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Le, Roux Peter David. "Neuron-glial interactions in dendrite growth." Doctoral thesis, University of Cape Town, 1995. http://hdl.handle.net/11427/27039.
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Interactions between neurons and glia occupy a central role in many aspects of development, maintenance, and function of the central nervous system (CNS). A fundamental event in CNS development is the elaboration of two distinct neuronal processes, axons and dendrites. The overall aim of this research was to characterize the interactions between central nervous system neurons and astroglial cells that regulate dendrite growth from cerebral cortical neurons. Embryonic (E18) mouse cerebral cortical neurons were cocultured with early postnatal (P4) rat astroglia derived from cerebral cortex, retina, olfactory bulb, mesencephalon, striatum and spinal cord. Axon and dendrite outgrowth from isolated neurons was quantified using morphological and double-labeling immunohistochemical techniques at 18 hours and 1, 3 and 5 days in vitro. Neurons initially extended the same number of neurites, regardless of the source of glial monolayer; however, astroglial cells differed in their ability to maintain primary dendrites. Homotypic cortical astroglia maintained the greatest number of primary dendrites. Astroglia derived from the olfactory bulb and retina maintained intermediate numbers of dendrites, whereas only a small number of primary dendrites were maintained by astroglia derived from striatum, spinal cord or mesencephalon. Initially longer axons were observed from neurons grown on astroglia that did not maintain dendrite number. After 5 days in vitro, axon growth was similar on the various monolayers, total primary dendrite outgrowth, however, was nearly threefold greater on astroglia derived from the cortex, retina and olfactory bulb than on astroglia derived from mesencephalon, striatum or spinal cord. This effect was principally on the number of primary dendrites rather than the elongation of individual dendrites and was independent of neuron survival. Similar morphological differences were observed after 5 days in vitro when cortical neurons were grown on polylysine in either a noncontact coculture system where astroglia continuously conditioned the culture medium or in astroglial conditioned medium. Preliminary biochemical analysis of the medium conditioned by cortical astroglia using heat and trypsin degradation, ultracentrifugation, dialysis, and heparin affinity chromatography suggested that a heparin binding protein with a molecular weight between 10 and 100kDa may be responsible for astroglial mediated dendrite growth. Neurons that were grown in medium conditioned by either mesencephalic or cortical astroglia for the first 24 hours followed by culture medium from astroglia of the alternate source for 4 days in vitro, confirmed that astroglia maintained, rather than initiated, the outgrowth of the primary dendritic arbor. In the next series of experiments, E18 mouse cortical neurons were cocultured with neonatal (P4) or mature (P12) rat astroglia derived from cortex and mesencephalon or astroglia derived from P4 and P12 lesioned cortex. After 5 days in vitro, the maturational age of astroglia did not appear to alter the extent of primary dendrite growth; instead dendrite growth reflected the region of the CNS from which the astroglia were derived. By contrast, a reduced ability to support axon growth from mouse cortical neurons in culture was observed on astroglia derived from mature rat cortex or mesencephalon. Reactive astroglia demonstrated similar neurite supporting characteristics to mature astroglia and were able to maintain dendrite growth, principally primary dendrite number. Axon elongation, however, was reduced on both neonatal and mature reactive astroglia. Neuron survival did not correlate with the ability of the various astroglia to support process outgrowth. Collectively these results indicate: 1) neuron-glial interactions are critical for the regulation of process outgrowth from embryonic cortical neurons in vitro, 2) axon and dendrite growth appear to be differently controlled by astroglia, 3) CNS astroglia demonstrate regional differences in maintaining, but not initiating growth of the primary dendritic arbor, 4) this effect may be due, in part, to release of a diffusible heparin binding protein factor, and 5) mature and reactive astroglia support primary dendrite, but limited axon growth. We propose therefore that the local astroglial environment maintains primary dendrite growth from neurons until synaptic contacts can be established. A mechanism that maintains the primary dendritic arbor and allows separate regulation of axon and dendrite growth, prior to the arrival of afferents, may be critical for establishing appropriate and specific synaptic connections. These findings have important implications in understanding development and function of the mammalian central nervous system and may lead to novel strategies for intervention in acute and chronic neurological disorders.
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Zhang, Ye. "The role of the secretory pathway in dendrite and axon development." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390087.
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Krol, Alexandra. "Regulation of Neuronal Dendrite Development and Migration by the Atypical Cadherin Fat3." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467479.
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Neuronal shape and position are critical to the formation and function of neuronal circuits. Although neurons develop axons and dendrites cell-autonomously in vitro, how extracellular cues in vivo direct neurite specification and placement remains poorly understood. The role of atypical cadherin Fat3 in amacrine cell development illustrates how the same extracellular cue can guide both dendrite formation and migration.
In the mouse retina, amacrine cells have a bipolar morphology during their migration. Upon reaching the nascent inner plexiform layer (IPL), they elaborate one neurite into the IPL and retract the other. Loss of Fat3 leads amacrine cells to develop an extra dendrite outside the IPL as well as errors in migration. We found Fat3 protein is concentrated at the IPL throughout amacrine cell development, suggesting Fat3 detects a directional signal. Here we investigated the signaling pathways upstream and downstream of Fat3 that mediate its role in amacrine cell development.
In Drosophila, Fat’s ligand is Dachsous. Fat and Dachsous binding is modulated by the kinase Four-jointed. Our analysis of mutant retinas determined that Fat3 and vertebrate Four-jointed genetically interacted. However knockout studies of vertebrate Dachsous homologues suggested they are not relevant Fat3 ligands in the retina. Instead, analysis of retinas missing retinal ganglion cells suggested Fat3-mediated homophilic adhesion between amacrine cells may be important.
Sparse loss of Fat3 from amacrine cells also led to extraneous neurites, suggesting Fat3 acts cell autonomously. Ex vivo live imaging revealed both migration and neurite dynamics were less directed in Fat3 mutant amacrine cells. We hypothesized Fat3 acts to target asymmetric localization of cytoskeletal regulators to the leading neurite. To identify downstream Fat3 effectors, we performed a pulldown assay using the Fat3 intracellular domain. We identified several cytoskeletal regulators as candidate binding partners. We focused on the actin regulators Ena/VASP and demonstrated a direct interaction with the Fat3 intracellular domain. In the retina, Ena/VASP localized with Fat3 to the IPL, and loss of Fat3 changed Ena/VASP distribution. Furthermore, forcing uniform membrane recruitment of Ena/VASP in developing amacrine cells phenocopied loss of Fat3. Together these results suggest Fat3 polarizes the activity of cytoskeletal effectors to help direct amacrine cell migration and dendrite placement.<br>Medical Sciences
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Mahnke, Amanda Hope. "Alterations to Dendrite Morphology in Response to Antipsychotic Drug Treatment and Hypoglutamatergia." Thesis, Tulane University School of Science and Engineering, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3639160.
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<p> Schizophrenia is a prevalent neurological disorder characterized by disrupted neuronal circuitry. Antipsychotic drugs (APDs) are capable of ameliorating the symptoms of schizophrenia with varying efficacy. Clozapine, the "gold-standard" for antipsychotic drug treatment, has been shown by this lab to induce the outgrowth of mediodorsal thalamic (MDT) dendritic arbor in rodents, a brain region which has altered function and decreased regional volume in schizophrenic patients. These studies further explored the ability of APD treatment to restructure dendrite arbor and the mechanisms of clozapine's ability to elaborate MDT arbor. Additionally, glutamate hypofunction is thought to contribute to the schizophrenic disease state. Using a novel model of perinatal glutamate hypofunction, we examined the long-term effects on dendritic architecture of developmental glutamate signaling disruption. </p><p> MDT dysfunction is hypothesized to contribute to cognitive symptoms of schizophrenia. Clozapine has increased efficacy in ameliorating these symptoms. To further understand clozapine's actions to remodel MDT dendritic architecture, we examined whether clozapine-induced morphological alterations are limited to the thalamus or if they also occur in additional regions associated with cognitive schizophrenic pathology, the hippocampus and striatum. We found that clozapine can induce dendritic remodeling in the hippocampus, but the not to the amplitude of remodeling seen in the thalamus, indicating that the MDT is uniquely altered by clozapine treatment and may be an important locus of clozapine's action. </p><p> The mechanisms of clozapine's remodeling of MDT arbor, we examined changes to mRNA and miRNA expression and calcium dynamics in the MDT in response to APD treatment. Clozapine-treatment altered the expression of genes involved in cytoskeletal remodeling, external membrane receptors, and calcium dynamics, as well as increased the rate of calcium influx into thalamic neurons. </p><p> Disruption to glutamate signaling has been hypothesized to contribute to schizophrenic pathology. Disruption to perinatal vesicular glutamate packaging along the corticolimbic axis has long term effects for neuronal morphology and function. Interestingly, we find that disruption along the corticolimbic axis also has downstream effects on MDT dendritic architecture. </p><p> These studies show that the MDT is an important locus of action for clozapine and is capable of remodeling dendritic architecture in response to afferent circuitry dysfunction.</p>
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Carlsen, Robert Means III. "Neural Plasticity and the Development of Intersensory Functioning in Bobwhite Quail (Colinus virginianus)." Diss., Virginia Tech, 1999. http://hdl.handle.net/10919/30196.
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Previous research has demonstrated that augmented prenatal sensory stimulation can influence the emergence of normal or species-typical patterns of intersensory perception. For example, unusually early visual experience can produce a facilitative effect on subsequent postnatal perceptual responsiveness, while substantially augmented prenatal visual stimulation can interfere with early postnatal responsiveness. In constructing a link between early experience and neuronal plasticity, it has been established that unusual visual experience can produce measurable changes in post-synaptic structures, particularly dendritic morphology, in brain areas responsible for vision. In avian species, the brain area responsible for vision is the visual Wulst, thought to be analogous to the mammalian visual cortex.
This study examined the effects of differing amounts of augmented prenatal visual stimulation on the plasticity of neurons in the visual Wulst and on subsequent postnatal visual responsiveness to maternal cues in bobwhite quail chicks. Results revealed that the pattern of neuronal organization and postnatal behavior was influenced by the amount of prenatal visual experience subjects were provided. Specifically, chicks exposed to 240 min of prenatal visual stimulation during the last 24 hr prior to hatching had neurons with significantly fewer spines/10 mm dendrite and displayed accelerated patterns of species-typical visual responsiveness. In contrast, chicks provided 900 min of prenatal visual stimulation had more complex neurons (including more spines, longer dendrites, and more branches) and failed to display normal species-specific visual responsiveness in the days following hatching. These results suggest that neuronal organization in the bobwhite Wulst proceeds in a selective fashion, molded by experience, and appears to influence early perceptual development and organization during the perinatal period<br>Ph. D.
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Gaddy, Joshua L., and Joshua L. Gaddy. "The Effects of Developmental Nicotine Exposure on Hypoglossal Motoneuron Primary Dendrite and Soma Development in the Neonatal Rat." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/621005.
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Nicotine from smoking or from other products containing nicotine has adverse effects on the fetus during pregnancy, such as respiratory problems. Our laboratory has previously shown that exposure to nicotine during development (DNE) alters hypoglossal motor neuron (XII MN) function, including decreased excitatory synaptic input, desensitized nicotinic acetylcholine receptors, increased input resistance, and differences in the precision and reliability of spike timing in XIIMNs. Evidence of DNE effects on XIIMN function prompted us to test the hypothesis that DNE will affect the development of primary dendrites and the soma. Brainstem slices were collected from neonates and motoneurons were filled with neurobiotin via whole-cell patch clamp. Filled cells were visualized with heavy metal intensified-3,3'-Diaminobenzidine (DAB) reaction. DAB-stained cells were analyzed using Neurolucida hardware and software. On average, the maximum soma diameter of more rostral XIIMNs was larger than that in more caudal cells. Also, caudal XIIMNs had more primary nodes than rostral XIIMNs, and there was a significant treatment effect on minimum soma diameter (Control, 13.76 ± 0.71 µm; DNE, 18.09 ± 1.22 µm). The results from this study uncovered potential effects of nicotine on XIIMNs found in rostral and caudal regions of the hypoglossal nucleus.
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Sears, James Cooper. "FoxO Regulates Microtubule Dynamics and Polarity to Promote Dendrite Branching in Drosophila Sensory Neurons." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1476705366788041.
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Molumby, Michael Jacob. "Gamma-protocadherin Cis- and Trans-interactions regulate the development of dendrite arbors and synapses in the cerebral cortex." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5815.
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The alpha-, beta-, and gamma-Protocadherins (gamma-Pcdhs) are cadherin superfamily adhesion molecules encoded by clustered gene families. The 22 gamma-Pcdhs are combinatorially expressed in the central nervous system (CNS) by neurons and astrocytes, and play critical roles in synaptogenesis, dendrite arborization, and the survival of subsets of neurons. The gamma-Pcdhs promiscuously form cis-multimers that interact strictly homophilically in trans (Molumby et al., 2016; Schreiner and Weiner, 2010); the alpha- and beta-Pcdhs were subsequently shown to interact in a similar homophilic manner (Rubinstein et al., 2015; Thu et al., 2014). The Pcdh gene clusters thus have the potential to generate millions of distinct adhesive interfaces, providing CNS cells with molecular identities that shape neuronal morphology.
We demonstrated previously that, in mice lacking the gamma-Pcdhs in the cerebral cortex, pyramidal neurons exhibit severely reduced dendrite arborization (Garrett et al., 2012a). This, combined with many studies of gamma-Pcdh interactions in vitro, suggests that homophilic, adhesive gamma-Pcdh interactions between neurons, and between neurons and glia, provide a positive signal for dendrite growth. However, in retinal starburst amacrine cells and cerebellar Purkinje cells, loss of the gamma-Pcdhs resulted in aberrant dendrite fasciculation and self-crossing (Lefebvre et al., 2012), suggesting that these molecules can mediate repulsive self-avoidance between a neuron’s own dendrites.
In Chapter I of this thesis I utilized transgenic mice to manipulate expression in vivo, to show that the complexity of a cortical neuron’s dendritic arbor is determined by homophilic gamma-Pcdh isoform matching with other cells. Expression of the same single isoform in a neuron can result in either exuberant, or minimal, dendrite complexity depending on whether surrounding cells express the same isoform. Additionally, loss of gamma-Pcdh in astrocytes, or induced astrocyte-neuron mis-matching, reduces dendrite complexity cell non-autonomously. This indicates a neuron’s pattern of connectivity is indeed regulated by specific interactions between cells that are distinct from the repulsive self-avoidance seen in isoneuronal processes of planar cell types.
In addition to modulating dendrite branch development, the gamma-Pcdhs have been shown to regulate the progression of spinal cord synaptogenesis (Garrett and Weiner, 2009). A role for these molecules in cortical dendritic spines and synapses, however, had yet not been examined. In Chapter II of this thesis, I provide evidence that the gamma-Pcdhs negatively regulate synapse formation and spine morphogenesis in forebrain neurons. Mice lacking all gamma-Pcdhs in the cortex exhibit significantly increased spine and synapse density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 gamma-Pcdh isoforms. To explain this functional result, we present in vitro evidence to show that gamma-Pcdhs physically and functionally interact with the synaptic cell adhesion molecule neuroligin-1. This work suggests a potential new mechanism by which gamma-Pcdhs regulate the “choice” between dendrite arbor growth and formation and/or stabilization of dendritic spines and synapses in the developing brain.
Given that disruptions in the pattern and density of dendritic arbors and spines are a hallmark of neurodevelopmental disorders such as autism and Down, Rett, and fragile X syndromes, my work may provide the basic science foundation for future therapeutic approaches focused on Pcdhs and their associated signaling pathways.
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Dimitrova, Svetla. "Physiological Roles of Robo Receptor during dendrite development of the multidendritic arborization neurons of the Drosophila peripheral nervous system." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-78347.
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Amini, Mandana. "Analysis of Conditional Knock-out of Calpain Small Subunit, capns1, in Central Nervous System Development and Function." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31360.
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Calpains, a highly conserved family of calcium-dependent cysteine proteases, are divided in two groups; classical and non-conventional calpains. Calpain-1 and calpain-2, the classical ones, are ubiquitously expressed and abundant in the CNS. Findings through different experimental approaches, predominantly pharmacological calpain inhibitors, proposed the necessity of the proteases for the modulation of various biological events particularly in the CNS, or a functional link between calpain and neurodegeneration. Significant functions associated with calpain activity are neuronal proliferation/differentiation, signal transduction, apoptosis, and synaptic plasticity; or neuronal death in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and ischemic stroke. However, due to limited insights of the approaches taken, such as non-specificity of the inhibitors, the exact roles of calpains in the CNS and the key mechanisms underlying them remain controversial. Calpain-1/calpain-2 germline knock-out are embryonic lethal at a very early stage hindering the use of these lines as mouse models for CNS studies. Accordingly, this thesis research introduced a unique brain-specific calpain-1/calpain-2 knock-out and explored the role of the proteases in brain development/function and in neuronal death. The first set of analyses examined how the elimination of calpain-1/calpain-2 activities in mouse brain impacts CNS development in general and synaptic plasticity in CA1 neurons of hippocampus. CNS-specific elimination of CAPNS1, the common small subunit, abolished calpain-1/calpain-2 activities in mouse brain. In contrast to Calpain-1/calpain-2 germ line knock-outs, the brain-specific knock-outs are viable and the general development of mouse brain is normal. However, morphology of dendrites in pyramidal neurons of the hippocampal CA1 region showed significantly decreased dendritic branching complexity and spine density. Consistent with dendrite morphological abnormalities, electrophysiological analyses revealed a significant decrease in field excitatory postsynaptic potentials, long term potentiation, and learning and memory in the hippocampal CA1 neurons of the mutants. In the second part of this research we investigated the direct role of the calpains in neuronal death and their potential downstream targets in in vitro models of PD and ischemic stroke. Our findings indicated that ablation of calpains activity improves survival of different types of neurons against mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+), glutamate, and hypoxia. Importantly, we demonstrated an increase in p35-cleavage to p25, a cyclin dependent kinase 5 (Cdk5) activator, and that restoration of p25 significantly suppresses the neuronal survival associated with calpain deficiency. Taken together, this work unequivocally establishes two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.
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Dickey, Audrey Sarah. "Role of pp2a/bβ2 and pka/akap1 in brain development and function via dynamin-related protein 1 (drp1) control of mitochondria shape and bioenergetics". Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/3444.
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Mitochondria are critical for energy production and Ca2+ homeostasis and undergo fission and fusion reactions, perturbation of which can contribute to neuronal injury and disease. Mitochondrial fission is catalyzed by Drp1 (dynamin-related protein 1), a large GTPase tightly controlled by various posttranslational modifications, including phosphorylation. Bβ2 is a neuron-specific postnatally induced protein phosphatase 2A (PP2A) regulatory subunit that mediates PP2A translocation to the outer mitochondrial membrane (OMM) to promote mitochondrial fragmentation and sensitize neurons to various injuries. Opposing PP2A/Bβ2's effect on mitochondrial morphology and cell death is protein kinase A (PKA) anchored to the OMM via A kinase anchoring protein 1 (AKAP1). This dissertation describes how reversible phosphorylation of Drp1 at a conserved Serine residue by an outer mitochondrial kinase (PKA/AKAP1) and phosphatase complex (PP2A/Bβ2) affects dendrite and synapse development in hippocampal neurons and synaptic plasticity and learning and memory in vivo.
Inducing mitochondria fragmentation decreases dendritic arbor complexity, but increases spine and synapse number. Mitochondrial elongation induces opposite effects. L-carnitine increases mitochondria membrane potential and recapitulates the dendritic and synaptic effects of mitochondrial elongation. Epistasis experiments substantiate our hypothesis that PP2A/Bβ2 dephosphorylates and PKA/AKAP1 phosphorylates Drp1 to change mitochondrial shape and regulate mitochondria localization, dendrite outgrowth, and synapse development.
Bβ2 null mice are viable and fertile, without obvious abnormalities. Bβ2 null mice demonstrate significantly larger cortical and hippocampal neuronal mitochondria than in wildtype. Bβ2 deletion decreases spine number on apical and basal cortical dendrites and hippocampal dendrites. Bβ2 null mice display significantly decreased input/output relationship in the hippocampus, consistent with a decrease in synapse number. In a combined context and cued fear-conditioning protocol, the hippocampal-dependent context recall trial revealed significant deficits in Bβ2 null and heterozygous mice. This deficit is also seen in hippocampal-dependent Barnes maze performance. These results are consistent with the reduced hippocampal long-term potentiation (LTP) found in Bβ2 null mice and demonstrate the importance of Bβ2 in hippocampal synaptic plasticity and memory. In conclusion, PP2A/Bβ2 and PKA/AKAP1 have important roles in mitochondria regulation and dendritic and synaptic development as seen in our results in vitro with rat hippocampal cultures and in vivo with Bβ2 null mice.
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Castro, André Ferreira [Verfasser], Amparo [Akademischer Betreuer] Acker-Palmer, Gaia [Akademischer Betreuer] Tavosanis, Hermann [Akademischer Betreuer] Cuntz, Amparo [Gutachter] Acker-Palmer, and Gaia [Gutachter] Tavosanis. "Dissecting the structure and function relationship in drosophila dendrite development with the help of computational modelling / André Ferreira Castro ; Gutachter: Amparo Acker-Palmer, Gaia Tavosanis ; Amparo Acker-Palmer, Gaia Tavosanis, Hermann Cuntz." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2020. http://d-nb.info/1223538133/34.
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Wefelmeyer, Winnie. "Calcium and chloride dynamics in immature neurons and their role in dendritic growth." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:5b67b345-8469-4370-8e3f-68bef6a629e9.
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Activity-dependent dendritic development is an important process in the maturation of neuronal circuits. The precise morphology of a neuron’s dendritic tree dictates which other cells it is able to interact with and how it will receive and process synaptic information. The aim of this Thesis was to investigate the mechanisms by which dendrites grow and, in particular, how changes in intracellular ion concentrations contribute to these mechanisms. One important activity-dependent signal is calcium as it can translate neuronal activity into morphological changes. Despite this, very little is known about calcium signalling during the period of dendritic development. Using single-cell electroporation of immature CA1 hippocampal pyramidal neurons, I characterised the spatial and temporal properties of local calcium transients in growing dendrites. This revealed a high frequency of transients at shaft filopodia and stable branchpoints, but an almost complete absence from the tips of dendritic branches. Another important factor during development is the intracellular chloride concentration because this regulates neuronal excitability. Prematurely lowering intracellular chloride by expressing the chloride co-transporter KCC2 led to less stable dendritic filopodia and stunted dendritic growth. These effects were independent of local calcium signalling and suggested that chloride regulation itself may be fundamental to normal dendritic growth. To examine this further I developed imaging techniques to measure the spatial and temporal dynamics of chloride in growing dendrites. This work revealed a somatodendritic gradient of increasing intracellular chloride, whereby the highest concentrations were found at sites of growth. Further analysis suggested a close link between local chloride regulation and morphological changes. The dendritic tips that exhibited high intracellular chloride levels and the potential to rapidly modulate these levels, also exhibited the greatest morphological dynamics. These findings have important implications for understanding the mechanisms of dendritic growth and establish the spatiotemporal regulation of chloride as a key parameter.
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Otremba, Maik. "Standardisierungsaspekte bei der Gießtechnologieauswahl von Zylinderköpfen." Doctoral thesis, Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2015. http://nbn-resolving.de/urn:nbn:de:bsz:105-qucosa-163862.
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Für den Zylinderkopf ist das Schwerkraftgießen ein etabliertes Gießverfahren. Jedoch gehen die Gießereien in der Ausführung des Schwerkraftgusses unterschiedlich vor. Durch die mannigfaltigen Anschnittsysteme und die sich dadurch ergebenden Vor- bzw. Nachteile bei der Herstellung entstehen Unterschiede bei Qualität und Kosten. Ziel dieser Arbeit ist es, Standards und Vereinheitlichungen während der Produktentstehung eines Zylinderkopfes zu etablieren, um eine gleichbleibende Qualität der Zylinderköpfe in den Gießereien zu gewährleisten. Dazu sind vielfältige Ansatzpunkte zu verfolgen.
Eine Möglichkeit ist die geometrische Beurteilung des Zylinderkopfs, wie z.B. Wandstärken, Speisungswege und die Außengeometrien. Die nach Lastenheftvorgaben zu erfüllenden Eigenschaften spielen gleichermaßen eine Rolle und haben Einfluss auf die Wahl des Gießverfahrens. Mit Hilfe von speziellen Entscheidungsmethoden ist eine Vorauswahl für ein Gießverfahren möglich. Des Weiteren werden mittels experimentellen Untersuchungen die Entscheidungen gestützt.
Die Gießsimulation ist als zusätzliches Auslegungswerkzeug einzusetzen. Hierbei sind Gussfehler im Bauteil zu lokalisieren und zu vermeiden. Unzureichende Speisungswege oder zu geringe Wandstärken durch komplizierte Kerngeometrien sind zu ermitteln. Des Weiteren sind Vorhersagen zu Dendritenarmabständen und Materialausnutzung (Speiserdimensionierung) möglich, die direkt mit der Wahl des Gießverfahrens zusammenhängen.
Die Verzahnung von Geometrie- und Metallurgiefaktoren führt idealerweise zur Definition von Standardisierungsaspekten zur Auswahl der Gießtechnologie bei der Zylinderkopfentwicklung. Durch eine parallele Produkt- und Prozessentwicklung ist eine Verkürzung des Produktentstehungsprozesses erreichbar.
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Ito, Fumiaki. "Development of Advanced Dendritic Materials." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487261.
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Electroactive organic materials have been making progress towards technological applications such as organic light-emitting diodes (OLEDs). In particular, use of electroluminescent dendritic materials in OLEDs show significant promise for a wide range of practical requirements because of their macromolecular structure being highly controllable with regard to both the chemical and physical properties. This thesis describes the development of synthetic approaches to novel phosphorescent dendrimers containing either 1,3,S-triazine or benzimidazole dendrons with the aim to develop materials in which the high electron affinity of the dendrons would be higher than the core and hence facilit~te electron transport through emissive layers in OLEDs. At an early stage, significant difficulties in the stability of triazine derivatives were identified, requiring an introduction of stabilising groups onto triazine rings. With analysis of reactivity and stability of 1,3,S-triazine derivatives, a promising structural modification of using carbzolyl moieties attached to triazine-branching units was discovered. It was found that triazine-based dendronised ligands could not be complexed to iridium(III) to give a single compound due to multiple co-ordination sites. The introduction of an amine linker solved this problem with the dendrons being added to the already fonned complex. 2-Ethylhexyloxy surface groupS were found to increase the solubility of the dendrimers in common organic solvents and also decreased intermolecular interactions of the emissive cores. Dendrimers with benzimidazolyl units in the dendrons were also prepared. that the redox processes were also dendron-dependent. Molecular orbital calculations quantum yield was dependent on the dendron type. Electrochemical analysis showed The photophysical properties of the dendrimers showed that the photoluminescence of the orbital energies and distribution were consistent with the observed properties. containing a light-emitting dendrimer comprised of the dendrimer 114 blended with Finally, OLED devices were fabricated using the soluble dendrimers. The highest external quantum efficiency of 5.4% at 100 cdlcm2 was observed for a bilayer device 4,4'_bis(N-carbazolyl)biphenyl (CBP) as a host.
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Jin, Xiaoming. "Dendritic development of GABAergic cortical interneurons revealed by biolistic transfection with GFP." Morgantown, W. Va. : [West Virginia University Libraries], 2002. http://etd.wvu.edu/templates/showETD.cfm?recnum=2626.
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Thesis (Ph. D.)--West Virginia University, 2002.<br>Title from document title page. Document formatted into pages; contains vii, 218 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.
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Netravali, Ilka Arun. "Elucidation of plasmacytoid dendritic cell development." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11311.
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Most currently defined hematopoietic progenitor pools are heterogeneous, contributing to uncertainty regarding the development of certain blood cells. The origins of plasmacytoid dendritic cells, for instance, have long been controversial and progenitors exclusively committed to this lineage have never been described. We show here that the fate of hematopoietic progenitors is determined in part by their surface levels of 9-O-acetyl sialic acid. Pro-plasmacytoid dendritic cells were identified as lineage negative 9-O-acetyl sialic acid low progenitors that lack myeloid and lymphoid potential but differentiate into pre-plasmacytoid dendritic cells. The latter cells are also lineage negative, 9-O-acetyl sialic acid low cells but are exclusively committed to the plasmacytoid dendritic cell lineage. Levels of 9-O-acetyl sialic acid provide a distinct way to define progenitors and thus facilitate the study of hematopoietic differentiation.
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Tripodi, Marco. "Structural homeostasis during dendritic arbor development." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611147.
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Schnorfeil, Frauke Marie. "MicroRNAs regulate Dendritic Cell Development and Function." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-137930.
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Liu, Hao. "Dendritic cell development directed by stromal cells." Thesis, University of York, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516409.
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Zangerle, Murray Tamsin Florencia Pamela. "Development of dendritic cells in the intestine." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7570/.
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The intestinal tract is exposed to a large variety of antigens such as food proteins, commensal bacteria and pathogens and contains one of the largest arms of the immune system. The intestinal immune system has to discriminate between harmless and harmful antigens, inducing tolerance to harmless antigens and active immunity towards pathogens and other harmful materials. Dendritic cells (DC) in the mucosal lamina propria (LP) are central to this process, as they sample bacteria from the local environment and constitutively migrate to the draining mesenteric lymph nodes (MLN), where they present antigen to naïve T cells in order to direct an appropriate immune response. Despite their crucial role, understanding the function and phenotype of LP DC has been hampered by the fact that they share phenotypic markers with macrophages (mφ), which are the dominant population of mononuclear phagocyte (MP) in the LP. Recent work in our own and other laboratories has established gating strategies and phenotyping panels that allow precise discrimination between intestinal DC and mφ using the mφ specific markers CD64 and F4/80. In this way four bona fide DC subsets with distinct functions have been identified in adult LP based on their expression of CD11b and CD103 and a major aim of my project was to understand how these subsets might develop in the neonatal intestine. At the beginning of my PhD, the laboratory had used these new methods to show that signal regulatory protein α (SIRPα), an inhibitory receptor expressed by myeloid cells, was expressed by mφ and most DC in the intestine, except for those expressing CD103 alone. In addition, mice carrying a non-signalling mutation in SIRPα (SIRPα mt) had a selective reduction in CD103+CD11b+ DC, a subset which is unique to the intestinal LP. This was the basis for the initial experiments of my project, described in Chapter 3, where I investigated if the phenotype in SIRPα mt mice was intrinsic to haematopoietic cells or not. To explore this, I generated bone marrow (BM) chimeric mice by reconstituting irradiated WT mice with SIRPα mt BM, or SIRPα mt animals with WT BM. These experiments suggested that the defect in CD103+CD11b+ DC was not replicated in DC derived from BM of SIRPα origin. However as this seemed inconsistent with other data, I considered the possibility that 18 the phenotype may have been lost with age, as the BM chimeric mice were considerably older than those used in the original studies of SIRPα function. However a comparison of DC subsets in the intestine of WT and SIRPα mt mice as they aged provided no conclusive evidence to support this idea. As these experiments did show age-dependent effects on DC subsets, in Chapter 4, I went on to investigate how the DC populations appeared in the intestine and other tissues in the neonatal period. These experiments showed there were few CD103+CD11b+ DC present in the LP and migratory DC compartment of the MLN in the neonate and that as this population gradually increased in proportion with age, there was a reciprocal decrease in the relative proportion of CD103-CD11b+ DC. Interestingly, most of the changes in DC numbers in the intestine were found during the second or third week of life when the weaning process began. To validate my findings that there were few CD103+CD11b+ DC in the neonate and that this was not merely an absence of CD103 upregulation, I examined the expression of CD101 and Trem-1, markers that other work in the laboratory had suggested were specific to the CD103+CD11b+ DC lineage. My work showed that CD101 and Trem-1 were co- expressed by most CD103+CD11b+ DC in small intestine (SI) LP, as well as a small subset of CD103-CD11b+ DC in this tissue. Interestingly, Trem-1 was highly specific to the SI LP and migratory DC in the MLN, but absent from the colon and other tissues. CD101 expression was also only found on CD11b+ DC, but showed a less restricted pattern of distribution, being found in several tissues as well as the SI LP. The relative timing of their development suggested there might be a relationship between CD103+CD11b+ and CD103-CD11b+ DC and this was supported by microarray analysis. I hypothesised that the CD103-CD11b+ DC that co-expressed CD101 and Trem-1 may be the cells that developed into CD103+CD11b+ DC. To investigate this I analysed how CD101 and Trem-1 expression changed with age amongst the DC subsets in SI LP, colonic LP (CLP) and MLN. The proportion of CD101+Trem-1+ cells increased amongst CD103+CD11b+ DC in the SI LP and MLN with age, while amongst CD103+CD11b+ DC in the CLP this decreased. This was not the same in CD103-CD11b+ DC, where CD101 and Trem-1 expression was more varied with age in all tissues. CD101 and Trem-1 were not expressed to any great extent on CD103+CD11b- or CD103-CD11b- DC. The phenotypic development of the 19 intestinal DC subsets was paralleled by the gradual upregulation of CD103 expression, while the production of retinoic acid (RA), as assessed by the AldefluorTM assay, was low early in life and did not attain adult levels until after weaning. Thus DC in the neonatal intestine take some time to acquire the adult pattern of phenotypic subsets and are functionally immature compared with their adult counterparts. In Chapter 5, I used CD101 and Trem-1 to explore the ontogeny of intestinal DC subsets in CCR2-/- and SIRPα mt mice, both of which have selective defects in one particular group of DC. The selective defect seen amongst CD103+CD11b+ DC in adult SIRPα mt mice was more profound in mice at D7 and D14 of age, indicating that it may be intrinsic to this population and not highly dependent on environmental factors that change after birth. The expression of CD101 and Trem-1 by both CD103+CD11b+ and CD103-CD11b+ DC was reduced in SIRPα mt mice, again indicating that this entire lineage was affected by the lack of SIRPα signalling. However there was also a generalised defect in the numbers of all DC subsets in many tissues from early in life, suggesting there was compromised development, recruitment or survival of DC in the absence of SIRPα signalling. In contrast to the findings in SIRPα mt mice, more CD103+CD11b+ DC co-expressed CD101 and Trem-1 in CCR2-/- mice, while there were no differences in the expression of these molecules amongst CD103-CD11b+ DC. This may suggest that CCR2+ CD103-CD11b+ DC are not the cells that express CD101 and Trem-1 that are predicted to be the direct precursors of CD103+CD11b+ DC. I also examined the expression of DC growth factor receptors on DC subsets from mice of different ages, but no clear age or subset- related patterns of the expression of mRNA for Csf2ra, Irf4, Tgfbr1 and Rara could be observed. Next, I investigated whether Trem-1 played any role in DC development. Preliminary experiments in Trem-1-/- mice show no differences between any of the DC subsets, nor were there any selective effects on individual subsets when DC development from Trem-1-/- KO and WT BM was compared in competitive chimeras. However these experiments were difficult to interpret due to viability problems and because I found an unexpected defect in the ability of Trem-1-/- BM to generate all DC, irrespective of whether they expressed Trem-1 or not. 20 The final experiments I carried out were to examine the role of the microbiota in driving the differentiation of intestinal DC subsets, based on the hypothesis that this could be one of the environmental factors that might influence events in the developing intestine. To this end I performed experiments in both antibiotic treated and germ free adult mice, both of which showed no significant phenotypic differences amongst any of the DC subsets. However the study of germ free mice was compromised by recent contamination of the colony and may not be the conclusive answer. Together the data in this thesis have shown that the population of CD103+CD11b+ DC, which is unique to the intestine, is not present at birth. These cells gradually increase in frequency over time and as this occurs there is a reciprocal decrease in the frequency of CD103-CD11b+ DC. Along with other results, this leads to the idea that there may be a linear developmental pathway from CD103-CD11b+ DC to CD103+CD11b+ DC that is driven by non-microbial factors that are located preferentially in the small intestine. My project indicates that markers such as CD101 and Trem-1 may assist the dissection of this process and highlights the importance of the neonatal period for these events.
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Mauss, Alex Stefan. "Development and patterning of motorneuron dendrites in the Drosophila embryo." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611196.
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Kurz, Thorben Andreas. "Development of techniques for single dendritic spine analysis." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-148813.
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Saovapakhiran, Angkana. "Development of novel dendrimer carriers for drug delivery." Thesis, University of Reading, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492737.
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Polyamidoamine (PAMAM) dendrimers represent a novel type of polymer with numerous pharmaceutical applications and have been en investigated as transcellular carriers. However, the mechanisms of cellular uptake and intracellular processing of dendrimers are not fully understood. In this study the mechanism of cellular uptake of PAMAM dendrimer and surface-modified PAMAM dendrimers was investigated in order to optimise dendrimers as potential drug carriers.
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Uhler, Jennifer Pamela. "The development of dendritic arbors in Drosophila motorneurons." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621930.
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Milne, Paul. "Dendritic cell development in haematological malignancies and neoplasia." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/3015.
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Dendritic cells (DC) play a major role in the detection of antigens, initiation of immunity and induction and regulation of tolerance. DCs are Bone Marrow (BM) derived and their development may be influenced by haematological malignancy in several ways. Firstly, myelodysplastic, myeloproliferative or leukaemic transformation of bone marrow progenitors may involve DC precursors directly, when they become part of a malignant clone, or indirectly when neoplastic expansion of other lineages compromises the development of DCs. Secondly, neoplasia of the dendritic cell lineage itself may occur in a heterogeneous group of histiocytic disorders including Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). The first part of this thesis concerns the effect of haematological malignancies on the generation of DCs; in particular the relationship between DC, monocyte, B and NK lymphoid cell (DCML) deficiency, caused by GATA2 gene mutations, sporadic myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Comprehensive flow cytometric methods for profiling of the DCs and monocytes in the peripheral blood (PB) and peripheral tissues, and the CD34+ progenitors of the BM have been developed. Using these methods, it was possible to see that patients with the three diseases differed on several grounds. DCML deficiencies associated with a younger age of presentation, better preserved haemoglobin, neutrophils and platelets and much more severe defects of DCs, monocytes, and lymphoid cells. In patients with MDS, deficiencies are more moderate and mononuclear cell generation in AML patients is surprisingly preserved. Serum levels of Fms-like tyrosine kinase 3 ligand (FLT3L) also differed, with massively increased levels in DCML deficiency, stable levels in MDS and deficiencies in AML. Finally, strategies of grouping of AML patients have proven to be possible by using progenitor cell or DC related phenotypic markers which may correlate to known cytogenetic abnormalities. The second part of this thesis explores the origin of the cells of LCH and ECD, both neoplasia involving DC-like cells. RT-PCR assays were developed to detect the BRAFV600E mutation, which is present in ~60% of LCH and ECD viii cases. Surprisingly, it was seen that LCH and ECD express BRAFV600E in differing peripheral blood fractions. In LCH, 78-94% of all BRAFV600E alleles were found in HLA-DR+Lineage- cells, localised to the monocytes and CD1c+ myeloid DCs (mDCs). However in ECD, 80-82% of mutated alleles were recovered from the HLA-DR-Lineage- quadrant, localised to CD33+ early myeloid cells, and no mutation was found in the monocytes or mDCs. The final part of the thesis examines whether the circulating cells which carry the BRAFV600E mutation in LCH and ECD can actually develop into LCH-like cells. In order to do this, culture systems were developed with a variety of cytokines and conditions. These experiments showed that CD14+ and CD16+ monocytes and CD1c+ mDCs could all induce the Langerhans Cell (LC) markers CD1a and Langerin in response to GM-CSF, TGFβ and BMP7, however only the CD1c+ mDCs could express Langerin at the high levels seen in LCs, along with EpCam and Birbeck granules. Several techniques have been developed to study DCs in haematological malignancies. Throughout this thesis, these techniques have provided valuable data on the development and homeostasis of human DCs.
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Rathinam, Chozhavendan. "Elucidation of transcription factor controlled development of dendritic cells." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=97667842X.
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劉恩梅 and Enmei Liu. "The development of cord blood monocyte-derived dendritic cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B3124340X.
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Liu, Enmei. "The development of cord blood monocyte-derived dendritic cells /." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B24520901.
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Kawabata, Kelly. "Functional Analysis of MTSS1 Regulation of Purkinje Cell Dendritic Development and Actin Dynamics." Kyoto University, 2018. http://hdl.handle.net/2433/235121.
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Ahmed, Rami M. Y. "Development of rifampicin loaded in surface-modified 4.0 G PAMAM dendrimer as a novel antituberculosis pulmonary drug delivery system." University of the Western Cape, 2020. http://hdl.handle.net/11394/8073.
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Philosophiae Doctor - PhD<br>Introduction: Tuberculosis (TB) is a serious bacterial infections caused by the Mycobacterium Tuberculosis (MTB) organism affecting mainly the lungs. Occasionally, MTB bacilli may be transported out of the pulmonary region and infect peripheral organs causing extra-pulmonary tuberculosis. Many therapeutic agents were developed over the years to combat TB, however the rapid emergence of resistant strains hampered their use. Furthermore, most of the current anti-TB drugs experience many challenges, which can be summarized in treatment regimen factors, drug-drug interactions, and physicochemical characteristics factors (such as hydrophobicity and low permeability into alveolar macrophages). These challenges have a significant role in treatment failure and the emergence of resistant TB. Due to the lack of newly discovered anti-TB drugs, and the absence of effective vaccines, many scientists have suggested the use of novel modalities for the current anti-TB drugs to enhance their efficacy and overcome some of the drawbacks. One of these modalities is nanotechnology-based drug delivery systems. Most of the anti-TB drugs experience low drug distribution to the lung and particularly alveolar macrophages within which the MTB resides, leading to treatment failure. Employing nanoparticles as drug delivery systems can have a significant impact on improving the pharmacokinetic profile of anti-TB drugs, the feasibility of different routes of administration, enhancing drug permeability, controlled/sustained drug release, and targeting specific disease sites. Collectively, these impacts will aid in enhancing drug concentration at the site of infection and reduce dosing and regimen duration. Dendrimers, such as polyamidoamine (PAMAM) dendrimers, are synthetic polymeric nanoparticles that have unique features that afford a dendrimer-conjugate complex the possibility to overcome the most common hurdles associated with drug delivery and treatment of diseases. Obstacles associated with solubility, permeability, inadequate biodistribution associated side effects may be enhanced. Manipulating the outermost surface functional groups with various ligands and polymers, will enhance the dendrimer properties and targeting potential. Aim: This study aims to develop a novel pulmonary delivery system for the anti-TB drug rifampicin using surface-modified G4 PAMAM dendrimer nanoparticles (polyethylene glycol (PEG) or mannose moieties), to improve drug solubility, prolong-release, enhance permeability into the macrophages, and decrease the toxicity of the drug-dendrimer conjugates. Methods: PAMAM dendrimers having increasing concentrations of poly(ethylene glycol) (PEG) 2 kDa or mannose residues were synthesized. The 4-nitrophenyl chloroformate was used as an activator in the case of PEG functionalization, while for the mannose conjugation the 4-isothiocyanatophenyl alpha-D-mannopyranoside (4-ICPMP) directly interacted with the primary amines of the dendrimer. The conjugated PEG polymers and mannose moieties on the dendrimer periphery were confirmed using FTIR and 1H NMR analytical techniques. Thereafter, rifampicin was loaded into the native and surface-modified dendrimers via a simple dissolution solvent evaporation method. Rifampicin-loaded dendrimers were then characterized using several analytical techniques namely; FTIR, DSC, NMR, SEM, and DLS. The polymer encapsulation efficiency (EE%) and percentage of drug loading (DL%) were determined directly using a validated HPLC method. In vitro drug release was studied at pH 7.4 and pH 4.5. The MTT technique was used to assess the cytotoxicity of the dendrimer formulations against raw 264.7 cell lines. Finally, the uptake of dendrimer nanoparticles by raw macrophages was studied using a flow cytometer and fluorescence microscopy techniques. Results: The percentage coverage of 4.0 G PAMAM dendrimer peripheral with PEG was achieved in a range of 38% - 100%, while for mannose moieties was from 44% - 100%. The EE% of unmodified dendrimer was 7.5% (w/w). The EE% of PEGylated dendrimers ranged from 65.0% - 78.75% (w/w), whereas for mannosylated dendrimers was from 43.43% - 57.91% (w/w). The size of the unloaded dendrimer nanoparticles was less than 25 nm, a gradual increase in the size after drug conjugation followed. The zeta potential of dendrimers was positive with values greater than 12 mV, the nanoparticle's zeta potential decreased upon increasing the density of PEG/mannose and after drug loading. FTIR and NMR data showed that rifampicin molecules were conjugated to the dendrimer at three sites; at the surface amines via electrostatic linkages, within the PEG/mannose, and into the dendrimer interior. SEM images of dendrimer nanoparticles confirmed the spherical shape of particles, and DSC data verified drug entrapment. Drug release was found to be affected by the pH of the medium and the extent of dendrimer functionalization. At the physiologic pH, surface-modified dendrimers showed a slower release rate compared to the unmodified dendrimer and free drug. Among surface-modified dendrimers, the release rate was inversely associated with the density of PEG/mannose molecules. At pH 4.5, a relatively higher drug release from all formulations was observed which suggests a burst release inside the alveolar macrophages. Toxicity studies showed that the unmodified dendrimer experienced time-dependent and concentration-dependent cytotoxicity against raw 264.7 cells. The toxicity gradually decreased upon increasing the density of PEG/mannose, and negligible toxicity was detected for formulations with 100% functionalization. Dendrimer nanoparticles were successfully internalized into raw cells after 24 hrs of incubation. The order of nanoparticles permeability was PEG 100% < PEG 85% < PEG 70% < PEG 49% < PEG 38% < unmodified dendrimer < mannose 44% < mannose 69% < mannose 93% < mannose 100%. The significant increase in the uptake of mannosylated dendrimers was due to the interaction with lectin receptors at the surface of raw macrophages, whereas the lower internalization of PEGylated dendrimers was due to the shielding of the surface positive charges. Conclusion: The in-vitro and ex-vivo data studies suggested that the developed novel surface-modified G4 PAMAM dendrimers are suitable drug carriers in terms of biocompatibility, release behaviour, and site-specific delivery of the anti-TB drug rifampicin.
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Wu, Qian. "Involvement of Cdk5/p35 in EphB2-dependent dendritic spine development /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BICH%202008%20WUQ.
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Robinson, Stephen Paul. "Developmental aspects of normal and malignant dendritic cells." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325518.
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Sio, Alexander. "The effects of mammary tumours on hematopoiesis and dendritic cell development." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44689.
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Goyal, Poorva. "Development of dendritic and polymeric scaffolds for biological and catalysis applications." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/24826.
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Thesis (Ph.D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008.<br>Committee Chair: Weck, Marcus; Committee Member: Bunz, Uwe H. F.; Committee Member: Dickson, Robert M; Committee Member: Fahrni, Christoph J; Committee Member: Jones, Christopher W; Committee Member: Murthy, Niren.
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Chwalla, Barbara. "Genes and mechanisms underlying the development of dendrites in the central nervous system of the Drosophila embryo." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608389.
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Oliver, Devyn. "Constructing and Maintaining the Nervous System: Molecular Insights Underlying Neuronal Architecture, Synaptic Development, and Synaptic Maintenance Using C. elegans." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1123.
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In the nervous system, billions of neurons undergo a multistep process to establish functional circuits. This entails accurate extension of dendritic and axonal processes and coordinated efforts of pre- and postsynaptic neurons to form synaptic connections. Although many axon guidance molecules and synaptic organizers have been identified, the molecular redundancy and the vast number of synapses in the brain has complicated attempts to define their precise roles. In order to understand the molecular mechanisms that encompass these processes, my studies utilize the genetic strengths and cellular precision available in Caenorhabditis elegans for in vivo investigations of nervous system development. In this work, I unravel cell-specific requirements for the transmembrane receptor integrin in regulating developmental axon guidance of GABAergic motor neurons. Furthermore, I address important questions about mechanisms of synapse formation and maintenance using a novel dendritic spine model in C. elegans. Using high resolution microscopy, I find that the formation of immature presynaptic vesicles and postsynaptic receptors are established prior to the outgrowth of dendritic spines at nascent synapses. During this early period of synapse formation, the kinesin-3 family protein UNC-104/KIF1A transports a transsynaptic adhesion molecule neurexin/NRX-1 to developing active zones, in order to maintain postsynaptic receptors and dendritic spines in the mature circuit. In the absence of nrx-1, spines initially form normally but collapse following their extension. These findings demonstrate that presynaptic NRX-1 is required to maintain postsynaptic structures. Together my work provides new insights into molecular mechanisms that define spatiotemporal characteristics of nervous system development and the maintenance of connectivity.
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Adams, Eddie William 1972. "Oligosaccharide-mediated targeting of dendritic cells and the development of carbohydrate microarrays." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/106721.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.<br>Vita.<br>Includes bibliographical references.<br>Bone-marrowed derived dendritic cells (DCs) constitute a critical arm of the immune system capable of polarizing the immune response toward active immunity or tolerance. Successful therapeutic modulation of DC function in vivo should create opportunities for more potent, efficacious vaccines and, in setting of autoimmunity, strategies aimed at the limiting the numbers and character of autoreactive T cells. This thesis describes work aimed at accessing DCs in vivo by way of cell-surface carbohydrate binding proteins expressed by these cells. Synthetic oligosaccharides bearing a tri(ethylene glycol) linker with a reactive thiol handle were chemically coupled to model antigens to generate oligosaccharide-antigen conjugates. These conjugates were evaluated for their ability to specifically target DCs in vitro. Those oligosaccharide moieties that led to enhanced presentation of model antigen to antigen-specific T cells were evaluated for their ability to access DCs in vivo upon subcutaneous immunization and the immunological outcome of DC targeting was studied in detail. The development of carbohydrate microarrays as tools for the identification of the carbohydrate specificities of carbohydrate-binding proteins (lectins and antibodies) is also described here. High density carbohydrate arrays were generated with synthetic saccharides bearing the aforementioned thiol linker.<br>(cont.) These arrays were used to study the glycan-dependent interactions of two gpl20-binding proteins of immunological consequence, the dendritic cell lectin DC-SIGN and the broadly neutralizing antibody, 2G12, as well as two inhibitors of HIV infection isolated from cyanobacteria, cyanovirin-N and scytovirin. The structural diversity of immobilized carbohydrates represented on these arrays enabled the unambiguous characterization of the structural determinants required for gpl20 recognition by each of these proteins.<br>by Eddie William Adams.<br>Ph.D.
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Acton, Aaron L. "The development of dendritic polymer drug delivery systems for use in chemotherapy." Thesis, University of Reading, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.617035.
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The conjugation of anticancer drugs to polymers to produce drug delivery systems has been demonstrated to improve the therapeutic efficacy and reduce toxicities associated with several common drugs used in chemotherapy. This chapter first outlines the limitations associated with several anticancer drugs used in chemotherapy and highlights the ability of drug delivery systems to improve the therapeutic performance of many conventional anticancer drugs. The second section introduces the concept and mechanism of action of polymer-drug conjugates to selectively target cancerous tumours and summarises the current status of polymer-drug conjugates within chemotherapy. This is followed by a discussion of the importance of molecular architecture on the pharmacokinetics and biodistribution of polymer-drug conjugates and in particular, the use of branched dendritic polymers as drug delivery systems. Finally, the recent application of polymer-drug conjugates to deliver multiple therapeutic agents simultaneously for use in combination chemotherapy is reviewed.
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Fletcher, Jonathan S. "Inflammation in plexiform neurofibroma development and growth." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1539079196783167.
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Aungier, Susan Rebecca. "Identification of microRNAs involved in the development and function of follicular dendritic cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9627.
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Follicular dendritic cells (FDCs) are key elements of secondary lymphoid organs where they form the stromal component of B-cell follicles. FDCs possess extensive dendritic process that trap intact antigen via Fc and complement receptors on the cell surface. The antigen is displayed to B-cells, providing a basis for selection of high affinity B cells. FDC also have important roles in facilitating the clearance of apoptotic B cells by the secretion of the opsonising factor MFGE8. It is well established that lymphotoxin signalling is required for FDC maturation but the specific details of the molecular mechanisms that regulate FDC development and differentiation are not fully understood. MicroRNAs (miRNAs) are non-coding RNAs of approximately 18-25 nucleotides in length that regulate gene expression at the post-transcriptional level. MiRNAs bind to their target gene transcripts as part of the RNA induced silencing complex and repress translation of the target gene product. The objective of this study was to identify miRNAs that play a role in the development and function of FDCs. An in vivo murine model of FDC de-differentiation was used to provide material for miRNA analysis. By comparison of miRNA profiles from spleen tissue with FDC at different stages of de-differentiation, we would be able to obtain a miRNA signature for mature FDC. Spleens were collected at various time points over a 28 day period following transient blockade of lymphotoxin signalling. A variety of methods were used to profile the miRNAs expressed at different time points during the suppression and recovery of the FDC network. Comparison of the miRNA profiles of spleens containing mature, partially de-differentiated, and fully de-differentiated FDC identified a number of miRNAs that were differentially expressed during FDC de-differentiation. To assess the role of specific miRNAs in FDC development, the mouse FDC-like cell line, FL-YB, was used as an in vitro model system. FL-YB cells were used to perform gain-offunction and loss-of-function studies on selected miRNAs and to assess the effects of various stimuli/conditions on miRNA expression. The effects of different treatments on cell proliferation, morphology and adhesion, and on gene expression by FL-YB, were monitored. Loss-of-function studies for one of the selected miRNA (miR-100-5p) revealed a significant effect on a number of gene transcripts involved in mediation of the germinal centre response (Il-6, Tlr4, Ptgs1/2). These data indicate that miR-100-5p has a role in regulating Il-6, Tlr4 and Ptgs1/2 transcripts. None of these transcripts contain predicted target sites for miR-100-5p and so the effect of miR-100-5p on these transcripts is likely to be indirect. Further studies on these miRNA: target interactions are required to elucidate the mechanisms and biological consequences of miRNA regulation in FDCs.
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Ni, Xianglian. "Developmental Regulation and Function of AMPA Receptor Subunits in Chicken Lumbar Motoneurons." ScholarWorks @ UVM, 2009. http://library.uvm.edu/dspace/bitstream/123456789/206/1/Ni%20Dissertation.pdf.
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Lee, Kevin Fu-Hsiang. "Dynamics of Synapse Function during Postnatal Development and Homeostatic Plasticity in Central Neurons." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32449.
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The majority of fast excitatory neurotransmission in the brain occurs at glutamatergic synapses. The extensive dendritic arborisations of pyramidal neurons in the neocortex and hippocampus harbor thousands of synaptic connections, each formed on tiny protrusions called dendritic spines. Spine synapses are rapidly established during early postnatal development – a key period in neural circuit assembly – and are subject to dynamic activity-dependent plasticity mechanisms that are believed to underlie neural information storage and processing for learning and memory. Recent decades have seen remarkable progress in identifying diverse plasticity mechanisms responsible for regulating synapse structure and function, and in understanding the processes underlying computation of synaptic inputs in the dendrites of individual neurons. These advances have strengthened our understanding of the biological mechanisms underlying brain function but, not surprisingly, they have also raised many new questions. Using a combination of whole-cell electrophysiology, 2-photon imaging and glutamate uncaging in rodent brain slice preparations, I have helped to document the subtype-specific regulation of glutamate receptors during a homeostatic form of synaptic plasticity at CA1 pyramidal neurons of the hippocampus, and have discovered novel synaptic calcium dynamics during a critical period of neural circuit formation. First, we found that during a homeostatic response to prolonged inactivity, both AMPA and NMDA subtypes of glutamate receptors undergo a switch in subunit composition at synapses, but exhibit a divergence in their subcellular localization at extrasynaptic regions of the plasma membrane (this work was published in the Journal of Neuroscience in 2013). In separate series of experiments using 2-photon calcium imaging, I discovered a functional coupling between NMDA receptor activation and intracellular calcium release at dendritic spines and dendrites that is selectively expressed during a critical period of synapse formation. This synaptic calcium signaling mechanism enabled the transformation of distinct spatiotemporal patterns of synaptic input into salient biochemical signals, and is thus apt to locally regulate synapse development along individual dendritic branches. Consistent with this hypothesis, I found evidence for non-random clustering of synapse development between neighboring dendritic spines. Together, these experimental results expand the current understanding of the dynamics of synapse function during homeostatic plasticity and early postnatal development.
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Les synapses glutamatergiques soutiennent la majorité de la neurotransmission excitatrice rapide du cerveau. Des milliers de ces synapses, localisées sur de minuscules saillies appelées épines dendritiques, décorent les vastes arborisations dendritiques des neurones pyramidaux du néocortex et de l'hippocampe. Ces synapses sont formées tôt lors du développement postnatal et sont soumises à des mécanismes dynamiques de plasticité qui sous-tendent, croit-on, les capacités d'apprentissage et de mémoire du cerveau. Les dernières décennies ont vu des progrès remarquables dans l'identification de divers mécanismes de régulation de la structure et de la fonction des synapses sur différentes échelles de temps, et dans la compréhension des processus qui régissent l’intégration des inputs synaptiques au niveau des dendrites individuelles. Ces progrès ont renforcé notre compréhension des éléments fondamentaux régissant la fonction cérébrale et ont ouvert de nouvelles voies d’investigations neurophysiologiques. En utilisant une combinaison d’électrophysiologie cellulaire, d'imagerie à deux-photons et de photolibération de glutamate sur des neurones pyramidaux de la région CA1 de l'hippocampe de rats, j’ai contribué à la découverte et à la caractérisation de nouvelles régulations des récepteurs du glutamate durant la plasticité synaptique homéostatique. J’ai également découvert un nouveau type de dynamique de calcium synaptique relié à une organisation spatiale du développement des synapses pendant une période critique de l’ontogénie des circuits neuronaux. Dans la première étude, nous avons constaté que lors d'une plasticité de type homéostatique induite par une inactivité prolongée, les récepteurs de glutamate de types AMPA et NMDA sont soumis à un changement important dans la composition de leurs sous-unités. De plus, nous avons observé un ciblage différentiel de ces récepteurs vers des compartiments subcellulaires spécifiques des neurones. Dans une série d'expériences séparée utilisant l’imagerie calcique à deux-photons, j’ai découvert un couplage fonctionnel durant le développent entre l'activation des récepteurs NMDA et une libération de calcium intracellulaire qui envahit tant les épines dendritiques que les dendrites. J’ai également trouvé que ce mécanisme de signalisation de calcium synaptique transforme des motifs spatiotemporels d’activités synaptiques spécifiques en signaux biochimiques post-synaptiques de manière à potentiellement réguler l’organisation spatiale des synapses durant le développement. Conformément à cette hypothèse, j’ai observé des manifestations fonctionnelles claires de regroupement dans l’espace de synapses de forces similaires le long de branches dendritiques individuelles. Ensemble, ces résultats expérimentaux élargissent notre compréhension actuelle de de la fonction des synapses durant la plasticité homéostatique ainsi que durant le développement postnatal du cerveau. En étudiant les mécanismes neurophysiologiques de base, il sera possible d'avoir un aperçu plus profond du fonctionnement du cerveau et de ses pathologies.
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Schnorfeil, Frauke Marie [Verfasser], and Thomas [Akademischer Betreuer] Brocker. "MicroRNAs regulate Dendritic Cell Development and Function / Frauke Marie Schnorfeil. Betreuer: Thomas Brocker." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1018615865/34.
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Klangsinsirikul, Phennapha. "The role of dendritic cells in the development of graft versus host disease." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394917.
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Norkett, R. "Contribution of the schizophrenia associated protein DISC1 to mitochondrial dynamics and dendritic development." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1478349/.
Full textAbstract:
Correct neuronal function is an energy costly process, highly dependent upon the ATP production and calcium buffering capabilities of mitochondria. Further, it is crucial that these organelles are correctly distributed throughout the neuron, matching local energy demand. To achieve this, mitochondrial fusion and transport dynamics must be precisely regulated. Trafficking is dependent upon microtubule based transport of these organelles, mediated by kinesin motors, TRAK adaptors and the mitochondrial anchor, Miro. Mitofusins orchestrate mitochondrial fusion at the outer membrane. Disrupted in schizophrenia 1 (DISC1) – a major candidate susceptibility factor for psychiatric disease – also plays a role in mitochondrial transport. However, the mechanisms of this regulation, and subsequent roles in neuronal development, are poorly understood. In this study, the interactions between DISC1 and mitochondrial trafficking proteins Miro and TRAKs are investigated. DISC1 is shown to couple to the mitochondrial transport and fusion machinery in brain. Live cell imaging demonstrates the importance of these interactions for normal mitochondrial transport. A schizophrenia associated mutation in DISC1 – the DISC1-Boymaw fusion protein – is shown to disrupt these transport dynamics and similarly impair mitochondrial fusion. Further, this mutation alters contact area between the endoplasmic reticulum and the mitochondria. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro/TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Finally, mitochondrial dynamics in human neurons, differentiated from induced pluripotent stem cells, are explored. This innovative system is used to investigate impact of pathogenic mutations associated with schizophrenia and Alzheimer’s disease upon mitochondrial dynamics. This work highlights DISC1 as an important regulator of mitochondrial dynamics in neurons to mediate transport, fusion and cross-talk of these organelles. Moreover, pathological DISC1 isoforms disrupt this critical function, leading to abnormal neuronal development. These findings implicate regulation of mitochondrial dynamics in aetiology of psychiatric disease.
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Chiang, Chih-Yuan. "Cortical development & plasticity in the FMRP KO mouse." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22055.
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Autism is one of the leading causes of human intellectual disability (ID). More than 1% of the human population has autism spectrum disorders (ASDs), and it has been estimated that over 50% of those with ASDs also have ID. Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is the leading known genetic cause of autism, affecting approximately 1 in 4000 males and 1 in 8000 females. Approximately 30% of boys with FXS will be diagnosed with autism in their later lives. The cause of FXS is through an over-expansion of the CGG trinucleotide repeat located at the 5’ untranslated region of the FMR1 gene, leading to hypermethylation of the surrounding sequence and eventually partially or fully silencing of the gene. Therefore, the protein product of the gene, fragile X mental retardation protein (FMRP), is reduced or missing. As a single-gene disorder, FXS offers a scientifically tractable way to examine the underlying mechanism of the disease and also shed some light on understanding ASD and ID. The mouse model of FXS (Fmr1−/y mice) is widely accepted and used as a good model, offering good structural and face validity. Since a primary deficit of FXS is believed to be altered neuronal communication, in this thesis I examined white matter tract and dendritic spine abnormalities in the mouse model of FXS. Loss of FMRP does not alter the gross morphology of the white matter. However, recent brain imaging studies indicated that loss of FMRP could lead to some minute abnormalities in different major white matter tracts in the human brain. The gross white matter morphology and myelination was unaltered in the Fmr1−/y mice, however, a small but significant increase of axon diameter in the corpus callosum (CC) was found compared to wild-type (WT) controls. Our computation model suggested that the increase of axon diameter in the Fmr1−/y mice could lead to an increase of conduction velocity in these animals. One of the key phenotypes reported previously in the loss of FMRP is the increase of “immature” dendritic spines. The increase of long and thin spines was reported in several brain regions including the somatosensory cortex and visual cortex in both FXS patients and the mouse model of FXS. Although recent studies which employed state-of-the-art microscopy techniques suggested that only minute differences were noticed between the WT and Fmr1−/y mice. In agreement with previous findings, I found an increase of dendritic spine density in the visual cortex in the Fmr1−/y mice, and spine morphology was also different between the two genotypes. We found that the spine head diameter is significantly increased in the CA1 area of the apical dendrites of the Fmr1−/y mice compared to WT controls. Dendritic spine length is also significantly increased in the same region of the Fmr1−/y mice. However, apical spine head size does not alter between the two genotypes in the V1 region of the visual cortex, and spine length is significantly decreased in the Fmr1−/y mice compared to WT animals in this region. Lovastatin, a drug known as one of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, functions as a modulator of the mitogen-activated protein kinases (MAPK) pathway through inhibiting Ras farnesylation, was used in an attempt to rescue the dendritic spine abnormalities in the Fmr1−/y mice. Mice lacking FMRP are susceptible to audiogenic seizure (AGS). Previous work has shown that 48 hr of lovastatin treatment reduced the incidence of AGS in the Fmr1−/y mice. However, chronic lovastatin treatment failed to rescue the spine density and morphology abnormalities in the Fmr1−/y mice. Mouse models are invaluable tools for modelling human diseases. However inter-strain differences have often confounded results between laboratories. In my final Chapter of this thesis, I compared two commonly used C57BL/6 substrains of mice by recording their electrophysiological responses to visual stimuli in vivo. I found a significant increase of high-frequency gamma power in adult C57BL/6JOla mice, and this phenomenon was reduced during the critical period. My results suggested that the C57BL/6JOla substrain has a significant stronger overall inhibitory network activity in the visual cortex than the C57BL/6J substrain. This is in good agreement with previous findings showing a lack of open-eye potentiation to monocular deprivation in the C57BL/6JOla substrain, and highlights the need for appropriate choice of mouse strain when studying neurodevelopmental models. They also give valuable insights into the genetic mechanisms that permit experience-dependent developmental plasticity. In summary, these findings give us a better understanding of the fine structure abnormalities of the Fmr1−/y mice, which in turn can benefit future discoveries of the underlying mechanisms of neurodevelopmental disorders such as ID and ASDs.
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Salvermoser, Johanna [Verfasser], and Barbara [Akademischer Betreuer] Schraml. "Dendritic cell progenitor trafficking and identification and functional analyses of dendritic cells with distinct developmental origin / Johanna Salvermoser ; Betreuer: Barbara Schraml." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1212362845/34.
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Schlitzer, Andreas Bernhard [Verfasser], and Stefan [Akademischer Betreuer] Bauer. "Development and plasticity of murine plasmacytoid dendritic cells / Andreas Bernhard Schlitzer. Betreuer: Stefan Bauer." Marburg : Philipps-Universität Marburg, 2012. http://d-nb.info/1020706384/34.
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Costigliola, Emanuele. "Development of herpes simplex virus 1 vectors for dendritic cell based immunotherapy of malaria." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444585/.
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Herpes simplex virus 1 (HSV-1) naturally infects dendritic cells but this prevents the cell from undergoing maturation. Removal of the virus host shutoff protein (vhs) has been shown to improve the ability of both human dendritic cells and mouse bone marrow dendritic cells to mature following virus infection. An HSV-1 vhs" backbone was further modified by deletion of the ICP47 gene and mutation of the VP 16 gene resulting in a vector that does not interfere at all with the ability of mouse dendritic cells to mature. This virus therefore, provided a good candidate for use as vector for antigen delivery in immunotherapy. A recombinant vhs"ICP47"VP16" virus expressing the full length influenza nucleoprotein (NP) was constructed and used to determine the ability of this virus to induce immune responses upon immunisation with virus alone or upon immunisation with infected DCs. Both cellular and humoral responses were investigated and a CD8+ CTL response to both the NP gene and to the virus was obtained after different immunisation regimes confirming the potential of the virus to be used for immunotherapy. In the attempt to further improve the vector, mGMCSF was added to the viral constructs and viruses expressing both mGMCSF and NP or full length Plasmodium yoelii sporozoite surface protein 2 (PySSP2) or circumsporozoite protein (PyCS) were constructed. The effect of co-expressing mGMCSF from the virus was investigated. A convincing CD8+ CTL response was obtained against - the antigen upon direct virus injection though co-expression of mGMCSF did not seem to confer a significant advantage. Overall an HSV-1 vector has been developed and optimised for the infection of dendritic cells and then successfully used for induction of specific CTL and antibody response to full length NP, PySSP or PyCS.