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Dave, Emma. "The physiology of the Escherichia coli pyruvate dehydrogenase complex." Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364242.
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Sim, Jae Hoon. "Imaging, physiology, and biomechanics of the malleus-incus complex /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Ollivier, Julien. "Scalable methods for modelling complex biochemical networks." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104586.
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In cells, complex networks of interacting biomolecules process both environmental and endogenous signals to control gene expression and other cellular processes. This poses a challenge to researchers who attempt to develop mathematical and computational models of biochemical networks that reflect this complexity. In this thesis, I propose methods that help manage complexity by exploiting the finding that, as for other biological systems, cellular networks are characterized by a modularity that appears at all levels of organization.The first part of this work focuses on the modular properties of proteins and how their function can be characterized through their structure and allosteric properties. I develop a modular rule-based framework and formal modelling language that describes the computations performed by allosteric proteins and that is rooted in biophysical principles. Rule-based modelling conventionally addresses the problem of combinatorial complexity, whereby protein interactions can generate a combinatorial explosion of protein complex states. However, I explore how these same interactions can potentially require a combinatorial number of parameters to describe them. I demonstrate that my rule-based framework effectively addresses this problem of regulatory complexity, and describes allosteric proteins and networks in a unified, consistent, and modular fashion. I use the framework in three applications. First, I show that allostery can make macromolecular assembly more efficacious when a protein that joins two separable parts of a complex is present in excessively high concentrations. Second, I demonstrate that I can straightforwardly analyze the complex cooperative interactions that arise when competitive ligands bind to a multimeric protein. Third, I analyze a new model of G protein-coupled receptor signalling and demonstrate that it explains the functional selectivity of these receptors while being parsimonious in the number of parameters used. Overall, I find that my rule-based modelling framework, implemented as the Allosteric Network Compiler software tool, can ease of modelling and analysis of complex allosteric interactions.If cellular networks are modular, this implies that small sub-systems can be studied in isolation, provided that external inputs and perturbations to the system can be modelled appropriately. However, cellular networks are subject to both intrinsic noise, which is endogenous to the system, but also extrinsic noise, arising from noisy inputs. Furthermore, many inputs may be dynamic, whether due to experimental protocols or perhaps reflecting the cyclic process of cell division. This motivates my development, in the second part of this work, of efficient stochastic simulation algorithms for biochemical networks that can accommodate time-varying biochemical parameters. Starting from Gillespie's well-known First Reaction Method and Gibson and Bruck's Next Reaction Method, I develop two new algorithms that allow time-varying inputs of arbitrary functional form while scaling well to systems comprising many biochemical reactions. I analyze their scaling properties and find that a modified First Reaction Method may scale better than a modified Next Reaction Method in some applications.The third and last part of this thesis introduces a new software tool, Facile, that eases the creation, update and simulation of biochemical network models. Models created through a simple and intuitive textual language are automatically converted into a form usable by downstream tools, for example ordinary differential equations for simulation by Matlab. Also, Facile conveniently accommodates mathematical and time-varying expressions in rate laws.<br>Au niveau cellulaire, des réseaux complexes d'interaction biomoléculaire traitent les signaux tant environnementaux qu'endogènes dans le but de contrôler l'expression génétique ainsi que d'autres processus cellulaires. Ceci est un défi pour les chercheurs qui veulent concevoir des modèles mathématiques et calculatoires des réseaux biochimiques. Dans cette thèse, je propose des méthodes qui facilitent la gestion de cette complexité en exploitant la constatation que, tout comme d'autres systèmes biologiques, les réseaux cellulaires se caractérisent par une modularité qui transparaît à tous les niveaux d'organisation.Dans la première partie, je mets l'accent sur les propriétés modulaires des protéines et sur la façon de caractériser leur fonction, compte tenu de leur structure et de leurs propriétés allostériques. J'ai mis au point un cadre modulaire à base de règles ainsi qu'un langage formel de modélisation qui permet de décrire les calculs effectués par les protéines allostériques et qui découle de principes biophysiques. La modélisation à base de règles s'adresse conventionnellement au problème de la complexité combinatoire, où les interactions entre les protéines peuvent générer une explosion combinatoire d'états des complexes protéiques. J'examine, cependant, comment il peut s'avérer nécessaire d'utiliser un nombre combinatoire de paramètres pour décrire ces mêmes interactions. Je démontre que notre cadre à base de règles peut régler efficacement ce problème de la complexité régulatoire, et permet de décrire les protéines et les réseaux allostériques de façon unifiée, cohérente et modulaire. J'utilise le cadre développé dans trois applications. Tout d'abord, je montre que l'allostérie peut rendre l'assemblage macromoléculaire plus efficace lorsqu'une protéine qui unit deux parties distinctes d'un complexe protéique est présente en concentration excessive. Deuxièmement, je démontre qu'il est relativement simple d'analyser les interactions coopératives complexes qui surviennent lorsque des ligands compétitifs se lient à une protéine multimérique. En troisième lieu, j'analyse un nouveau modèle de la signalisation des récepteurs couplés aux protéines G qui explique leur sélectivité fonctionnelle tout en limitant le nombre des paramètres utilisés. Globalement, je montre que ce cadre basé sur des règles, qui est implémenté dans le logiciel ‘Allosteric Network Compiler', peut faciliter la modélisation et l'analyse d'interactions allostériques complexes.Si les réseaux cellulaires sont modulaires, il en résulte que des sous-systèmes peuvent être étudiés séparément, à la condition que les entrées et les perturbations externes du système puissent être modélisées adéquatement. Cependant, ces réseaux sont soumis à l'influence du bruit intrinsèque, qui est endogène au système, mais également au bruit extrinsèque, venant des entrées bruyantes. De plus, de nombreuses entrées peuvent être dynamiques. Cela motive, dans la deuxième partie de ce travail, le développement d'algorithmes efficients de simulation stochastique pour les réseaux biochimiques qui peuvent tenir compte de paramètres biochimiques dynamiques. En me fondant sur la méthode maintenant célèbre de Gillespie, d'appellation ‘First Reaction Method', et sur celle de Gibson et Bruck, la ‘Next Reaction Method', j'ai développé deux nouveaux algorithmes qui permettent des entrées dynamiques de forme fonctionnelle arbitraire tout en s'échelonnant bien sur les systèmes qui comportent de nombreuses réactions biochimiques. J'analyse leurs propriétés d'échelonnement et je constate que, pour certaines applications, la ‘First Reaction Method' modifiée s'échelonne mieux que la ‘Next Reaction Method' modifiée.La troisième et dernière partie cette thèse est la présentation d'un nouvel outil informatique, Facile, qui simplifie la création, la mise à jour et la simulation de modèles de réseaux biochimiques.
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Caudron, Quentin. "Neuronal computation on complex dendritic morphologies." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/57056/.
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When we think about neural cells, we immediately recall the wealth of electrical behaviour which, eventually, brings about consciousness. Hidden deep in the frequencies and timings of action potentials, in subthreshold oscillations, and in the cooperation of tens of billions of neurons, are synchronicities and emergent behaviours that result in high-level, system-wide properties such as thought and cognition. However, neurons are even more remarkable for their elaborate morphologies, unique among biological cells. The principal, and most striking, component of neuronal morphologies is the dendritic tree. Despite comprising the vast majority of the surface area and volume of a neuron, dendrites are often neglected in many neuron models, due to their sheer complexity. The vast array of dendritic geometries, combined with heterogeneous properties of the cell membrane, continue to challenge scientists in predicting neuronal input-output relationships, even in the case of subthreshold dendritic currents. In this thesis, we will explore the properties of neuronal dendritic trees, and how they alter and integrate the electrical signals that diffuse along them. After an introduction to neural cell biology and membrane biophysics, we will review Abbott's dendritic path integral in detail, and derive the theoretical convergence of its infinite sum solution. On certain symmetric structures, closed-form solutions will be found; for arbitrary geometries, we will propose algorithms using various heuristics for constructing the solution, and assess their computational convergences on real neuronal morphologies. We will demonstrate how generating terms for the path integral solution in an order that optimises convergence is non-trivial, and how a computationally-significant number of terms is required for reasonable accuracy. We will, however, derive a highly-efficient and accurate algorithm for application to discretised dendritic trees. Finally, a modular method for constructing a solution in the Laplace domain will be developed.
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Wells, Cathy Clarke. "The complex spatial topography of visual attention : behavior and physiology /." View online version; access limited to Brown University users, 2005. http://wwwlib.umi.com/dissertations/fullcit/3174692.
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Florman, Jeremy T. "Neuroendocrine Modulation of Complex Behavior and Physiology in C. elegans." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1109.
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To survive, animals must adapt to a complex and challenging world in a way that is flexible and responsive, while maintaining internal homeostasis. Neuromodulators provide a means to systemically alter behavioral or physiological state based on intrinsic or extrinsic cues, however dysregulated neuroendocrine signaling has negative consequences for fitness and survival. Here I examine neuroendocrine function and dysfunction using the escape response in Caenorhabditis elegans. The RFamide neuropeptide FLP-18 is a co-transmitter with the monoamine tyramine and functions both synergistically and antagonistically to tyramine in coordinating escape behavior. Using behavioral analysis and calcium imaging, I show that FLP-18 functions primarily through the G-protein coupled receptor (GPCR) NPR-5 to increase calcium levels in muscle, enhancing locomotion rate, bending and reversal behavior during the escape response.
Furthermore, I examine the relationship between persistent acute stress and resilience using repeated activation of the escape response as a model of neuroendocrine dysregulation. Repeated activation of the escape response shortens lifespan and renders animals more susceptible to thermal, oxidative, and nutritional stress. Tyramine release is necessary and sufficient for this effect and activity of the tyraminergic RIM neurons is differentially regulated by acute versus long-term stressors. Impaired stress resistance requires both the GPCR TYRA-3 in the intestine and intestinal neuropeptide release. Activation of the insulin receptor DAF-2 is downstream of TYRA-3 and inhibits the transcription factors DAF-16/FOXO, SKN-1/Nrf2 and HSF-1, linking monoamine signaling in acute stress to the insulin signaling pathway and impaired resilience to long-term stressors.
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Burgess, Alexandra Jacquelyn. "The variable light environment within complex 3D canopies." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/38967/.
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With an expanding population and uncertain consequences of climate change, the need to both stabilise and increase crop yields is important. The relationship between biomass production and radiation interception suggests one target for improvement. Under optimal growing conditions, biomass production is determined by the amount of light intercepted and the efficiency with which this is converted into dry matter. The amount of light at a given photosynthetic surface is dependent upon solar movement, weather patterns and the structure of the plant, amongst others. Optimising canopy structure provides a method by which we can improve and optimise both radiation interception and also the distribution of light among canopy layers that contribute to net photosynthesis. This requires knowledge of how canopy structure determines light distribution and therefore photosynthetic capacity of a given crop species. The aim of this thesis was to assess the relationships between canopy architecture, the light environment and photosynthesis. This focused on two core areas: the effect of varietal selection and management practices on canopy structure and the light environment and; the effect of variable light on select photosynthetic processes (photoinhibition and acclimation). An image-based reconstruction method based on stereocameras was employed with a forward ray tracing algorithm in order to model canopy structure and light distributions in high-resolution. Empirical models were then applied using parameterisation from manually measured data to predict the effects of variable light on photosynthesis. The plasticity of plants means that the physical structure of the canopy is dependent upon many different factors. Detailed descriptions of canopy architecture are integral to predicting whole canopy photosynthesis due to the spatial and temporal differences in light profiles between canopies. This inherent complexity of the canopy means that previous methods for calculating light interception are often not suitable. 3-dimensional modelling can provide a quick and easy method to retain this complexity by preserving small variations. This provides a means to more accurately quantify light interception and enable the scaling of cellular level processes up to the whole canopy. Results indicate that a canopy with more upright leaves enables greater light penetration to lower canopy layers, and thus higher photosynthetic productivity. This structural characteristic can also limit radiation-induced damage by preventing exposure to high light, particularly around midday. Whilst these features may lead to higher photosynthetic rates per unit leaf area, per unit ground area, photosynthesis is usually determined by total leaf area of the canopies, and within this study, the erect canopies tended to have lower total leaf areas than the more horizontal canopies. The structural arrangement of plant material often led to low levels of light within the lower canopy layers which were punctuated by infrequent, high light events. However, the slow response of photosynthesis to a change in light levels meant that these sun flecks cannot be used by the plant and thus the optimal strategy should be geared towards light harvesting and efficient photosynthesis under low light conditions. The results of this study contribute to our understanding of photosynthetic processes within the whole canopy and provide a foundation for future work in this area.
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Jones, Benjamin R. "Engineering a fluorescent calmodulin for use in complex models of cardiac physiology." Connect to resource, 2009. http://hdl.handle.net/1811/37210.
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Hughes, Ruth. "Serpentine tolerance in the Mimulus guttatus complex." Thesis, University of Exeter, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286489.
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Stojanovic, Marina. "Role BAP31 complex at the endoplasmic reticulum in normal cell physiology and apoptosis." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102730.
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The endoplasmic reticulum (ER) plays a vital role in synthesis, folding and sorting of newly synthesized secretory cargo proteins. Quality control mechanism in the ER is a key regulator of this process, which separates correctly folded proteins from immature or misfolded secretory proteins, and ultimately retains and disposes the latter before they can exit the ER. Numerous diseases have been associated with defects in the regulation of the egress of the nascent membrane proteins out of ER to the cell surface. BAP31, a polytopic integral membrane protein at the ER, has been implicated as a putative quality control factor and/or cargo protein in regulating the export of specific sets of nascent membrane proteins. Here, I demonstrate BAP31 to be an important player in regulating and maintaining functional integrity of the cell surface. Both truncated (p20BAP31) and deletion (BAP31-null) mutants of BAP31 significantly abrogated expression of tetraspanins at the cell surface, and thus integrin-mediated cell adhesion and survival due to BAP31 effects on tetraspanin transport from the ER. Consistent with its role as a chaperone or cargo receptor, BAP31 was found to interact with Sec61beta and TRAM, components of the nascent protein translocation machinery and to form an important part of the ribosome-translocon complexes at the ER. In addition to its predicted role in quality control mechanism in the ER, BAP31, a BCL-2 associated protein, is recognized as an important regulator of apoptosis, an essential physiological mechanism of cell suicide in development and homeostasis in all multicellular organisms. Here, I characterized SPIKE, a new proposed pro-apoptotic BCL-2 protein and interacting partner of BAP31. SPIKE is a novel and untypical pro-apoptotic BH3 only protein capable of inducing apoptosis without binding to anti-apoptotic BCL-2 partners and endogenous BAP31, whose role in specific apoptotic pathway remains to be elucidated. Thus, BAP31 plays important, but distinct roles in both normal cell physiology and apoptosis.
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Schmitt, Daniel T. "Time series analysis of real-world complex systems - climate, finance, proteins, and physiology." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-60656.
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Mahdee, Anas Falah. "Physiology and pathophysiology of the dentine-pulp complex in response to dentine exposure." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3936.
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Therapies to promote pulp repair and regeneration after injury should be underpinned by a deep understanding of normal tissue behaviour, and cellular signalling mechanisms. The objectives of this work were to understand normal structure of the tooth and to identify changes in its cellular elements and their complex interactions in response to dentine exposure. Revisiting pulp structure and function with a range of contemporary techniques may formalize observations into new concepts of tooth physiology and pathophysiology, and reveal new opportunities for therapeutic intervention. Studies within this thesis employed rodent mandibular incisors and molars with structural and functional investigations on demineralised teeth, non-demineralised freshly extracted pulp tissues and tissue explants. Observations were made on ground sections, haematoxylin-eosin stained sections, immunohistochemically-stained sections, and on quantitative reverse transcription polymerase chain reaction (q-RT-PCR) examination of tissue explants. Complex cellular structure and heterogeneity was observed within odontoblast and subodontoblast cellular populations. Previously undescribed odontoblast processes were identified within the predentine region during crown development and in the radicular pulp after tooth development. Programmed retraction of odontoblast processes was observed after dentine exposure by cavity preparation or tooth wear. Two phases of reactionary dentine deposition (atubular followed by tubular) was identified after tooth wear. This revealed a programmed cellular defensive mechanism which lead to tissue recovery and regeneration. This process could be controlled by autocrine or paracrine signalling mechanisms, as indicated by the presence of NGF and NGFR, in addition to a complex network of CGRP-IR axons. Observations suggested revision of established hypotheses including the hydrodynamic theory of dentine sensitivity and the role of extracellular pH in biomineralisation. This hypothesis could provide coherent explanation for several well-known dental mysteries including pulp stone development, dentine sclerosis and the mode of action of high pH materials (calcium hydroxide, and hydraulic calcium silicate cements) in the repair of pulp wounds.
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Wolf, Mary Caroline. "Neural and behavioral responses to complex stimuli using crayfish as a model system." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=bgsu1130864221.
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Davies, Julie Katrina. "An investigation into the anatomy and physiology of the nucleus isthmi complex in quail." Thesis, Imperial College London, 1987. http://hdl.handle.net/10044/1/38280.
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Sengupta, Shomit. "The role of mammalian target of rapamycin complex 1 in hepatic physiology and disease." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57673.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>The multi-component kinase mTOR complex 1 (mTORC 1) coordinates nutrient and growth factor inputs with numerous downstream processes including protein translation, autophagy, metabolism and cell growth. We have found that inhibition of mTORC 1 with rapamycin treatment suppressed whole-body postnatal growth similar to reduced caloric intake. We found that while feeding activated mTORC 1 in almost every tissue, there was variability in the upstream activating stimuli. The role of mTORCl in organ growth was further elucidated by studies we performed using liver-specific mTORC1 gain and loss of function mutants. Confirming our studies with rapamycin, genetic activation or suppression of mTORC 1 increased and decreased liver size respectively, and rendered the liver insensitive to nutrients. Rendering the liver insensitive to nutrients also had functional consequences. In response to starvation, the liver shifts to fatty acid catabolism and generates ketone bodies to supplement lowered glucose levels. We find that constitutive activation of mTORC1 prevents the liver from initiating fatty-acid oxidation and ketone production in response to fasting. Many aspects of the hepatic fasting response malfunction in old age including fatty acid catabolism and ketogenesis. We find this aging-dependent process is mediated by mTORC 1, and thus loss of mTORC 1 function throughout the adult life of the animal prevents the aging induced decrease in hepatic ketogenesis. As such, pharmaceutical inhibition of mTORC 1 may be beneficial in battling metabolic disorders due to aging.<br>(cont.) Pharmaceutical inhibition of mTORC is a potential treatment for patients suffering from tuberous sclerosis complex (TSC). The disease TSC in humans is initiated by loss of TSC1 or TSC2, which results in hyperactive mTORC 1 activity. The disease can involve development of multiple lesions including brain harmatomas, angiomyolipomas (AMLs), and lymphangioleiomyomatosis (LAM). We have engineered transgenic mice that express Rheb2, an mTORC 1 activator, in a doxycycline-inducible manner. Overexpression of Rheb2 led to cystic growths with characteristics of both LAM and AML. We hope this mouse model will be helpful in furthering our understanding of the pathology behind these lesions, and provide a mouse model for therapeutic intervention for TSC.<br>by Shomit Sengupta.<br>Ph.D.
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Teo, Ee Hiok. ""The morphology of the pineal complex in the scincid lizard, Tiliqua rugosa" /." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09pht314.pdf.
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Tang, Haoran. "Scar/WAVE complex suppresses cell invasion and cancer cell transformation." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3633/.
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The mechanisms by which cancer cells hijack the actin cytoskeleton to invade and disseminate to distant sites of metastasis remains one of the great frontiers in cancer research. Many actin-regulating proteins have been identified to be important in cancer cell invasion and metastasis. However the role of a major actin assembly promoting complex, Scar/WAVE regulatory complex (WRC) in cancer cell invasion is poorly understood. WRC has a well-known motility-promoting role in 2D planar cell migration, but a recent study on human epithelial cancers suggests WRC may be anti-invasive in vivo. To investigate the controversy, human epithelial cancer cells with reduced WRC expression were tested in multiple 3D cell motility assays. Interestingly, WRC demonstrates a robust anti-invasive role in these exciting experiments. To understand how loss of WRC promotes invasion, the molecular mechanism is investigated. N-WASP is the other major actin assembly promoting protein. Unlike WRC, N-WASP is interestingly not required for 2D planar cell migration, but is important for motility in 3D. The interplay of the two major actin assembly promoting proteins has not been explored in 3D cell motility. I report here that loss of WRC promotes hyper-activation of focal adhesion kinase that leads to N-WASP accumulation and activation at the invasive front. This chain of events results in enhanced invasion providing a molecular mechanism of WRC’s anti-invasive function.  In addition to this FAK-N-WASP core mechanism, I also identified a novel pro- invasive role of HSPC300 independently of WRC. Loss of WRC possibly releases free HSPC300 that could subsequently interact with and regulate N-WASP activation during invasion providing a potential direct molecular link between the two proteins. Furthermore, WRC also supresses focal adhesion kinase mediated cell transformation and tumour formation in vivo. In this thesis I therefore demonstrate novel anti-invasion and anti-tumourigenesis functions of WRC. I also show how a novel WRC binding protein, NHS, could negatively regulate WRC function.
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Menke, Nathan. "A COMPUTATIONAL BIOLOGY APPROACH TO THE ANALYSIS OF COMPLEX PHYSIOLOGY: COAGULATION, FIBRINOLYSIS, AND WOUND HEALING." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2093.
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The birth of complexity research derives from the logical progression of advancement in the scientific field afforded by reductionist theory. We present in silico models of two complex physiological processes, wound healing and coagulation/fibrinolysis based on two common tools in the study of complex physiology: ordinary differential equations (ODE) and Agent Based Modeling (ABM). The strengths of these two approaches are well-suited in the analysis of clinical paradigms such as wound healing and coagulation. The complex interactions that characterize acute wound healing have stymied the development of effective therapeutic modalities. The use of computational models holds the promise to improve our basic approach to understanding the process. We have modified an existing ordinary differential equation model by 1) evolving from a systemic model to a local model, 2) the incorporation of fibroblast activity, and3) including the effects of tissue oxygenation. Possible therapeutic targets, such as fibroblast death rate and rate of fibroblast recruitment have been identified by computational analysis. This model is a step toward constructing an integrative systems biology model of human wound healing. The coagulation and fibrinolytic systems are complex, inter-connected biological systems with major physiological roles. We present an Agent Based Modeling and Simulation (ABMS) approach to these complex interactions. This ABMS method successfully reproduces the initiation, propagation, and termination of blood clot formation and its lysis in vitro due to the activation of either the intrinsic or extrinsic pathways. Furthermore, the ABMS was able to simulate the pharmacological effects of two clinically used anticoagulants, warfarin and heparin, as well as the physiological effects of enzyme deficiency/dysfunction, i.e., hemophilia and antithrombin III-heparin binding impairment, on the coagulation system. The results of the model compare favorably with in vitro experimental data under both physiologic and pathophysiologic conditions. Our computational systems biology approach integrates reductionist experimental data into a cohesive model that allows rapid evaluation of the effects of multiple variables. Our ODE and AMBS models offer the ability to generate non-linear responses based on known relationships among variables and in silico modeling of mechanistic biological rules on computer software, respectively. Simulations of normal and disease states as well as effects of therapeutic intervention demonstrate the potential uses of computer simulation. Specifically, models may be applied to hypothesis generation and biological advances, discovery of new diagnostic and therapeutic options, platforms to test novel therapies, and opportunities to predict adverse events during drug development. The ultimate aim of such models is creation of bedside simulators that allow personalized, individual medicine; however, a myriad of opportunities for scientific advancement are opened through in silico experimentation.
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Ono, Santa Jeremy. "Major histocompatibility complex association of insulin-dependent diabetes in the BB rat." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74607.
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BB rats spontaneously develop an insulin-dependent diabetes mellitus strikingly similar to the syndrome observed in man. The disorder requires the presence of multiple susceptibility genes and unknown environmental factors. At least one susceptibility gene resides within the u haplotype of the rat major histocompatibility complex (RT1). Restriction fragment length polymorphism analysis of genomic DNA from rats generated from a series of intercrosses between diabetic BB rats and Buffalo rats (RT1$ sp{ rm b})$ demonstrated that animals heterozygous throughout the RT1 developed IDDM. A single dose of the high risk allele was thus shown to be sufficient for the development of IDDM if other susceptibility factors are present. RFLP analysis of DNA from rats generated in three other breeding studies involving the r8 and r4 recombinant haplotypes mapped the IDDM susceptibility genes between the RT1.A and RT1.C loci, the immune response region. As the u regions of the various haplotypes used in these studies were not derived from the BB rat, the development of IDDM in the progeny strongly suggested that the MHC requirement for IDDM is only for a "u" allele and not a particular or "diabetogenic" u allele.<br>Analysis of the expression of MHC genes in isolated islets of age-matched BB and Wistar-Furth rats demonstrated enhanced class I MHC gene expression in the islets of prediabetic BB rats. Immunohistochemical analysis confirmed that enhanced class I expression was an early event during the pathogenesis of IDDM, and did not detect aberrant expression of class II antigen on beta cells. Investigation of the inducibility of class I and II MHC genes on the rat insulinoma cell line RIN5F by crude lymphokine preparations or recombinant gamma-interferon indicated that although both classes of genes were inducible, their kinetics of induction are quite different. In vitro nuclear transcriptions demonstrated that induction of the genes had a transcriptional basis. Although class II genes were induced by gamma-interferon, class II antigen was not detected by flow cytometric analysis.
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Bishop, Clayton. "Biochemical and Structural studies of AAV-2 Rep68-AAVS1 complex assembly." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3511.
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Multiple DNA transactions are at the center of almost all processes regulating the AAV life cycle. A common feature shared by all transactions is the binding of the large AAV Rep proteins Rep78/Rep68 onto DNA sites harboring multiple GCTC repeats. AAV mediated site-specific integration is contingent upon the formation of a productive complex between Rep78/Rep68 and the AAVS1 site located at chromosome 19. In order to understand the mechanistic details of the initial assembly process we carried out equilibrium binding experiments of Rep68 and its individual domains with a 42-mer AAVS1 site. Results show that although Rep68 binds AAVS1 with high affinity (69 nM), both the OBD and helicase individual domains bind DNA weakly with affinities of >>60μM and 22μM respectively under our experimental conditions. Mutant Rep68 proteins that have a defective oligomerization interface bind DNA poorly suggesting that productive binding requires both the concerted interaction of the individual domains with DNA and oligomerization. Moreover, we show that a minimal number of two repeats is required to form a stable complex. In addition, initial studies were done to characterize the interaction between Rep68 and the viral ITR DNA sequences using AUC and electron microscopy.
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Fort, Loïc. "FAM49B : first negative regulator of the Scar/WAVE complex : from evolution to an in vivo analysis." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8673/.
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Sauer, Juergen. "Human skill maintenance in complex work environments : applications to extended spaceflight." Thesis, University of Hull, 1997. http://hydra.hull.ac.uk/resources/hull:8298.
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This thesis examines human performance under sub-optimal working conditions during work with complex and highly-automated process control systems. The operational context focuses on applications in extended spaceflight but the generic approach allows for generalisations beyond this target work environment The methodological approach is based on the use of a computerised multiple-task environment to carry out generic simulations of real work environments (micro-worlds) with a high level of ecological validity. For that purpose, a PC-based task. environment was developed to simulate the operation of a life support system in a spacecraft. This task environment has been used in lab-based experiments with trained participants from the student population and with real space crews during large-scale mission simulations. A series of six experiments was carried out (3lab and 3 field studies) to investigate the impact of different configurations of sub-optimal working conditions and unfavourable operator states, using the following independent variables: sleep deprivation, dialogue control, social isolation and confinement, training, noise, extended lay-off period and different types of system faults (corresponding to variations in workload). The task environment comprised up to five tasks, allowing for the observation of differential effects of the independent variables on different levels of cognitive activity. Dependent variables included primary task performance, secondary task performance, system control behaviour, information sampling behaviour, and subjective state measures. The findings suggested that primary performance was rarely affected, whereas certain secondary task measures and, notably, information sampling strategies appeared to be good indicators of changes in demand under the unfavourable conditions. The isolation and confinement experiments revealed no serious breakdown of performance among the crew but some indications of strain were observed. The use of two different training approaches displayed a very complex picture, with no method showing clear superiority over the other concerning performance, though there were differences in knowledge structure and system management behaviour. An important implication of the experimental work is that a broad methodological approach is needed in order to investigate the complex adjustment patterns displayed by individuals during the management of task demands under unfavourable conditions.
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Hoy, Jennifer Lyn 1981. "The Development of Excitatory Synapses and Complex Behavior." Thesis, University of Oregon, 2011. http://hdl.handle.net/1794/12068.
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xi, 111 p. : ill. (some col.)<br>Excitatory glutamatergic synapses facilitate important aspects of communication between the neurons that govern complex forms of behavior. Accordingly, small differences in the molecular composition of glutamatergic synapses have been suggested to underlie neurodevelopment disorders, drive evolutionary changes in brain function and behavior, and enhance specific aspects of cognition in mammals. The appropriate development and later function of these structures in the adult involves the wellcoordinated activities of hundreds of molecules. Therefore, an important goal in neuroscience is to identify and characterize how specific molecules contribute to the development of excitatory synapses as well as how manipulations of their function impact neural systems and behavior throughout life. This dissertation describes two important contributions toward this effort, (1) that the newly discovered molecule, Synaptic Cell Adhesion Molecule 1 (SynCAM1) specifically contributes to the early stages of glutamatergic synapse formation and (2) that Neuroligin1 (NL1) contributes to the mature function of glutamatergic synapses and mature forms of behavior in vivo.
In the first set of experiments, I developed an in vitro cell based assay in order to determine the minimal molecular components necessary to recruit developmentally relevant glutamate receptor subtypes to sites of adhesion mediated by SynCAM1. In these experiments we discovered that protein 4.1B interacted with SynCAM1 in order to cause the specific recruitment of the NMDA type glutamate receptor containing the NR2B subunit. In the second set of experiments, we show that expression of NL1 missing the terminal 55 amino acids enhanced short term learning and flexibility in behaving mice while increasing the number of immature excitatory postsynaptic structures. Interestingly, this behavioral profile had components more consistent with 1 month old juvenile controls than age matched control littermates. In contrast, full length NL1 overexpression impaired learning and enhanced perseverance while yielding an increase in the proportion of synapses with mature characteristics. These results suggest that NL1's C-terminus drives the synaptic maturation process that shapes the development of complex behavior. Both studies bolster our understanding of how specific molecules impact the development of excitatory synapses and complex behavior.
This dissertation includes both my previously published and unpublished co-authored material.<br>Committee in charge: William Roberts, Chairperson;
Philip Washbourne, Advisor;
Victoria Herman, Member;
Michael Wehr, Member;
Judith Eisen, Member;
Clifford Kentros, Outside Member
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Sayegh, Camil E. "The role of the B cell receptor complex in avian B cell development dissected by retroviruses /." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37621.
Full textAbstract:
During embryogenesis, B cell precursors that have undergone productive Ig V(D)J rearrangement are selected to expand in oligoclonal follicles of the bursa of Fabricius. Because Ig V(D)J recombination in chickens results in minimal diversity, diversity being generated instead by gene conversion in the follicles of the bursa of Fabricius, B cell precursors express a limited range of Ig specificities prior to colonization of the bursa. It has been proposed that recognition of endogenous ligands by this 'pre-diversified' B cell receptor is critical to the progression of normal B cell development. To test this hypothesis, we constructed a truncated IgM receptor (Tmu) lacking the V and Cmu1 domain, which does not associate with Ig L chain proteins nor does it require IgL chains for surface expression, and used a retroviral gene transfer system to introduce it in developing chick embryos. In these embryos, Tmu+ B cell precursors productively colonized bursal follicles as efficiently as B cell precursors expressing endogenous sIg. Furthermore, we detected low but significant levels of IgL VJ rearrangements in Tmu + bursal cells. The analysis of these VJ junctions revealed no selection for in-frame products as these cells are maintained by the Tmu receptor. Interestingly, we showed that the rearranged VL segments derived from Tmu+ bursal cells underwent gene conversion indistinguishably from rearranged VL segments derived from bursal cells expressing endogenous sIg. Taken together, we have ruled out a role for V(D)J encoded determinants in the normal development of B cells in avian embryos. Sequence analysis of 80 IgL VJ segments derived from Tmu+ bursal allowed the unique opportunity to assess the efficiency of gene conversion in vivo, in the absence of selection. Using this system, we demonstrated that >97% of gene conversion events maintain the sequence in-frame. Following hatching, the bursa undergoes morphological changes initiated by the migration of bursal cells ba
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Sunu, Shawn Y. "MITOCHONDRIAL THERAPEUTICS DURING ISCHEMIA-REPERFUSION; MODULATION OF COMPLEX I: EFFECT OF METFORMIN." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3822.
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The modulation of the electron transport during ischemia-reperfusion has been shown to be protective. We hypothesized that metformin, a Complex I inhibitor, may exhibit characteristics of a pharmacological agent that could achieve long-term therapeutic intervention against ischemia-reperfusion injury. Mitochondria were harvested from adult male mice and incubated with or without metformin at 30oC for 15 minutes, while being shaken at 300 rpm. Metformin decreased Complex I oxidative phosphorylation and Complex I activity. However, metformin also increased injury and decreased the maximum membrane potential. Even though there was a decrease in maximum membrane potential, the proton motive force (PMF) was still intact as the ADP/O ratio was not affected. In conclusion, metformin does exhibit some characteristics of a drug that could achieve long-term therapeutic benefit against ischemia-reperfusion.
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Bauer, Eric Edmond. "Responses of cells of the dorsal nucleus of the lateral lemmniscus to species-specific and other complex sounds." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3035940.
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Song, Zhe. "Immunofluorescent approaches to investigate the mammalian target of rapamycin (mTOR) complex in human skeletal muscle." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6338/.
Full textAbstract:
The mammalian target of rapamycin (mTOR) complex is a key regulator of protein synthesis, with resistance exercise and protein ingestion both shown to increase mTOR activity in human skeletal muscle. It has recently been proposed that mTOR activity is regulated via its intracellular localization and protein complex interaction. However, no research to date has examined this process in human skeletal muscle. Accordingly, the aims of this thesis were to (1) develop immunofluorescent-based methodologies to study mTOR in human skeletal muscle, and (2) apply this approach to the study of mTOR in acute and chronic resistance exercise scenarios. This thesis describes a novel approach to study mTOR regulation in human skeletal muscle in vivo. Taking advantage of this approach, novel data was presented on mTOR distribution, translocation and association with regulators in response to resistance exercise in human skeletal muscle in vivo. It is hoped that this approach will provide insight into the cellular regulation of skeletal muscle protein synthesis and by extension the control of skeletal muscle mass in humans during scenarios of health and chronic disease.
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Siddiqui, Jalal K. "Modeling the response of troponin C to calcium in increasingly complex systems." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480258715871156.
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Smith, Cody Don. "Characterization of the LKB1-MO25-STRAD AMPKK Complex in Adult Mouse Skeletal Muscle." BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2803.
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In liver tissue, the AMP-activated protein kinase kinase (AMPKK) complex was identified as the association of LKB1, MO25α/β, and STRADα/β proteins; however, this complex has yet to be characterized in skeletal muscle. In this report, we demonstrate the expression of the LKB1-MO25-STRAD AMPKK complex in adult skeletal muscle, confirm the absence of mRNA splice variants, and report the relative mRNA expression levels of these complex-forming proteins. To facilitate this characterization we used control (ctrl) and muscle-specific LKB1 knockout (LKB1-/-) mice. LKB1 detection in untreated ctrl and LKB1-/- muscle lysates revealed two protein bands at approximately 50 and 60 kDa; although, only the heavier band was significantly diminished in LKB1-/- samples (ctrl: 55±2.5 AU; LKB1-/-: 13±1.5 AU; p<0.01), suggesting that LKB1 is not represented at 50 kDa as cited previously. Detection of LKB1 at the higher molecular weight was further confirmed following purification of the AMPKK complex using polyethylene glycol (PEG) (ctrl: 43±5 AU; LKB1-/-: 8.4±4 AU; p<0.01). Following ion-exchange-fast protein liquid chromatography (FPLC) the low protein band was undetectable in ctrl and LKB1-/- fractions. Mass spectrometry of PEG-treated ctrl lysates confirmed LKB1 protein detection in the 60 kDa protein band while none was detected in the 50 kDa band. Co-immunoprecipitation assays demonstrated associations between all combinations of LKB1, MO25, and STRAD in LKB1-positive samples, confirming proper complex formation. Quantitative-PCR revealed significantly reduced expression of MO25α and STRADβ in LKB1-/- muscle. Lastly, detection of CaMKKα/β protein in ctrl and LKB1-/- muscle lysates confirmed the presence of another AMPKK in muscle. Interestingly, CaMKKβ protein is increased in LKB1-/- muscle (ctrl: 19±4.3 AU; LKB1-/-: 47±9.2 AU; p<0.05) without an increase in mRNA levels, suggesting compensation for null LKB1 expression. In all, these findings confirm the presence of the LKB1-MO25-STRAD complex in adult skeletal muscle, suggest a novel post-translational modification of LKB1, and identify a potential compensatory mechanism for loss of LKB1 protein in skeletal muscle.
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Liu, Zheng-Xian. "Antioxidant activity of Mn-salophen complex and its effects on antioxidant enzymes in Escherichia coli." Diss., Virginia Tech, 1994. http://hdl.handle.net/10919/40046.
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Mn-salophen complex with superoxide-scavenging activity was prepared from manganese(III) acetate dihydrate and salophen in ethanol. Visible absorption spectrum of the red-brown solution exhibited a broad absorption band at 430 - 450 nm with two shoulders between 500 and 600 nm which were absent with either salophen or manganic acetate alone. Titration of salophen with manganese(III) was consistent with a 1:1 Mn to salophen stoichiometry of the complex based on changes in the absorbance at 500 nm or of superoxide scavenging activity. The SOD-like activity of the complex in the xanthine-xanthine oxidase/cytochrome <i>c</i> assay was 1450 units/mg salophen. The SOD activity of the complex was suppressed 50% in the presence of EDTA (1 mM), but was not altered in the presence of bovine serum albumin (1 mg/ml) or crude protein extract of <i>E. coli</i> QC779 <i>sodA sodB</i> (1 mg/ml). <i>E. coli</i> QC779 <i>sodA sodB</i> grew scantily after an 8 hour lag phase in aerobic M63 glucose minimal medium.<br>Ph. D.
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Bohara, Gyanendra. "Application of Statistical Physics in Human Physiology: Heart-Brain Dynamics." Thesis, University of North Texas, 2018. https://digital.library.unt.edu/ark:/67531/metadc1248449/.
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This dissertation is devoted to study of complex systems in human physiology particularly heartbeats and brain dynamics. We have studied the dynamics of heartbeats that has been a subject of investigation of two independent groups. The first group emphasized the multifractal nature of the heartbeat dynamics of healthy subjects, whereas the second group had established a close connection between healthy subjects and the occurrence of crucial events. We have analyzed the same set of data and established that in fact the heartbeats are characterized by the occurrence of crucial and Poisson events. An increase in the percentage of crucial events makes the multifractal spectrum broader, thereby bridging the results of the former group with the results of the latter group. The crucial events are characterized by a power index that signals the occurrence of 1/f noise for complex systems in the best physiological condition.
These results led us to focus our analysis on the statistical properties of crucial events. We have adopted the same statistical analysis to study the statistical properties of the heartbeat dynamics of subjects practicing meditation. The heartbeats of people doing meditation are known to produce coherent fluctuations. In addition to this effect, we made the surprising discovery that meditation makes the heartbeat depart from the ideal condition of 1/f noise.
We also discussed how to combine the wave-like nature of the dynamics of the brain with the existence of crucial events that are responsible for the 1/f noise. We showed that the anomalous scaling generated by the crucial events could be established by means of a direct analysis of raw data. The efficiency of the direct analysis procedure is made possible by the fact that periodicity and crucial events is the product of a spontaneous process of self-organization. We argue that the results of this study can be used to shed light into the nature of this process of self-organization.
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Rattray, Benjamin, and n/a. "The validation of physiological field testing in elite orienteers." University of Canberra. Sports Studies, 2002. http://erl.canberra.edu.au./public/adt-AUC20050629.113059.
Full textAbstract:
The complex physiology of orienteering performance is not well understood but recent
advances in technology allow for more in-depth investigation. The purpose of this
study was to develop and validate physiological field tests for elite orienteers in
Australia.
Seven male and three female elite orienteers volunteered to take part in the study.
Subjects completed an incremental fixed-distance (803m) trial in Australian forest
terrain, paced by a bicycle equipped with a speedometer. This was replicated in the
laboratory using a 4.5% grade for treadmill running. Subjects also completed four
(males) or three (females) laps of a 1340m terrain loop incorporating uphill, track and
downhill sections. Subjects then repeated this test in the laboratory, with treadmill grade
manipulated to replicate the gradient profile of each section. Heart rate (HR) and
oxygen uptake (VCh) were recorded continuously with telemetry during each stage/lap.
Blood [La] and RPE were recorded after each stage/lap.
In the incremental tests, no significant differences (p=0.05 level) were observed in HR,
VO2, blood [La] or RPE between the Field test, and its Laboratory replication over the
entire range of speeds tested. The actual speeds run during the Field tests were
significantly faster than the Laboratory test at the slowest speed (8 kmh- 1 ) attempted,
and slower at the fastest speed (18 km-h-1) attempted. In the time-trial tests, no
significant differences were observed in HR, VO2, blood [La] or RPE between the
Field test and its Laboratory replication. The running speeds in the Field tests were
significantly slower than the Laboratory tests. Running speed appeared inversely
related to the course profile and the terrain also affected the speeds that could be
achieved. Despite the changes in the course profile, the physiological responses to the
course were maintained within a narrow range at a high level (-95% of maximal heart
rate, 80-90% of VO2max, blood [La] -10 mM) for the duration of the 20-25 minute test.
The Field tests that were developed in this study for elite orienteers in Australian forest
terrain were successfully validated by replicating the protocols in a Laboratory setting.
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López, Begines Santiago. "Unveiling novel components of the protein complex responsible for cGMP synthesis in retinal photoreceptors: role in cell physiology and disease." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/461890.
Full textAbstract:
In photoreceptor cells of the retina, light triggers a protein G-mediated enzymatic cascade that leads to hydrolysis of cGMP. The drop in cGMP levels causes the closure of cGMP-channel at the plasma membrane, decreasing the influx of cations, mainly Na+ and Ca2+, hyperpolarizing the cell. This hyperpolarization decreases the rate of neurotransmitter release at the synaptic terminal. Photoreceptor cells must recover the darkness equilibrium and adapt their light sensitivity to the wide range of light intensities present in the natural world. Genetic defects at both activation and termination cascades leads to inherited retinal dystrophies.
The cGMP levels are restored to darkness equilibrium by new synthesis by the complex formed by a membrane form of guanylate cyclase (RetGC) which is bound to a couple of proteins that confers it calcium sensitivity, Guanylate Cyclase Activating Proteins (GCAP1 and GCAP2). RetGC activity is stimulated by the drop of Ca2+ concentration because of close of cGMP-channels. There is a feedback loop between cGMP and Ca2+ that has a fundamental role in the processes of termination of light response and light adaptation. RetGC1 is responsible for cGMP synthesis in rods and cones. Mutations of genes involved in the cGMP synthesis complex have been linked to autosomal dominant inherited retinal dystrophies, both retinitis pigmentosa (adRP) as Leber’s congenital amaurosis (LCA)
The regulation of RetGC by GCAPs proteins has been extensively studied in vitro, at biochemical and structural levels. However, many relevant aspects of regulation and trafficking of this complex in vivo remains unknown.
By subretinal electroporation, we have analyzed the molecular determinants of subcellular distribution of GCAPs. We have determined that the complex between RetGC1 and GCAP1 is assembled in the inner segment and then transported to the outer segment, playing a determinant role the myristoylation of GCAP1 and the binding of GCAP1 to the cyclase. On the other hand, phosphorylation plays an essential role in subcellular distribution of GCAP2, and failures in subcellular localization of GCAP2 could contribute to explain the pathophysiology of the human G157R mutation linked to adRP.
We here report a proteomic approach to identify novel interactors of Guanylate Cyclase Activating Protein 1 (GCAP1) that led to the unexpected discovery of inosine monophosphate dehydrogenase 1 (IMPDH1) interaction with retinal guanylate cyclase 1 (RetGC1). IMPDH1 is the rate-limiting step in de novo GTP synthesis, and mutations in impdh1 gene have been associated to adRP and LCA. We reveal an unanticipated direct interaction between IMPDH1 and RetGC1 at photoreceptor outer segments where phototransduction takes place. The interaction involves the dimerization and catalytic domains of RetGC1, and is significantly affected by IMPDH1 mutations associated to blindness. This finding links de novo GTP synthesis to GTP conversion to cGMP, bridging blindness-causative genes so far considered unrelated and creating a new scenario for the development of therapeutic strategies. By bridging distinct blindness-causative genes in a common biochemical pathway, we here contribute to reduce the apparent complexity of inherited retinal dystrophies grouping them on base common metabolic pathways. The main aim of this strategy of grouping genes on base of their function is to identify “hubs” of cell damage.
We also have characterized the interaction between RetGC1 and Creatine kinase B, which could be supplying locally the ATP needed to maintain the catalytic activity in cones.
This work aid to understanding about regulation and trafficking of RetGC/GCAPs complex, as well as the interplaying between the cGMP synthesis complex and de novo GTP synthesis, opening a new conceptual framework for pharmacological treatment of diseases that trigger changes in intracellular levels of cGMP, which in a prolonged way affect to cell survival, leading to inherited blindness.<br>En fotorreceptores de retina, la respuesta a luz desencadena la hidrólisis del cGMP. La síntesis de cGMP recae en el complejo formado por una forma de membrana de la guanilato ciclasa (RetGC1 y RetGC2) y unas proteínas que le confieren sensibilidad a calcio (Guanylate Cyclase Activating Proteins GCAP1 y GCAP2). Mutaciones en los genes que codifican para las proteínas integrantes de este complejo han sido ligadas distrofias hereditarias de retina autosómicas dominantes. La regulación de este complejo ha sido extensamente estudiada in vitro, sin embargo, muchos aspectos relacionados con este complejo en el entorno de la célula viva se desconocen.
Determinamos mediante electroporación subretinal que el ensamblaje del complejo formado por RetGC1 y GCAP1 precede a su transporte hacia el segmento externo y tanto la miristoilación como la unión a la ciclasa por parte de GCAP1 son necesarias para su transporte. Por otro lado, la fosforilación juega un papel clave en la distribución celular de GCAP2, y fallos en la localización de GCAP2 podrían contribuir a explicar la patofisiología de la mutación hG157R ligada a retinosis pigmentaria autosómica dominante.
Mediante una aproximación proteómica para identificar nuevos interactores de GCAP1, hemos caracterizado la interacción directa entre la guanilato ciclasa y la inosina monofosfato deshidrogenasa (IMPDH1), la enzima responsable del paso limitante en la síntesis de novo de GTP. Mutaciones en el gen impdh1 se han asociado a distrofias hereditarias de retina autosómicas dominantes. Ambas proteínas se localizan en el compartimento sensorial, interaccionan en el orden micromolar, involucrando a los dominios de dimerización y catalítico de RetGC1 y la interacción se afecta significativamente por los mutantes asociados a ceguera en IMPDH1.
Además también se ha caracterizado la interacción de RetGC con la Creatina quinasa B (CKB), la cual podría está proporcionando el ATP local necesario para mantener la actividad catalítica específicamente en conos.
Este trabajo arroja luz sobre la regulación y transporte del complejo RetGC/GCAPs, así como la interconexión entre los complejos de síntesis de cGMP y síntesis de novo de GTP, integrando genes asociados a enfermedad en base a su implicación en procesos metabólicos comunes, abriendo un nuevo escenario para el tratamiento farmacológico de enfermedades que provoquen cambios en los niveles de cGMP intracelulares.
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GAMA, ARACHCHIGE NALIN SURANJITH. "PHYSICAL DORMANCY IN SEEDS, WITH SPECIAL REFERENCE TO GERANIACEAE: MORPHO-ANATOMY, DEVELOPMENT, PHYSIOLOGY, BIOMECHANICS AND CLASSIFICATION OF WATER-GAP COMPLEXES." UKnowledge, 2013. http://uknowledge.uky.edu/biology_etds/11.
Full textAbstract:
The primary aims of this dissertation were to (1) identify and characterize the water-gap complex in seeds of Geraniaceae, (2) investigate its role in physical dormancy (PY) break and (3) develop a new classification system for water-gap complexes in seeds of angiosperms. The winter annuals Geranium carolinianum and G. dissectum were selected as the main representative species for the study, and seeds of an additional 29 species from the Geraniaceae were used to compare the water-gap complex within the family. A new classification system for water-gap complexes in species with PY was developed by comparing the morpho-anatomical features of PY seeds and fruits of 16 families.
The water-gap complex of G. carolinianum was identified as a micropyle-hinged valve gap complex, and only a slight morpho-anatomical variation was observed within the family. Ontogenetic studies of the seed coat of G. carolinianum revealed that the water-gap region of Geraniaceae develops as an entity of the micropyle. The timing of seed germination with the onset of autumn can be explained by PY-breaking processes involving (a) two-temperature-dependent steps in G. carolinianum, and (b) one or two moisture-dependent step(s) along with the inability to germinate under high temperatures in G. dissectum. Step-I and step-II in PY-breaking of G. carolinianum are controlled by chemical and physical processes, respectively. This study indicates the feasibility of applying the developed thermal time model to predict or manipulate sensitivity induction in seeds with two-step PY-breaking processes. The model is the first and the most detailed one yet developed for sensitivity induction in PY-break. Based on the morpho-anatomical features, three basic water-gap complexes (types I, II and III) were identified in species with PY in 16 families. Depending on the number of openings involved in initial imbibition, the water-gap complexes were subdivided into simple and compound. The new classification system enables the understanding of relationships between water-gap complexes of taxonomically unrelated species with PY.
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McGuire, Vincent Michael. "Assembly and function of the PsB multiprotein complex during spore differentiation in Dictyostelium discoideum /." free to MU campus, to others for purchase, 1996. http://wwwlib.umi.com/cr/mo/fullcit?p9737858.
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Parrish, Austin R. "Effect of hybrid/complex N-glycosylation on cardiac voltage-gated ion channel expression." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1558106533403433.
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Bach, Eva C. "NMDA RECEPTORS IN THE DORSAL VAGAL COMPLEX OF NORMAL AND DIABETIC MICE." UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/14.
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The dorsal vagal complex (DVC), containing the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus nerve (DMV), plays a pivotal role in autonomic regulation. Afferent fibers from peripheral organs and higher brain centers synapse in the NTS, which integrates these synaptic connections as well as information from systemically circulating hormones and metabolites. The integrated information is relayed to the dorsal motor nucleus of the vagus nerve (DMV), which in turn, projects motor fibers to elicit parasympathetic control of digestive and other viscera. Physiological functions mediated by the DVC are disrupted in diabetic patients and synaptic plasticity within the DVC has been linked to these complications. N-methyl-D-aspartic acid (NMDA) receptors have been extensively studied for their involvement in synaptic plasticity in a variety of central nervous system disorders; and their activation in the DVC modulates hepatic glucose production and feeding behavior. Although chronic disease can alter NMDA function, changes in DVC expression and/or sensitivity of NMDA receptors in diabetic states has not been addressed. Using whole cell electrophysiology, functional properties of the nuclei in the DVC were investigated in normoglycemic and type 1 diabetic mice. Preterminal NMDA (preNMDA) receptors were discovered to tonically modulate excitatory neurotransmission on terminals contacting DMV neurons. While these preNMDA receptors were not found to differentially modulate tonic excitatory neurotranmission, soma-dendritic NMDA receptor responses of NTS neurons were augmented in type 1 diabetic mice. Through the use single-cell PCR, increased NMDA receptor responses could be correlated to neurons that mediate excitatory neurotransmission and would argue that augmented NMDA receptor responses increase vagal output. In general, enhancing vagal output decreases activity of connected peripheral organs. Molecular approaches were employed to corroborate the observed functional NMDA receptors changes to their protein and mRNA expression levels. Overall, results argue that NMDA receptors are involved in synaptic plasticity in DVC of type 1 diabetic mice to enhance excitatory neurotransmission. This modulation may potentially serve as a physiological counter regulatory mechanism to control pathological disturbances of gastrointestinal homeostatic reflex responses.
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Varga, Adrienn Gabriella. "The Neural Basis of Head Direction and Spatial Context in the Insect Central Complex." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1487249074487484.
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Branvold, Devon Jack. "Regulation of LKB1-STRAD-MO25 Complex Expression and Activation of AMPK in Skeletal Muscle by Thyroid Hormone." BYU ScholarsArchive, 2007. https://scholarsarchive.byu.edu/etd/1407.
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AMP-activated protein kinase (AMPK), a heterotrimeric protein which serves as a metabolic master switch in skeletal muscle, is a research target for the pharmaceutical treatment and prevention of type 2 diabetes. The expression of all of the isoforms of the subunits of AMPK and AMPK activity are increased in skeletal muscle tissue of hyperthyroid rats. Activity of AMPK is regulated by an upstream kinase (AMPKK). The LKB1-STRAD-MO25 complex is a major AMPKK in skeletal muscle. This experiment was designed to determine whether the increase in AMPK activity is accompanied by a thyroid hormone-induced increase in the expression of the LKB1-STRAD-MO25 complex. LKB1-STRAD-MO25 complex protein expression was determined by Western blots in control rats, in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 4 weeks, and in rats given 0.01% propylthiouracil (PTU) in drinking water for 4 weeks. The relative expression of LKB1, MO25, and STRAD, as well as PGC-1α, increased in the soleus of thyroid hormone treated rats vs. the controls. MO25 mRNA increased with thyroid hormone treatment, and STRAD mRNA increased with PTU treatment. Phospho-AMPK and phospho-ACC increased in response to electrical stimulation in muscles of all treatment groups, but was most markedly increased in hyperthyroid rats. Thyroid hormone treatment also increased the amount of phospho-CREB in the soleus, heart, and red quadriceps. These data provide evidence that thyroid hormone partially controls expression of the LKB1-STRAD-MO25 complex, as well the subsequent activation of AMPK.
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Deng, Wei. "Sialylation and Cardiomyocyte Complex N -Glycosylation Protect Against Dilated Cardiomyopathy and Heart Failure." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6221.
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Dilated cardiomyopathy (DCM) is the third most common cause of heart failure, often associated with arrhythmias and sudden cardiac death if not controlled. Metabolic and/or environmental factors, such as alcohol abuse, obesity, diabetes and Chagas disease, alter glycoprotein glycosylation, can lead to DCM. Inherited genetic disease, such as the human congenital disorders of glycosylation (CDG), causes multi-system manifestations including DCM. Non-congenital changes in glycosylation are also occurred in humans with and in animal models of DCM and heart failure. However, mechanisms responsible for glyco-dependent DCM are not understood. Here we sought to investigate the impact of sialylation and N-glycosylation in cardiac function.
Partial reduction of N-α2,3-sialylation achieved through ST3Gal4 deletion (ST3Gal4-/-) led to adult late-onset DCM. The DCM symptoms progressed gradually, developing thinner left ventricular walls and dilation of all four chambers by 18-month old, but with preserved systolic function. Transverse aortic constriction (TAC) was used as a chronic stressor on 16-20 week old mice to determine whether the ability of the ST3Gal4-/- heart to compensate against pathologic insult is compromised. TAC’d ST3Gal4-/- mice presented with insufficient hypertrophy and reduced systolic function that deteriorated into congestive HF within six weeks post-surgery, while constricted WT hearts remained well-adapted throughout (ejection fraction, ST3Gal4-/-=34±5.2%; WT =53.8±7.4%; p<0.05).Calcineurin expression was decreased in ST3Gal4-/- (compared to TAC’d WT), contributed to the maladaptation of TAC’d ST3Gal4-/-.
In order to better understand the role of glycosylation on cardiac function, we generated a cardiomyocyte specific knockout (αMHC-Cre) of glycosyltransferase responsible for synthesizing complex and hybrid N-glycans, Mgat1, (Mgat1CKO). Similar to but much more severe than that observed in ST3Gal4-/-, Mgat1CKO developed early-onset of DCM, late adult mortality, severely impaired cardiac systolic and diastolic function and frequent arrhythmias. Marked sex-difference in cardiac phenotype was observed in this autosomal gene (Mgat1) deletion, with male Mgat1CKO more severely affected. Both ST3Gal4 and Mgat1 did not participate in murine cardiogenesis, evidenced by normal litter size, Mendelian distribution of genotypes, no septal defect or vessel deformation under autopsy or echocardiography.
In conclusion, we provided here the first and direct evidence of desialylation-elicited idiopathic dilated cardiomyopathy (DCM), reporting the cardiac phenotype of ST3Gal4-/-and cardiac-specific knockout of Mgat1. Our data showed sialylation and complex N-glycosylation are essential for cardiac function, and reduced N-glycosylation or sialylation leads to DCM development, contractile dysfunction and arrhythmia.
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Matott, Michael Patrick. "The Effects of Oxygen on the Electrophysiology of CO2/H+-Chemosensitive and -Insensitive Neurons of the Solitary Complex of the Rat." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4148.
Full textAbstract:
This study tested the hypothesis that decreasing the control O2 level from 95% to 40% (5% CO2 + 55% N2) maintains viability in caudal solitary complex (cSC) neurons in transverse slices (~300-400ꝳ) prepared from neonatal rat (P2-22) maintained at 32-34°C. The underlying rationale is to reduce exposure to redox and nitrosative stimuli generated during several hours of exposure to 95% O2 that produces a tissue O2 tension throughout the slice which is in excess of 203 kPa (2.0 atmospheres absolute,ATA) oxygen. Whole cell recordings of cSC neurons maintained in 40% O2 exhibited spontaneous firing and had similar membrane potentials (Vm) and input resistances (Rin) as cSC neurons maintained in 95% O2. Neurons maintained in 40% O2, however, had significantly lower intrinsic firing rates than those maintained in 95% O2. 67% of neurons maintained in 40% O2 control were stimulated by hyperoxia, compared to 81% of neurons maintained in 95% O2 that were stimulated by reoxygenation from relative hypoxia. cSC neurons maintained in 40% O2 also exhibited CO2/H+-sensitivity, including CO2/H+-excitation (31%) and CO2H+-inhibition (31%) and most CO2/H+-sensitive neurons were also stimulated by hyperoxia and reoxygenation or inhibited by lower O2. It is also suggested that acute exposure to lower concentrations of O2 may increase the incidence of CO2-inhibited cSC neurons. Anoxia reduced or eliminated all firing in essentially all cSC neurons. Our findings indicate that brainstem slice viability is retained in 40% O2 control and that hyperoxia is a general stimulant of many cSC neurons, including chemosensitive neurons. We therefore recommend that 40% O2 be used for brainstem electrophysiology studies.
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Ferraz, Marcus Cima. "Um modelo para a dinâmica de abertura e fechamento dos estômatos de uma folha." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/43/43134/tde-20052014-161150/.
Full textAbstract:
Onde há luz suficiente ,os estômatos, pequenos poros localizados na superfície das folhas, com abertura regulável, tendem a abrir . Isto permite a absorção de C02 (e, portanto, a fotossíntese) , e a evaporação de água, que não pode, porém, ser excessiva. As plantas conseguem ajustar a sua abertura dos estômatos, otimizando a absorção de C02 e adequando-se, ao mesmo tempo, à disponibilidade de água no ambiente. Recentemente, inúmeras experiências mostraram que, ao contrário do que se supunha, a abertura de um estômato parece depender da interação deste com seus estômatos vizinhos. Sob estresse hídrico, o movimento de abrir e fechar, dos estômatos de uma região da folha, freqüentemente se sincroniza, formando padrões espaço-temporais persistentes. Este trabalho teve como objetivo o estudo da dinâmica desses padrões. Reproduzimos, num primeiro momento deste estudo, um modelo proposto por Haefner e colaboradores, para entender melhor o problema. Este modelo , no entanto, demonstrou ser ineficiente sob vários aspectos, ao contrário do que observam os autores. Novos modelos foram então propostos, com resultaados mais próximos aos observados nos experimentosque apresentam melhor concordância com os experimentos. Em particular, destacamos o Modelo de Veias Aleatórias com Histerese, que utiliza a hipótese da existência de um retardo e uma histerese no mecanismo de abertura e fechamento dos estômatos, com resultados que reproduzem a diversidade de comportamento da dinâmica estomática observada experimentalmente.<br>When there is enough light, stomata - variable aperture pores distributed on plant´s leaves - tend to open. This mechanism allows the absorption of C02 (and so the reaction of photosynthesis) as well as the evaporation of water. The plant can adjust its stomatal aperture over time, in order to maximize C02 uptake with an water loss compatible with environmental conditions. Recently, many experiments have shown that the aperture of a single stomata depends on its interaction with the neighbors in an emergent complex behavior. Under water stress the opening and closing of stomata aperture often becomes synchronized in spatially extended patches, with a rich dynamical behavior. In this work we have studied this phenomena. We first reproduce a model proposed by Haefner and collaborators, in an attempt to better understand this phenomena. The model, however, has been unable to generate patches or an oscillatory behavior in the steady state, as claimed by th authors. We proposed then new models, that show better agreement with experiments. In a particular, the model called by us Randon Vein Model with Hysteresis was able to reproduce most of the behaviors observed in real leaves, including the formation of patches and an non-regular oscillations in the steady state.
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Theurer, Miles E. "Objective monitoring of cattle." Diss., Kansas State University, 2015. http://hdl.handle.net/2097/32794.
Full textAbstract:
Doctor of Philosophy<br>Department of Diagnostic Medicine/Pathobiology<br>Robert L. Larson<br>Bradley J. White<br>There are multiple modalities available to evaluate health or stress status of animals. The objective of my research was to evaluate different modalities including behavior, rectal and nasal temperature, and blood samples to determine the relationship with these outcomes of interest in bovine respiratory disease (BRD) events, environmental conditions, transportation, and Mannheimia haemolytica challenge model. The objective for the final project was to determine whether diagnostic sensitivity or specificity resulted in greater economic value for the industry using simulation models for identification of BRD.
There was a positive association with rectal temperature and probability of not finishing the production cycle normally, but this relationship was not linear. Rectal temperature of feedlot calves at first treatment for BRD had limited value as a prognostic indicator of whether those calves would finish the production cycle normally. A positive association between rectal temperature and ambient temperature and temperature-humidity index was determined. Environmental conditions must be considered when rectal temperature is used as a diagnostic tool.
At 48 hours after initiation of transportation there were no differences in body weight, rectal temperature, and time spent at various locations in the pen detected between transported and non-transported control heifers. Transportation of heifers during periods of high ambient temperatures caused transient changes in physiologic and behavioral indices of heifers. Calves challenged with Mannheimia haemolytica had more changes in behavior, body weight, and blood biomarkers during high ambient temperatures compared to control calves. Results of this study may guide research in development of objective assessment tools for identification and management of cattle affected with BRD during extreme summer conditions.
For both low and high apparent prevalence cohorts, increasing diagnostic specificity resulted in more rapid, positive change in net returns compared to change in increasing sensitivity. Improvement of diagnostic specificity, perhaps through a confirmatory test or pen-level diagnostics, can increase diagnostic value. Mortality risk was the primary driver for net returns. Results from this study are important for determining future research priorities to analyze diagnostic techniques for BRD and provide a novel way for modeling diagnostic tests.
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Cheung, Amy. "The Role of Neurexins in Serotonin Signaling and Complex Behaviors." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1134.
Full textAbstract:
Extensive serotonin (5-HT) fiber innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behavior, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD) which often co-occurs with other neuropsychiatric conditions. While 5-HT therapeutics are used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Neurexins (Nrxns) are presynaptic cell adhesion molecules that maintain synapse function for proper neural circuit assembly. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and behavioral impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying ASD.
Using fluorescence in situ hybridization, I found that the three Nrxn genes (Nrxn1, Nrxn2, and Nrxn3) are differentially expressed in 5-HT neurons in the dorsal raphe nucleus (DRN) and median raphe nucleus which contain the primary source of 5-HT neurons in the brain. Our lab generated a mouse model with selective deletion of Nrxns in 5-HT neurons to investigate the function of Nrxns in 5-HT signaling. The loss of Nrxns at 5-HT release sites reduced 5-HT release in the DRN and hippocampus and altered 5-HT innervation in specific brain regions. The lack of 5-HTergic Nrxns also reduced sociability and increased depressive-like behavior in males. This mouse model provides mechanisms to shed new light on 5-HT neurotransmission in the generation of complex behaviors.
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Negrin, Kimberly A. "Complex Roles of Macrophages in Lipid Metabolism and Metabolic Disease: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/713.
Full textAbstract:
The worldwide prevalence of obesity and metabolic disease is increasing at an exponential rate and current projections provide no indication of relief. This growing burden of obesity-related metabolic disorders, including type 2 diabetes mellitus (T2DM), highlights the importance of identifying how lifestyle choices, genetics and physiology play a role in metabolic disease and place obese individuals at a greater risk for obesity-related complications including insulin resistance (IR). This increased risk of IR, which is characterized by a decreased response to insulin in peripheral tissues including adipose tissue (AT) and liver, is associated with a chronic, low grade inflammatory state; however, the causative connections between obesity and inflammation remains in question. Experimental evidence suggests that adipocytes and macrophages can profoundly influence obesity-induced IR because adipocyte dysfunction leads to ectopic lipid deposition in peripheral insulin sensitive tissues, and obese AT is characterized by increased local inflammation and macrophage and other immune cell populations. Attempts to delineate the individual roles of macrophage-derived pro-inflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), have demonstrated causative roles in impaired systemic insulin sensitivity, adipocyte function and hepatic glucose and lipid metabolism in obese animal models. Thus, the attenuation of macrophage-derived inflammation is an evolving area of interest to provide insight into the underlying mechanism(s) leading to obesity-induced IR.
Thus, in the first chapter of this thesis, I describe experiments to refine the current paradigm of obesity-induced AT inflammation by combining gene expression profiling with computational analysis of two anatomically distinct AT depots, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to address whether the inflammatory signature of AT is influenced by diet-induced obesity (DIO). Microarray and qRT-PCR analysis data revealed that DIO mouse SAT is resistant to high fat diet (HFD)-induced inflammation and macrophage infiltration, and our data support the current model of obesity-induced visceral adipose tissue macrophage (VATM) enrichment. Our data demonstrated robust increases in VAT pro-inflammatory cytokine expression, which are consistent with the significant increases in macrophage-specific gene expression and consistent with previous reports in which VAT inflammation is enhanced and attributed to classically activated (M1) macrophage infiltration. However, these data are only observed relative to the expression of invariant housekeeping gene expression. When M1-specific genes are expressed relative to macrophage-specific standards like F4/80 expression, these inflammatory makers are unchanged. These data indicate that the changes in the overall inflammatory profile of DIO mouse VAT is because of quantitative changes in adipose tissue macrophage (ATM) number and not qualitative changes in activation state. These observations are consistent with the idea that infiltrating ATMs may have roles other than the previously described role in mediating inflammation in obese adipose tissue.
Hepatic IR occurs partly as a consequence of adipocyte dysfunction because the liver becomes a reservoir for AT-derived fatty acids (FAs), which leads to obesity-related non-alcoholic fatty liver disease (NAFLD). In the second part of my thesis, I used clodronate liposome-mediated macrophage depletion to define the role of macrophages in hepatic lipid metabolism regulation. We discovered that i.p. administration of clodronate liposomes depletes Kupffer cells (KCs) in ob/ob mice without affecting VATM content, whereas clodronate liposomes depletes both KCs and VATMs in DIO mice. To this end, we established that clodronate liposome-mediated KC depletion, regardless of VATM content in obese mice, abrogated hepatic steatosis by reducing hepatic de novo lipogenic gene expression. The observed reductions in hepatic inflammation in macrophage-depleted obese mice led to the hypothesis that IL-1β may be responsible for obesity-induced increased hepatic triglyceride (TG) accumulation. We determined that IL-1β treatment increases fatty acid synthase (Fas) protein expression and TG accumulation in primary mouse hepatocytes. Pharmacological inhibition of interleukin-1 (IL-1) signaling by interleukin-1 receptor antagonist (IL-1Ra) administration recapitulated these results by reducing hepatic TG accumulation and lipogenic gene expression in DIO mice. Thus, these data highlight the importance of the inflammatory cytokine IL-1β in obesity-driven hepatic steatosis and suggests that liver inflammation controls hepatic lipogenesis in obesity.
To this end, the studies described herein provide new insight and appreciation to the multi-functional nature of macrophages and clinical implications for anti-inflammatory therapy in obesity and NAFLD treatment. We demonstrate the complexities of macrophage-mediated functions in insulin sensitive tissues and a role for obesity-induced inflammatory cytokine IL-1β in hepatic lipid metabolism modulation, which is reversed via IL-1Ra intervention. The use of anti-inflammatory therapy to ameliorate obesity-associated NAFLD was perhaps the most important contribution to this body of work and is full of promise for future clinical application. It is likely that the future of therapeutics will be multi-faceted and combine therapeutic approaches to enhance glucose tolerance and overall health in obese, IR and T2DM patients.
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Negrin, Kimberly A. "Complex Roles of Macrophages in Lipid Metabolism and Metabolic Disease: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/713.
Full textAbstract:
The worldwide prevalence of obesity and metabolic disease is increasing at an exponential rate and current projections provide no indication of relief. This growing burden of obesity-related metabolic disorders, including type 2 diabetes mellitus (T2DM), highlights the importance of identifying how lifestyle choices, genetics and physiology play a role in metabolic disease and place obese individuals at a greater risk for obesity-related complications including insulin resistance (IR). This increased risk of IR, which is characterized by a decreased response to insulin in peripheral tissues including adipose tissue (AT) and liver, is associated with a chronic, low grade inflammatory state; however, the causative connections between obesity and inflammation remains in question. Experimental evidence suggests that adipocytes and macrophages can profoundly influence obesity-induced IR because adipocyte dysfunction leads to ectopic lipid deposition in peripheral insulin sensitive tissues, and obese AT is characterized by increased local inflammation and macrophage and other immune cell populations. Attempts to delineate the individual roles of macrophage-derived pro-inflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), have demonstrated causative roles in impaired systemic insulin sensitivity, adipocyte function and hepatic glucose and lipid metabolism in obese animal models. Thus, the attenuation of macrophage-derived inflammation is an evolving area of interest to provide insight into the underlying mechanism(s) leading to obesity-induced IR.
Thus, in the first chapter of this thesis, I describe experiments to refine the current paradigm of obesity-induced AT inflammation by combining gene expression profiling with computational analysis of two anatomically distinct AT depots, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to address whether the inflammatory signature of AT is influenced by diet-induced obesity (DIO). Microarray and qRT-PCR analysis data revealed that DIO mouse SAT is resistant to high fat diet (HFD)-induced inflammation and macrophage infiltration, and our data support the current model of obesity-induced visceral adipose tissue macrophage (VATM) enrichment. Our data demonstrated robust increases in VAT pro-inflammatory cytokine expression, which are consistent with the significant increases in macrophage-specific gene expression and consistent with previous reports in which VAT inflammation is enhanced and attributed to classically activated (M1) macrophage infiltration. However, these data are only observed relative to the expression of invariant housekeeping gene expression. When M1-specific genes are expressed relative to macrophage-specific standards like F4/80 expression, these inflammatory makers are unchanged. These data indicate that the changes in the overall inflammatory profile of DIO mouse VAT is because of quantitative changes in adipose tissue macrophage (ATM) number and not qualitative changes in activation state. These observations are consistent with the idea that infiltrating ATMs may have roles other than the previously described role in mediating inflammation in obese adipose tissue.
Hepatic IR occurs partly as a consequence of adipocyte dysfunction because the liver becomes a reservoir for AT-derived fatty acids (FAs), which leads to obesity-related non-alcoholic fatty liver disease (NAFLD). In the second part of my thesis, I used clodronate liposome-mediated macrophage depletion to define the role of macrophages in hepatic lipid metabolism regulation. We discovered that i.p. administration of clodronate liposomes depletes Kupffer cells (KCs) in ob/ob mice without affecting VATM content, whereas clodronate liposomes depletes both KCs and VATMs in DIO mice. To this end, we established that clodronate liposome-mediated KC depletion, regardless of VATM content in obese mice, abrogated hepatic steatosis by reducing hepatic de novo lipogenic gene expression. The observed reductions in hepatic inflammation in macrophage-depleted obese mice led to the hypothesis that IL-1β may be responsible for obesity-induced increased hepatic triglyceride (TG) accumulation. We determined that IL-1β treatment increases fatty acid synthase (Fas) protein expression and TG accumulation in primary mouse hepatocytes. Pharmacological inhibition of interleukin-1 (IL-1) signaling by interleukin-1 receptor antagonist (IL-1Ra) administration recapitulated these results by reducing hepatic TG accumulation and lipogenic gene expression in DIO mice. Thus, these data highlight the importance of the inflammatory cytokine IL-1β in obesity-driven hepatic steatosis and suggests that liver inflammation controls hepatic lipogenesis in obesity.
To this end, the studies described herein provide new insight and appreciation to the multi-functional nature of macrophages and clinical implications for anti-inflammatory therapy in obesity and NAFLD treatment. We demonstrate the complexities of macrophage-mediated functions in insulin sensitive tissues and a role for obesity-induced inflammatory cytokine IL-1β in hepatic lipid metabolism modulation, which is reversed via IL-1Ra intervention. The use of anti-inflammatory therapy to ameliorate obesity-associated NAFLD was perhaps the most important contribution to this body of work and is full of promise for future clinical application. It is likely that the future of therapeutics will be multi-faceted and combine therapeutic approaches to enhance glucose tolerance and overall health in obese, IR and T2DM patients.
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Glass, Jordan R. "Should I stay or should I go? Complex environments drive the developmental plasticity of flight capacity and flight-related tradeoffs." Scholarly Commons, 2018. https://scholarlycommons.pacific.edu/uop_etds/3535.
Full textAbstract:
Animals must balance multiple, fitness-related traits in environments that are complex and characterized by co-varying factors, such as co-variation in temperature and food availability. Thus, experiments manipulating multiple environmental factors provide valuable insight into the role of the environment in shaping not only important traits (e.g., dispersal capacity or reproduction), but also trait-trait interactions (e.g., trade-offs between traits). We employed a multi-factorial design to manipulate variation in temperature (constant 28°C vs. 28±5°C daily cycle) and food availability (unlimited vs. intermittent access) throughout development in the sand field cricket, Gryllus firmus. We found that fitness-related, life-history traits and trait trade-offs can be developmentally plastic in response to variation in temperature and food availability. Variability in temperature and food availability influenced development, growth, body size, reproductive investment, and/or flight capacity, and food availability also affected survival to adulthood. Further, both constant temperature and unlimited food availability promoted investment into key components of somatic and reproductive tissues while reducing investment into flight capacity. We develop an experimental and statistical framework to reveal shifts in correlative patterns of investment into different life-history traits. This approach can be applied to a range of animal systems to investigate how environmental complexity influences traits and trait trade-offs.
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Abd, El Rahim Metwally Galal Yahya. "Molecular retention mechanisms of the G1 cyclin/Cdk complex in budding yeast." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/368230.
Full textAbstract:
Budding yeast (Saccharomyces cerevisiae) cells coordinate cell growth and cell cycle progression essentially during G1, where they must reach a critical cell size to traverse Start and enter the cell cycle. The most upstream activator of Start is Cln3, a G1 cyclin that together with the cyclin-dependent kinase Cdc28 triggers a transcriptional wave that drives cell cycle entry. The Cln3 cyclin is a low abundant and very unstable protein whose levels respond very rapidly to nutritional changes. However, Cln3 expression is not sharply regulated through the cell cycle and it is already present in early G1 cells. Notably, most Cln3 is retained bound to the ER in early G1 with the assistance of Whi3, an RNA-binding protein that binds the CLN3 mRNA, and it is released in late G1 by Ydj1, a J-chaperone that might transmit growth capacity information to the cell cycle machinery. However, little is known on the molecular mechanisms that retain the Cdc28-C1n3 complex in the cytoplasm and how do these mechanisms transmit information of cell size to coordinate cell proliferation with cell growth. As Cdc28 is important for proper retention of Cln3 at the ER, we hypothesized that mutations weakening interactions to unknown ER retention factors would cause premature release of the Cdc28-C1n3 complex and, hence, a smaller cell size.
This thesis describes the isolation and characterization of a CDC28 quintuple mutant, which we refer to as CDC28wee, that causes premature entry into the cell cycle and a small cell size. Next we used isobaric tags for relative and absolute quantitation (iTRAQ) to identify direct interactors with lower affinities for mutant Cdc28wee, aiming at the identification of proteins with key regulatory roles in the retention mechanism. Among the identified proteins we found Sr13, a protein of unknown function, here renamed as Whi7. Here we show that Whi7 acts as an inhibitor of Start, associates to the ER and contributes to efficient retention of the Cln3 cyclin, thus preventing its unscheduled accumulation in the nucleus. Our results demonstrate that Whi7 acts in a positive feedback loop to release the G1 Cdk¬cyclin complex and trigger Start once a critical size has been reached, thus uncovering a key nonlinear mechanism at the earliest known events of cell cycle entry.
In addition to Whi7 we also identified Whi8, renamed here as Whi8, which is an RNA-binding protein present in both stress granules (SGs) and P bodies (PBs) with unknown biological function. We have found that Whi8 interacts with Cdc28 in vivo, binds and colocalizes with the CLN3 mRNA, and interacts with Whi3 in an RNA-dependent manner. Whi8-deficient cells showed a smaller budding cell size while, on the other hand, overexpression of Whi8 increased the budding volume. Cells lacking Whi8 were not capable of accumulating the CLN3 mRNA in SGs under stress conditions, and Cln3 synthesis remained high under glucose and nitrogen starvation, two environmental stress conditions that dramatically decrease Cln3 levels in the cell. Whi8 accumulation in SGs depended on an intrinsically disordered domain (IDD) identified at C-terminus of Whi8 and specific PKA phophosites. Our results suggest that Whi8 acts under stress as a safeguard that limits the influx of newly synthesized Cln3 (and likely other proteins) into the cell cycle machinery, by trapping the CLN3 mRNA in mRNA granules. Thus, we have found a unique target for signaling pathways that directly links stress response and cell cycle entry.
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Mitchell, Cassie S. "Viewpoint aggregation via relational modeling and analysis." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/28213.
Full textAbstract:
Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Lee, Robert; Committee Member: Kemp, Melissa; Committee Member: Prinz, Astrid; Committee Member: Ting, Lena; Committee Member: Wiesenfeld, Kurt.
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Szucs, Kimberly A. "Capturing Three-Dimensional Clavicle Kinematics During Arm Elevation: Describing the Contribution of Clavicle Motion and Associated Scapulothoracic Muscle Activation to Total Shoulder Complex Motion." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1275406915.
Full text