1,721,072 research outputs found
Inclusion of a glycogen regulation mathematical model into a contextual metabolic framework
Full text linkWhile we generally eat infrequently, metabolic processes within our body tightly regulate blood glucose levels. The metabolic system is comprised of various tissues, each of which contains specific regulatory pathways that determine the function of the tissue within the system. These tissues and their localized metabolic functions, complement one another through inter-tissue metabolic highways to form the entire metabolic system. The liver is a key control center of metabolism and thus, the mathematical model described in this thesis is heavily liver-centric. Though all hepatocytes, or liver cells, are capable of similar metabolic functions, the rate at which these functions are carried out depends on the location of the hepatocytes within the liver. At the intracellular level, the various metabolic pathways contain many intersections. Though the intracellular components of the metabolic system are spatially localized, I assume a well-mixed cell and ignore spatial heterogeneity While physiological layering is important to accurately model metabolism, the layering of regulation within the system is also of interest for our model. The biochemical processes that make up metabolic pathways are regulated on many levels, such as by metabolites, hormones and enzymes, and also at a pre-protein level through transcription. While the model developed here does not include all levels of metabolic control it does address the need for understanding of metabolism from a multi-level perspective. The main conclusions from this study are that while fats are utilized to help produce glucose during periods of low blood glucose levels, resulting ketone bodies are kept at a minimal level and that heatmaps are an effective visual tool in evaluating model simulations. The enzyme circuit of the glycogen regulatory system allows for efficient modification of activity of enzymes to quickly increase the rate at which excess glucose is stored as glycogen. Also, as blood glucose levels drop, this enzyme circuitry is modified so that glycogen, amino acids and fats are broken down to produce glucose so that blood glucose levels are stabilized. The proposed model suggests that while fats are utilized in this process, ketone bodies resulting from lipolysis are kept at low levels, which is essential to protect the system from ketoacidosis. A mathematical model of a reduced glycogen regulatory circuit was developed and compared to a model of the full glycogen regulatory circuit. Though simulations of these models were similar in isolation, they produced different results when immersed in a contextual model which captured the multiple tissue environment of the metabolic system. This method allowed investigation into the effects of the enzyme cascade in the glycogen regulatory system. Heatmaps enabled quick assessment of model simulations and were vital for obtaining an overall fluxomic picture of the state of the system
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Spatiotemporal Dynamics of Gradient Sensing and Polarization in Yeast
Full text linkCells are able to interpret different kinds of spatial information. Characterizing the spatiotemporal dynamics in signal transduction is essential to understand how a cell process information from its environment. Here, we quantitatively studied the gradient sensing and polarization in budding yeast Saccharomyces cerevisiae, using mathematical modeling and time-lapse microscopy. In the gradient sensing, we found that yeast cells can dynamically remodel local pheromone gradient and achieve better gradient sensing by secreting Bar1, a protease that degrades [alpha]-factor. Altering the local environment also avoids non-productive cell-cell interactions. During the polarity establishment without spatial cues, imaging with high spatiotemporal resolution revealed oscillation in the initial clustering of polarity factors, suggesting the presence of a negative feedback loop that disperses the factors. Mathematical modeling including an additional negative feedback reproduced similar dynamics and predicted that negative feedback would confer robustness to the polarity circuit, and make the kinetics of competition between polarity clusters relatively insensitive to the concentrations of polarity factors. These predictions were confirmed experimentally. Lastly, to understand how scaffold protein processes the spatial information of pheromone, we presented preliminary results for characterizing the kinetics of pheromone induced Ste5 membrane recruitment using time-lapse fluorescent imaging and single cell tracking
Mathematical modeling of signaling pathway dynamics and stochastic gene expression
Full text linkThis thesis presents the development and analysis of stochastic and deterministic models of cellular biochemical networks, such as signaling pathways and gene regulatory networks. First, the model of the yeast pheromone response pathway is constructed. Stochastic modeling reveals that the biochemical steps that regulate activation of the mitogen-activated protein kinase Fus3 can account for the graded-to-binary conversion. The model is also used to investigate the effects of protein turnover on the response of the pathway. It is demonstrated that the inclusion of protein turnover can lead too sustained oscillations of protein concentration in the absence of feedback regulation, which indicates protein turnover as a important signaling regulation mechanism. Second, an engineered promoter that allowed the simultaneous repression and activation of gene expression in Escherichia coli was constructed and used to construct a stochastic model to study synthetic gene networks under increasingly complex conditions: unregulated, repressed, activated and simultaneously repressed and activated, and in the presence of positive feedback. The stochastic model quantitatively captures the means and distributions of the expression from the engineered promoter of this modular system and accurately predict the in vivo behavior of an expanded network that includes positive feedback. The model also reveals the counterintuitive prediction that noise in protein expression levels can increase upon arrest of cell division, which was confirmed experimentally
Simulated Yeast with Mobile Polarity Sites Is More Sensitive to Pheromone Gradients
Full text linkCell polarity is the asymmetric distribution of cellular components and molecules. It is crucially important for effective cell motility and other directional functions. However, practically all types of cells were exposed in a large amount of molecular noise which interfered cell polarity, leading the cells to polarize in the wrong direction. Interestingly, though exposed in molecular noise, yeast cells can usually find and polarize in the direction of extracellular pheromone gradients during mating. This study investigated how yeast cells decoded the extracellular pheromone gradient to polarize in the right direction despite the noise. With particle-based simulations, we found that when exposed to a shallow signal gradient, the simulated yeast with mobile polarity sites interpreted the direction of the signal more accurately than the one with static polarity sites. Therefore, the highly dynamic polarity sites could help yeast cells to decode the extracellular pheromone gradient against molecular noise. Future studies will focus on adding more complex signaling pathways to the simulated yeast models to further investigate the effect of mobile polarity sites on yeast polarity establishment.Bachelor of Scienc
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Simulation methods for spatiotemporal models of biochemical signaling networks
Full text linkCells use signaling networks consisting of multiple interacting proteins to respond to changes in their environment. In many situations, such as chemotaxis, spatial and temporal information must be transmitted through a signaling network. Recent computational studies have emphasized the importance of cellular geometry in signal transduction, but have been limited in their ability to accurately represent complex cell morphologies. We present a finite volume method that addresses this problem. Our method uses Cartesian cut cells in a differential algebraic formulation to handle the complex boundary dynamics encountered in biological systems. The method is second order in space and time. Several models of signaling systems are simulated in realistic cell morphologies obtained from live cell images. We then examine the effects of geometry on signal transduction. External signals can trigger cells to polarize and move in a specific direction. During migration, spatially localized activity of proteins is maintained. To investigate the effects of morphological changes on intracellular signaling, we present a numerical scheme consisting of a cut cell finite volume spatial discretization coupled with level set methods to simulate the resulting advection-reaction-diffusion equation. We then show that shape deformations drive a Turing-type system into an unstable regime. The method is also applied to a model of a signaling network in a migrating fibroblast. Determining the signaling mechanisms used by membrane proteins that interact with the cytoskeleton is important for understanding phenomena such as T-cell activation and viral infection. To investigate these interactions, recent experiments have tracked the movements of single lipids and glycosyl-phosphatidylinositol (GPI) anchored protein clusters tagged with 40 nm gold particles. These experiments reveal regions of transient confinement and transient anchorage of the particles. The distribution of transient anchorage release times exhibits a long tail. We developed a stochastic model of the system to explain the transient anchorage release times and the underlying biochemical reaction system
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
