Science

Natal dispersal outcomes are an interplay between environmental conditions and individual phenotypes. Peripheral, isolated populations may experience altered environmental conditions and natal dispersal patterns that differ from populations in contiguous landscapes. We document nonphilopatric, sex-biased natal dispersal in an endangered small mammal, the Mt. Graham red squirrel (Tamiasciurus hudsonicus grahamensis), restricted to a single mountain. Other North American red squirrel populations are shown to have sex-unbiased, philopatric natal dispersal. We ask what environmental and intrinsic factors may be driving this atypical natal dispersal pattern. We test for the influence of proximate factors and ultimate drivers of natal dispersal: habitat fragmentation, local population density, individual behavior traits, inbreeding avoidance, competition for mates, and competition for resources, allowing us to better understand altered natal dispersal patterns at the periphery of a species' range. A juvenile squirrel's body condition and its mother's mass in spring (a reflection of her intrinsic quality and territory quality) contribute to individual behavioral tendencies for movement and exploration. Resources, behavior, and body condition have the strongest influence on natal dispersal distance, but affect males and females differently. Male natal dispersal distance is positively influenced by its mother's spring body mass and individual tendency for movement; female natal dispersal distance is negatively influenced by its mother's spring body mass and positively influenced by individual tendency for movement. An apparent feedback between environmental variables and subsequent juvenile behavioral state contributes to an altered natal dispersal pattern in a peripheral population, highlighting the importance of studying ecological processes at the both range center and periphery of species' distributions.