Theoretical investigations of intercellular communication in the microcirculation: Conducted responses, myoendothelial projections and endothelium derived hyperpolarizing factor

The contractile state of microcirculatory vessels is a major determinant of the blood pressure of the whole systemic circulation. Continuous bi-directional communication exists between the endothelial cells (ECs) and smooth muscle cells (SMCs) that regulates calcium (Ca2+) dynamics in these cells. This study presents theoretical approaches to understand some of the important and currently unresolved microcirculatory phenomena. ^ Agonist induced events at local sites have been shown to spread long distances in the microcirculation. We have developed a multicellular computational model by integrating detailed single EC and SMC models with gap junction and nitric oxide (NO) coupling to understand the mechanisms behind this effect. Simulations suggest that spreading vasodilation mainly occurs through Ca 2+ independent passive conduction of hyperpolarization in RMAs. Model predicts a superior role for intercellular diffusion of inositol (1,4,5)-trisphosphate (IP3) than Ca2+ in modulating the spreading response. ^ Endothelial derived signals are initiated even during vasoconstriction of stimulated SMCs by the movement of Ca2+ and/or IP3 into the EC which provide hyperpolarizing feedback to SMCs to counter the ongoing constriction. Myoendothelial projections (MPs) present in the ECs have been recently proposed to play a role in myoendothelial feedback. We have developed two models using compartmental and 2D finite element methods to examine the role of these MPs by adding a sub compartment in the EC to simulate MP with localization of intermediate conductance calcium activated potassium channels (IKCa) and IP3 receptors (IP 3R). Both models predicted IP3 mediated high Ca2+ gradients in the MP after SMC stimulation with limited global spread. This Ca 2+ transient generated a hyperpolarizing feedback of ∼ 2–3mV. ^ Endothelium derived hyperpolarizing factor (EDHF) is the dominant form of endothelial control of SMC constriction in the microcirculation. A number of factors have been proposed for the role of EDHF but no single pathway is agreed upon. We have examined the potential of myoendothelial gap junctions (MEGJs) and potassium (K+) accumulation as EDHF using two models (compartmental and 2D finite element). An extra compartment is added in SMC to simulate micro domains (MD) which have NaKα2 isoform sodium potassium pumps. Simulations predict that MEGJ coupling is much stronger in producing EDHF than alone K+ accumulation. On the contrary, K+ accumulation can alter other important parameters (EC V m, IKCa current) and inhibit its own release as well as EDHF conduction via MEGJs. The models developed in this study are essential building blocks for future models and provide important insights to the current understanding of myoendothelial feedback and EDHF.^

La ciudad, el poeta y su familia melancolica (Poesia Chilena de los ultimos 50 anos)

This dissertation explored the relationship among poets, cities, and the construction of nation-ness. It was an interpretive reading of Chilean poetry and Chilean-ness as a way of inventing the nation from its very origins, starting with the colonial epic poem La Araucana and the founding of Santiago, its capital city. In this dissertation, poetry not only dealt with cities or "city poets" but also with the very conception, drafting, and systematic invention of cities as a "dream of order". The construct of a "community" of Chileans has maintained family ties with "Melancholy" in the collective imagination. This structure of melancholy reinforced the idea of "an order and a community" passed along by poets through generations. This dissertation also explored the moment when this melancholic family was fractured, divided, and Santiago was darkened by the events of September 11, 1973 and the rise of dictatorship, brutality, and censorship. ^ The methodology employed to examine different aspects of the construction of the city-nation included theoretical approaches such as Benedict Anderson's idea of nations as "imagined communities," Ángel Rama's analysis of Latin American urban rationality in his book The Lettered City , and the idea of the poet as an urban seer or visionary, the "flâneur" studied by Walter Benjamin in Charles Baudelaire's poetry. A central finding was that this "imagined community" have been severely transformed since 1950. In Chilean poetry, two works served as major referents: Pablo Neruda's Canto General, a totalizing idea of collective identity carved from the stones of the ruins of Machu Picchu, and Nicanor Parra's Poemas y Antipoemas (1954), which begun to illustrate the slow "decomposition" of the "The Lettered City." Among such conflicting images of (post-)modernity, poet Enrique Lihn became the central counter-figure who put an end to a long tradition of producing canonical nation-building cultural artifacts. His book El paseo Ahumada (1983) impacted the new generations of Chilean poets. The conclusion brought together the five-century history and diverse poetic experiences of the traditional Lettered City with the latest currents of marginalized urban poetry (1987-2003), the so-called "barbarians," flâneurs who were (re)inventing Chilean-ness in the globalized, and anti-Utopian city of "Sanhattan." ^

Lions and roses: An interpretive history of Israeli-Iranian relations

This multi-disciplinary research project explores the religious and cultural foundations within the "master commemorative narratives" that frame Israeli and Iranian political discourse. In articulating their grievances against one another, Israeli and Iranian leaders express the tensions between religion, nationalism, and modernity in their own societies. The theoretical and methodological approach of this dissertation is constructivist-interpretivist. The concept of "master commemorative narratives" is adapted from Yael Zerubavel's study of ritualized remembrance in Israeli political culture, and applied to both Israeli and Iranian foreign policy. Israel’s master commemorative narrative draws heavily upon the language of the Hebrew Bible, situating foreign policy discourse within a paradigm of covenantal patrimony, exile, and return, despite the unrelenting hostility of eternal enemies and "the nations." Iran’s master commemorative narrative expresses Iranian suspicion of foreign encroachment and interference, and of the internal corruption that they engender, sacralizing resistance to the forces of evil in the figurative language and myths of pre-Islamic tradition and of Shi'a Islam. Using a constructivist-interpretive methodological approach, this research offers a unique interpretive analysis of the parallels between these narratives, where they intersect, and where they come into conflict. It highlights both the broad appeal and the diverse challenges to the components of these "master" narratives within Israeli and Iranian politics and society. The conclusion of this study explains the ways in which the recognition of religious and cultural conflicts through the optic of master commemorative narratives can complement the perspectives of other theoretical approaches and challenge the conventions of Security Studies. It also suggests some of the potential practical applications of this research in devising more effective international diplomacy.

Lions and Roses: An Interpretive History of Israeli-Iranian Relations

This multi-disciplinary research project explores the religious and cultural foundations within the “master commemorative narratives” that frame Israeli and Iranian political discourse. In articulating their grievances against one another, Israeli and Iranian leaders express the tensions between religion, nationalism, and modernity in their own societies. The theoretical and methodological approach of this dissertation is constructivist-interpretivist. The concept of “master commemorative narratives” is adapted from Yael Zerubavel’s study of ritualized remembrance in Israeli political culture, and applied to both Israeli and Iranian foreign policy. Israel’s master commemorative narrative draws heavily upon the language of the Hebrew Bible, situating foreign policy discourse within a paradigm of covenantal patrimony, exile, and return, despite the unrelenting hostility of eternal enemies and “the nations.” Iran’s master commemorative narrative expresses Iranian suspicion of foreign encroachment and interference, and of the internal corruption that they engender, sacralizing resistance to the forces of evil in the figurative language and myths of pre-Islamic tradition and of Shi‘a Islam. Using a constructivist-interpretive methodological approach, this research offers a unique interpretive analysis of the parallels between these narratives, where they intersect, and where they come into conflict. It highlights both the broad appeal and the diverse challenges to the components of these “master” narratives within Israeli and Iranian politics and society. The conclusion of this study explains the ways in which the recognition of religious and cultural conflicts through the optic of master commemorative narratives can complement the perspectives of other theoretical approaches and challenge the conventions of Security Studies. It also suggests some of the potential practical applications of this research in devising more effective international diplomacy.

Network construction and graph theoretical analysis of functional language networks in pediatric epilepsy

This dissertation introduces a new approach for assessing the effects of pediatric epilepsy on the language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI data. An auditory description decision task (ADDT) paradigm was used to activate the language network for 29 patients and 30 controls recruited from three major pediatric hospitals. Empirical evaluations illustrated that pediatric epilepsy can cause, or is associated with, a network efficiency reduction. Patients showed a propensity to inefficiently employ the whole brain network to perform the ADDT language task; on the contrary, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was carried out. The analysis revealed no substantial global network feature differences between the patient and control groups. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient's extent of activation network showed a tendency towards more random networks. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. The left hemispheric hubs displayed greater centrality values for patients, whereas the right hemispheric hubs displayed greater centrality values for controls. This hub hemispheric disparity was not correlated with a right atypical language laterality found in six patients. Finally it was shown that a multi-level unsupervised clustering scheme based on self-organizing maps, a type of artificial neural network, and k-means was able to fairly and blindly separate the subjects into their respective patient or control groups. The clustering was initiated using the local nodal centrality measurements only. Compared to the extent of activation network, the intensity of activation network clustering demonstrated better precision. This outcome supports the assertion that the local centrality differences presented by the intensity of activation network can be associated with focal epilepsy.^

Network Construction and Graph Theoretical Analysis of Functional Language Networks in Pediatric Epilepsy

This dissertation introduces a new approach for assessing the effects of pediatric epilepsy on the language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI data. An auditory description decision task (ADDT) paradigm was used to activate the language network for 29 patients and 30 controls recruited from three major pediatric hospitals. Empirical evaluations illustrated that pediatric epilepsy can cause, or is associated with, a network efficiency reduction. Patients showed a propensity to inefficiently employ the whole brain network to perform the ADDT language task; on the contrary, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was carried out. The analysis revealed no substantial global network feature differences between the patient and control groups. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient’s extent of activation network showed a tendency towards more random networks. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. The left hemispheric hubs displayed greater centrality values for patients, whereas the right hemispheric hubs displayed greater centrality values for controls. This hub hemispheric disparity was not correlated with a right atypical language laterality found in six patients. Finally it was shown that a multi-level unsupervised clustering scheme based on self-organizing maps, a type of artificial neural network, and k-means was able to fairly and blindly separate the subjects into their respective patient or control groups. The clustering was initiated using the local nodal centrality measurements only. Compared to the extent of activation network, the intensity of activation network clustering demonstrated better precision. This outcome supports the assertion that the local centrality differences presented by the intensity of activation network can be associated with focal epilepsy.