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1
Travelho, Jeronimo S. „The role of ions in soot formation“. Diss., Georgia Institute of Technology, 1987. http://hdl.handle.net/1853/12453.
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2
Gray, de Cristoforis Angelica [Verfasser], und Tanja [Akademischer Betreuer] Vogel. „Role of DOT1L in spinal cord formation“. Freiburg : Universität, 2021. http://d-nb.info/1238016545/34.
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3
Tankard-Evans, Tamsyn Amy. „The role of environment in galaxy formation“. Thesis, Durham University, 2015. http://etheses.dur.ac.uk/11345/.
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In this thesis we investigate the influence that environment has on the formation and evolution of galaxies in the Galaxy And Mass Assembly (GAMA) survey. The highly complete equatorial regions of GAMA cover 180 square degrees of the sky, providing spectroscopic redshifts for 180,000 galaxies brighter than m_r = 19.8. GAMA is the largest multi-wavelength spectroscopic survey of its kind to date, designed to study aspects of galaxy formation on scales of <1 Mpc. The dependence of the galaxy luminosity function (LF) on local environment is well described by linear relations with overdensity. The faint end slope of the LF is largely independent of environment but steepens in void regions. The environmental dependence shows little evolution over the last 3 Gyrs, and can again be parameterised by a linear relation when split by colour. The dependence of the LF on the cosmic web classification can be predicted from its dependence on overdensity and the distribution of overdensities within each cosmic web structure. Observations from the GAMA survey can be theoretically interpreted by comparing to predictions made by the semi-analytic galaxy formation model of GALFORM through lightcone mock catalogues, which exhibit the same selection criteria as GAMA. Galaxy groups trace the underlying distribution of dark matter haloes in the Universe, and the use of galaxy group properties to infer the properties of dark matter, such as halo mass, is explored. Measurements of the galaxy density profile in galaxy groups in the GAMA survey and in the lightcone mocks suggest that the GALFORM model predicts the galaxy density profile to be too centrally concentrated. Comparisons to galaxy surveys such as GAMA lead to a bright future for the studies of galaxy formation.
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Pantazis, Periklis. „Role of endocytic trafficking during Dpp gradient formation“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2004. http://nbn-resolving.de/urn:nbn:de:swb:14-1106665288062-25959.
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Morphogens are secreted signalling molecules that are expressed in restricted groups of cells within the developing tissue. From there, they are secreted and travel throughout the target field and form concentration gradients. These concentration profiles endow receiving cells with positional information. A number of experiments in Drosophila demonstrated that the morphogen Decapentaplegic (Dpp) forms activity gradients by inducing the expression of several target genes above distinct concentration thresholds at different distances from the source. This way, Dpp contributes to developmental fates in the target field such as the Drosophila wing disc. Although the tissue distribution as well as the actual shape and size of the Dpp morphogen concentration gradient has been visualized, the cell biological mechanisms through which the morphogen forms and maintains a gradient are still a subject of debate. Two hypotheses as to the dominant mechanism of movement have been proposed that can account for Dpp spreading throughout the Drosophila wing imaginal target tissue: extracellular diffusion and planar transcytosis, i. e. endocytosis and resecretion of the ligand that is thereby transported through the cells. Here, I present data indicating that implications of a theoreticalanalysis of Dpp spreading, where Dpp transport through the target tissue is solely based on extracellular diffusion taking into account receptor binding and subsequent internalization, are inconsistent with experimental results. By performing Fluorescence Recovery After Photobleaching (FRAP) experiments, I demonstrate a key role of Dynamin-mediated endocytosis for Dpp gradient formation. In addition, I show that most of GFP-Dpp traffics through endocytic compartments at the receiving epithelial cells, probably recycled through apical recycling endosomes (ARE). Finally, a Dpp recycling assay based on subcellular photouncage of ligand is presented to address specifically the Dpp recycling event at the receiving cells.
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Sinha, Natasha. „Rab14: Role in Cell Polarity and Junction Formation“. Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146930.
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The establishment of polarity in epithelial cells is dependent on the proper distribution of polarity proteins to the apical or basolateral domain. In addition, these cells are dependent on the necessary trafficking of junctional proteins to cells junctions for cell-cell interactions. Rab GTPases are involved in a number of membrane trafficking pathways in the cell. Here we show Rab14's role in regulating the establishment of polarity and junction formation in epithelial cells. Cyst culture was used to show inactive-Rab14 affects single lumen formation and targeting of gp135, an apically targeted protein, thus showing Rab14 may regulate epithelial polarity. In addition, calcium-switch experiments were used to show that not only do cells expressing inactive Rab14 take longer to lose their cell-to-cell contact, but they also regain their contacts more quickly, indicating Rab14 may be playing a role in junction formation. This was further supported by immunostaining experiments examining the distribution of junctional proteins; increased amounts of these proteins at the junction in inactive-Rab14 at the end-point showed that Rab14 may be involved in endocytosis or recycling of junctional components.
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Malbon, Rowena Katherine. „The role of black holes in galaxy formation“. Thesis, Durham University, 2006. http://etheses.dur.ac.uk/2892/.
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We incorporate a model for black hole growth during galaxy mergers into the semi-analytical galaxy formation model based on ACDM proposed by Baugh et al. (2005). Our black hole model has one free parameter, which we set by matching the observed zeropoint of the local correlation between black hole mass and bulge luminosity. We present predictions for the evolution with redshift of the relationships between black hole mass and bulge properties. Our simulations reproduce the evolution of the optical luminosity function of quasars. We study the demographics of the black hole population and address the issue of how black holes acquire their mass. We find that the direct accretion of cold gas during starbursts is an important growth mechanism for lower mass black holes and at high redshift. The reassembly of pre-existing black hole mass into larger units via merging dominates the growth of more massive black holes at low redshift. As redshift decreases, progressively less massive black holes have the highest fractional growth rates, in line with recent claims of 'downsizing’ in quasar activity. We are able to reproduce the observed population of rare, highly luminous quasars at z ~ 6 in the ACDM model, although we struggle when the model parameters are refined to those in the current best fit of Sanchez et al. (2006). which has been hinted at by recent observations. We find that the most massive black holes and the most luminous quasars at z ~ 6 are not hosted exclusively by the most massive dark matter haloes, as is often assumed. Finally, we repeat our study of the assembly histories of black holes using the new galaxy and black hole formation model of Bower et al. (2006), which includes AGN feedback. Black hole growth in this model is dominated by the accretion required to fuel AGN feedback at low redshifts and by the accretion during starbursts triggered by disc instabilities at high redshifts. At no redshift is growth by BH-BH mergers dominant, although we still predict a high BH-BH merger rate. The Bower et al. model gives a somewhat better match to the M(_BH) - bulge relations, while the Baugh et al. model gives a better match to the quasar luminosity function. We suggest future directions to explore with these models.
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Wardlow, Julie Louise. „The role of obscured activity in galaxy formation“. Thesis, Durham University, 2010. http://etheses.dur.ac.uk/426/.
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In this thesis I investigate the formation and evolution of the galaxies that eventually form the colour-magnitude relation (CMR) in local galaxy clusters. I survey galaxies that lie on the CMR in nine massive clusters at z~0.2, environments in which the build-up of the faint end of the CMR is still underway. I show that there are relatively few dwarf galaxies on the CMR in the outer, low-density regions of clusters, but that their fraction increases towards higher-density regions as the cluster environment transforms infalling, blue, star-forming galaxies into red, passive, CMR galaxies. However, in the highest density regions, at the very centres of clusters the relative fraction of dwarf galaxies on the CMR is suppressed, evidence that, dwarf galaxies in the highest density regions at z~0.2 are dynamically disrupted. I then use 1.1-mm observations of a massive cluster at z~0.54 to search for active, star-forming cluster galaxies, which would transform into CMR galaxies at lower redshifts as the star-formation terminates. I detect 36 sources in observations of 0.1 deg² of the cluster centre and identify counterparts to ~50% of these submillimetre galaxies (SMGs) using radio, 24-μm and IRAC data. Photometric redshifts suggest that at most two of the SMGs are potential cluster members. If this is the case they each have far-infrared luminosities of ~5x10¹¹ solar luminosities and star-formation rates (SFRs) of ~50 solar masses per year - a significant fraction of the combined SFR of the cluster. I next consider 126 SMGs detected in an 870-μm survey of the Extended Chandra Deep Field South (ECDFS). I derive a photometric redshift distribution of 74 robust radio, 24-μm and IRAC-identified counterparts that peaks at z=2.2. An analysis of sources within the positional error circles of unidentified SMGs identifies a population of likely counterparts with a redshift distribution that peaks at z=2.5±0.3 and likely comprises ~60% of the unidentified SMGs. The remainder are not detected in our IRAC imaging and likely lie at z≳3. In total, I find that ~30% of all SMGs are at z≳3, and the median redshift of all S₈₇₀μm>4 mJy SMGs is z=2.5±0.6. The contribution of SMGs to the global SFRD also peaks at z~2 and SMGs with S₈₇₀μm≳4 mJy and S₈₇₀μm≳1 mJy provide ~5% and ~50% of the global total at z~2, respectively. Analysis of the projected real-space cross-correlation function of SMGs at z=1-3 with IRAC-selected galaxies shows that SMGs are strongly clustered and reside in dark-matter halos of mass (6⁺¹²₋₅)x10¹² solar masses. This halo mass is comparable to that of quasars and the mass at which major mergers are most efficient at triggering starburst activity. I conclude that SMGs at z~2 have star-formation rates, stellar masses and clustering properties that suggests that they are the likely progenitors of the massive CMR galaxies that dominate local clusters.
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麥順桂 und S. K. Mak. „The role of motion in children's category formation“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31240732.
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Toh, Huishi. „The role of progranulin in blood vessel formation“. Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121113.
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Progranulin is a secreted glycoprotein that was initially identified and characterized in our laboratory. It has roles in cancer, immunomodulation, tissue repair and neurodegenerative disease. Progranulin acts like a growth factor, it stimulates cellular proliferation, migration and blunts apoptosis. We have hypothesized that one of progranulin's major roles is as a stimulatory regulatory protein during tissue remodeling. This is exemplified in a physiological context in wound healing, when progranulin is rapidly induced in the wound. Neither quiescent dermal fibroblasts nor vascular endothelia produces progranulin, however, in wounds both cell types show a rapid induction of progranulin expression once they are activated for tissue repair. Adding progranulin to dermal wounds increases the numbers of capillaries in the wound. Progranulin stimulates fibroblasts and endothelial cell to divide and migrate through collagen matrices. It also stimulates endothelial cells to form tubular structures in Matrigel, recapitulating the formation of luminal endothelial structures during angiogenesis in vivo. Progranulin is also present in endothelial cells in highly vascularized cancers and in the placenta. We proposed therefore that progranulin may regulate angiogenesis and vascular formation. A limitation to this hypothesis has been a lack of animal models with which to test the vascular roles of progranulin in vivo. Angiogenesis is a complex process with both positive and negative regulation. It could not, therefore be assumed that the ability of progranulin to stimulate endothelial cells in vitro applied also to the intact tissue in vivo. To address this criticism we constructed mice that express progranulin specifically in their endothelial cells. Since endothelial cells form well-defined structures in vivo, altered angiogenesis due to the targeted expression of progranulin could be assessed by abnormal growth or morphology of blood vessels in vivo. Briefly, we used a Tie2-promoter/enhancer vector to create an endothelial-specific Tie2-Pgrn targeting vector. Three Tie2-Pgrn lines were generated, designated PgrnHi, PgrnMid, and PgrnLo to reflect the Tie2-Pgrn copy number. The expression and endothelial specificity of the Tie2-Pgrn construct was confirmed by qRT-PCR and immunohistochemistry. All three Tie2-Pgrn mouse lines show increased mortality at birth, and show a negative linear correlation with Tie2-Pgrn copy number. Death of Tie2-Pgrn embryos occurred after E17.5 and continued for three days post partum, after which mice that survived tended to reach maturity and appeared normal. Affected blood vessels are highly expanded, thin-walled and typically show sparse coverage with mural cells. Hemorrhage is common, ranging from small focal hemorrhages to massive internal bleeding into the body cavities. There were no vascular abnormalities in E10.5 embryos, implying that the early vasculogenic phase of blood vessel development was not altered by targeted expression of progranulin in endothelial cells. The earliest vascular abnormalities were detected at E15.5, consisting of focal hemorrhage in the brain and skin. We conclude that the endothelial-specific targeting of progranulin confirms the hypothesis that progranulin is sufficient to influence vascular formation in vivo.La progranuline est une glycoprotéine qui a initialement été identifiée et décrite dans notre laboratoire. Elle est impliquée dans le cancer, l'immunomodulation, la réparation des tissus et les maladies neurodégénératives et agit comme un facteur de croissance; de plus, elle stimule la prolifération et la migration cellulaires et atténue l'apoptose. Nous avons émis l'hypothèse que l'un des rôles importants de la progranuline est en tant que protéine de stimulation et réglementation lors du remodelage de tissus. Dans cette thèse nous démontrons dans un contexte physiologique lors de la guérison des plaies, characterisee par l'induction rapide de la progranuline dans la plaie. Ni les fibroblastes dermiques en repos, ni l'endothélium vasculaire ne produisent de la progranuline. Cependant, dans les plaies, ces deux types de cellules montrent une induction rapide de la progranuline une fois qu'elles ont été activées pour la réparation tissulaire. L'ajout de la progranuline aux plaies dermiques augmente le nombre de capillaires dans la plaie. La progranuline stimule la division des fibroblastes et des cellules endothéliales, ainsi que leur migration à travers les matrices de collagène. Elle incite également les cellules endothéliales à former des structures tubulaires sur le Matrigel, récapitulant la formation de structures luminales endothéliales lors de l'angiogenèse in vivo. De plus, la progranuline est présente dans les cellules endothéliales dans des cas de cancers très vascularisés et dans le placenta. Nous proposons donc que la progranuline puisse réglementer l'angiogénèse et la formation vasculaire. Une des limites de cette hypothèse est le manque de modèles animaux permettant de tester les rôles vasculaires de la progranuline in vivo. L'angiogénèse est un processus compliqué. Il ne peut donc pas être supposé que la capacité de la progranuline à stimuler les cellules endothéliales in vitro puisse être également appliquée au tissu intact in vivo. Pour répondre à cette critique, nous avons élevé des souris qui expriment la progranuline dans leurs cellules endothéliales. Étant donné que les cellules endothéliales forment des structures bien définies in vivo, l'angiogenèse modifiée en raison de l'expression ciblée de la progranuline pourrait être marquée par une croissance ou une morphologie anormales des vaisseaux sanguins in vivo. En bref, nous avons utilisé un vecteur Tie2-promoteur/amplificateur pour créer un vecteur spécifique à l'endothélium qui vise Tie2-Pgrn. Trois lignées Tie2-Pgrn ont été générées, désignées PgrnHi, PgrnMid, and PgrnLo pour refléter le nombre de copie de Tie2-Pgrn. L'expression et la spécificité endothéliales de la construction Tie2-Pgrn ont été confirmées par qRT-PCR et l'immunohistochimie. Les trois lignées de souris Tie2-Pgrn montrent une mortalité à la naissance, ainsi qu'une corrélation linéaire négative avec le nombre de copie Tie2-Pgrn. La mort des embryons Tie2-Pgrn a eu lieu après E17.5 et a continué pendant trois jours post partum, après quoi les souris qui ont survécu ont tendance à arriver à maturité et semblent normales. Les vaisseaux sanguins affectés sont très élargis, à paroi mince et présentent généralement une couverture clairsemée de cellules murales. L'hémorragie est courante, allant de petites hémorragies focales à une hémorragie interne massive dans les cavités du corps. Il n'y a pas d'anomalies vasculaires dans les embryons âgés de 10.5 jours, ce qui implique que la phase précoce du développement vasculogène des vaisseaux sanguins ne fut pas altérée par l'expression ciblée de la progranuline dans les cellules endothéliales. Les premières anomalies vasculaires ont été détectées à E15.5, caractérisées par une hémorragie focale dans le cerveau et la peau. Nous concluons que le ciblage spécifique de l'endothélium par la progranuline confirme l'hypothèse selon laquelle la progranuline est suffisante pour influencer la formation vasculaire in vivo.
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Bate, Matthew Russell. „The role of accretion in binary star formation“. Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388852.
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Mak, S. K. „The role of motion in children's category formation /“. Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21806457.
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12
Kelton, Cathryn Renee. „The role of wnt8 in posterior mesoderm formation“. [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2322.
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Pantazis, Periklis. „Role of endocytic trafficking during Dpp gradient formation“. [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11611845.
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14
Natan, Ryan Gregory. „Putative role of innexins in neuronal arbor formation“. Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465082.
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Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed June 19, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 76-81).
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Jones, Michael Oliver. „The role of protostellar heating in star formation“. Thesis, University of Exeter, 2018. http://hdl.handle.net/10871/34560.
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Previous studies have shown that thermal feedback from protostars plays a key role in the process of low-mass star formation. In this thesis, we explore the effects of protostellar heating on the formation of stellar clusters. We describe new methods for modelling protostellar accretion luminosities and protostellar evolution in calculations of star formation. We then present results of a series of numerical simulations of stellar cluster formation which include these effects, and examine their impact. We begin by investigating the dependence of stellar properties on the initial density of molecular clouds. We find that the dependence of the median stellar mass on the initial density of the cloud is weaker than the dependence of the thermal Jeans mass when radiative effects are included. We suggest that including protostellar accretion luminosities and protostellar evolution may weaken this dependence further, and may account for the observed invariance of the median stellar mass in Galactic star-forming regions. Next, we investigate the effects of including accretion feedback from sink particles on the formation of small stellar groups. We find that including accretion feedback in calculations suppresses fragmentation even further than calculations that only include radiative transfer within the gas. Including feedback also produces a higher median stellar mass, which is insensitive to the sink particle accretion radius used. Finally, we compare calculations of small stellar clusters which model the evolution of protostars using a live stellar model with those which use a fixed stellar structure. We find that the dynamics of the clusters are primarily determined by the accretion luminosities of protostars, but that the relative effects of protostellar evolution depend on the accretion rate and advection of energy into the protostar. We also demonstrate how such calculations may be used to study the properties of young stellar populations.
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Quist, Sven Roy. „Role of Rac1 signalling in epidermal tumour formation“. Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708007.
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Matlak, Robert Gregory. „The Role of Askesis in Orthodox Christian Formation“. Thesis, Boston College, 2018. http://hdl.handle.net/2345/bc-ir:107903.
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Thesis advisor: Jane E. ReganThe Eastern Fathers through the centuries affirm that askesis—struggle and training in spiritual life—is integral to Christian growth, life, and maturity. It is a part of the Church’s basic mindset regarding growth in life in Christ. Within the US Orthodox Christian Education (OCE) field, however, no substantial treatment of this theme exists. The place of a discussion of askesis within OCE requires that one perceive how vitally and expansively the Orthodox Church understands this theme. Clearing lesser things from the heart, preparing room for divinity, learning to turn the eyes of the heart toward Christ, and to fix them on Him in all things are all vital to acquiring the Holy Spirit, whose fruit in us proclaims and brings about the Gospel of Jesus Christ. Christian witness presupposes fruit, while fruit is born of divine indwelling. Yet, as Gregory of Nyssa affirms, grace “does not naturally frequent souls which are fleeing from salvation.” We must engage. If spiritual maturity is important to the Church’s witness, then, so is developing maturity. In this way, askesis is integral to the mission of the Church. The Eastern Fathers understand this training in expansive ways. While askesis can indicate a subset of specific practices (vigils, fasting, chastity, etc.) in a larger sense it indicates active formation in spiritual life in general. Various Fathers affirm things as diverse as prayer, marriage, faith, childrearing, and patient endurance of suffering as opportunities for askesis. Since askesis is vital to Orthodox Christian life and faith, and given the gap in coverage, this study explores the theme, in three steps. First, after surveying recent OCE engagements with askesis, it considers in depth the spiritual anthropology and ascetical teaching of a relatively early figure, Gregory of Nyssa. Second, it explores three themes from the Byzantine period that display some of the Church’s broader, more settled sensibilities regarding askesis, namely, 1) the centrality of Jesus Christ in developing virtue and maturity; 2) the importance of the Church and Sacraments for spiritual growth; and 3) how material creation figures in spiritual life. Third, the study turns to the voices of more recent elders as they convey the Church’s expansive understanding of askesis. Again, three themes are developed: 1) how each and every aspect of human nature must be formed in Christ; 2) how, in God’s providence, the entire arena of life provides opportunities for Christian development; and 3) the ascetic character of an Orthodox Christian vision of education. This study is not a historical work of Christian spirituality, a history of the development of ascetical theology, or a comprehensive summary of its theme. Rather, it seeks to specify key elements of the developmental path to freedom in Christ proclaimed by the Orthodox faith, and to argue for their wisdom and fruitfulness. It aims to be a useful tool for those engaged in the task of forming the faithful. A final chapter summarizes implications in this regard
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Religious Education and Pastoral Ministry
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Miremadi, Ahmad. „Role of α6β4 integrin in epidermal tumour formation“. Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608785.
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19
Geisler-Lee, C. Jane. „The role of phragmoplastin in cell plate formation /“. The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu148646124681795.
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Callejas, Adriana. „The role of specialized competencies in identity formation“. FIU Digital Commons, 1996. http://digitalcommons.fiu.edu/etd/1978.
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This thesis investigated the role played by the exploration and identification of one's specialized competencies (i.e., interests, talents, and competencies) in the process of identity formation. The participants consisted of 155 (114 females and 41 males) undergraduate, psychology students. Each student was administered two measures of identity status (Identity Domain Scale and Ego Objective Measure of Identity Status-2) in addition to a measure of interest and competency (Self-Directed Search:SDS), and a measure of personal expressiveness (Personally Expressive Activities Questionnaire). As hypothesized, the results indicated that students who had committed to an identity (Foreclosed and Achieved) had a clearer or more differentiated sense of their specialized competencies as measured by the SDS. In addition, students who were classified as Identity achieved often chose activities on the SDS that were personally expressive or truly a part of their identity. Implications for interventions in identity formation are discussed.
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Bieri, Rebekka. „The Role of AGN Feedback in Galaxy Formation“. Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066292/document.
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L’objectif de ma thèse porte sur les interactions entre les noyaux actifs de galaxies et le milieu interstellaire des galaxies. En particulier, je mets l’accent sur les deux mécanismes possibles responsables de la production des vents par les trous noirs : les jets et les vents produits par le rayonnement de ces trous noirs. Les simulations hydrodynamiques de haute résolution des galaxies comprenant la rétroac- tion d’un jet ont montré que l’activité des noyaux actifs peut conduire à une pression exces- sive sur les régions denses de formation stellaire dans les galaxies, et donc à augmenter la formation d’étoiles, conduisant à un effet positif de rétroaction. Je montre que ces noyaux actifs induits par pression régulée et formation d’étoiles peuvent aussi être une explica- tion possible des taux de formation stellaire élevés observés dans l’Univers à haut décalage spectral. De plus, j’ai également étudié en détails comment le rayonnement émis à partir d’un disque d’accrétion autour du trou noir agit efficacement avec le milieu interstellaire et entraîne un fort vent galactique, en simulant la propagation des photons à partir des équations hydrodynamiques du rayonnement. Les simulations montrent que la grande luminosité d’un quasar est en effet capable de conduire des vents à grande échelle et à grande vitesse. Le rayonnement infrarouge est nécessaire pour transérer efficacement le gaz par multi-diffusion sur la poussière dans les nuages denses. Le nombre typique de multi-diffusion diminue rapidement quand le nuage central de gaz central se dilate et se rompt, ce qui permet au rayonnement de s’échapper à travers les canaux à faible densitéSupermassive black holes (SMBHs) are known to reside in the centres of most large galaxies. The masses of these SMBHs are known to correlate with large-scale properties of the host galaxy suggesting that the growth of the BHs and large-scale structures are tightly linked. A natural explanation for the observed correlation is to invoke a self-regulated mechanism involving feedback from Active Galactic Nuclei (AGN). The focus of this thesis is on the interactions between AGN outflows and the ISM and how the feedback impacts the host galaxy. In particular, it focuses on the two possible mechanism of outflows, namely, outflows related to AGN jets and outflows produced by AGN radiation. High resolution, galaxy scale hydrodynamical simulations of jet-driven feedback have shown that AGN activity can over-pressurise dense star-formation regions of galaxies and thus enhance star formation, leading to a positive feedback effect. I propose, that such AGN-induced pressure-regulated star formation may also be a possible explanation of the high star formation rates recently found in the high-redshift Universe. In order to study in more detail the effects of over-pressurisation of the galaxy, I have performed a large set of isolated disc simulations with varying gas-richness in the galaxy. I found that even moderate levels of over-pressurisation of the galaxy boosts the global star formation rate by an order of magnitude. Additionally, stable discs turn unstable which leads to significant fragmentation of the gas content of the galaxy, similar to what is observed in high-redshift galaxies. The observed increase in the star formation rate of the galaxy is in line with theoretical predictions. I have also studied in detail how radiation emitted from a thin accretion disc surrounding the BH effectively couples to the surrounding ISM and drives a large scale wind. Quasar activity is typically triggered by extreme episodes of gas accretion onto the SMBH, in particular in high-redshift galaxies. The photons emitted by a quasar eventually couple to the gas and drive large scale winds. In most hydrodynamical simulations, quasar feedback is approximated as a local thermal energy deposit within a few resolution elements, where the efficiency of the coupling between radiation of the gas is represented by a single parameter tuned to match global observations. In reality, this parameter conceals various physical processes that are not yet fully un- derstood as they rely on a number of assumptions about, for instance, the absorption of photons, mean free paths, optical depths, and shielding. To study the coupling between the photons and the gas I simulated the photon propagation using radiation-hydrodynamical equations (RHD), which describe the emission, absorption and propagation of photons with the gas and dust. Such an approach is critical for a better understanding of the coupling between the radiation and gas and how hydrodynamical sub-grid models can be improved in light of these results
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Naeem, A. S. „The role of Akt1 in skin barrier formation“. Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1450250/.
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Atopic Dermatitis (AD) is a chronic inflammatory disease characterised by pruritus, hyperkeratosis, parakeratosis and dry skin. Association of filaggrin mutations with AD has been reported, however not all AD patients have filaggrin mutations suggesting other mechanisms give rise to the barrier defect present in AD. Akt1 activity is essential for cornified envelope formation and correct profilaggrin processing, although the functional role of Akt1 in these processes remains unclear. The aim of this study was to investigate the role of downstream targets of Akt1 signaling in profilaggrin processing and cornified envelope formation. Using shRNA to knock down Akt1 activity in rat epidermal keratinocyte cell lines, an in vitro organotypic model was created that phenocopies AD displaying hyperkeratosis, parakeratosis and impaired filaggrin processing. Results show that reduced Akt activity led to decreased lamin A/C degradation disrupting nuclear disintegration process giving rise to parakeratosis. HspB1 is reported to interact with filaggrin and also involved in filaggrin processing. Inhibition of Akt activity demonstrated a switch between HspB1-filaggrin to HspB1- actin interaction in the upper epidermis, which may interfere with filaggrin processing. Cathepsin H (Ctsh) was down regulated 4-fold in our Akt1 knockdown cultures and its expression co-localized with filaggrin in the granular layer of human epidermis. Filaggrin processing was impaired in Ctsh shRNA knockdown cell lines, and both Ctsh+/− and Ctsh−/− mice displayed hyperkeratosis and reduced filaggrin expression. Inhibition of RAPTOR (a component of mTORC1) has previously been reported to increase Akt1 activity. Raptor overexpression in REKs showed a decrease in Akt phosphorylation, Ctsh and filaggrin processing, and treatment with Rapamycin, an mTORC1 inhibitor, reverses these effects. In uninvolved AD skin, increase in RAPTOR correlated with decrease in both Akt phosphorylation and filaggrin expression. This thesis presents a novel mechanism where increase in RAPTOR can lead to a reduction in epidermal granular Akt1 phosphorylation leading to impaired filaggrin processing and barrier defects in AD.
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Henzel, Steffen. „Inflation Dynamics and the Role of Inflation Expectation Formation“. Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-89335.
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Allsopp, Richard Patrick. „The role of the vascular endothelium in bone formation“. Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386827.
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Turner, Rhodri Thomas Owain. „Role of complement in tumour formation : friend or foe?“ Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/54370/.
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The aims of this thesis were to investigate and build on recent reports implicating the complement (C) system in tumour growth and progression. The respective contributions of specific C components and regulators to this effect were assessed by the use of two tumour induction protocols. Firstly, the chemical carcinogen 3-methylcholanthrene (3-MCA) was used to induce tumours in wild type mice and in animals deficient in C1q, C3 or double deficient in CD55 and CD59. Deficiency in the classical pathway of activation (C1q"7') or in the central component (C3"7') conferred a statistically significant protective effect against 3-MCA-induced tumourigenesis, suggesting that a fully functional C system was important for promotion of tumour progression in vivo. Additionally, a protective effect was observed in CD55"7".CD59"7' mice indicating an important role for C-regulatory proteins (CRegs) in tumour progression. In the second approach, novel fibrosarcoma lines were generated from 3- MCA-induced tumours. WT, C1q"7", C3"7" and CDSS.CDS lines were cloned and tested for specific characteristics including CReg expression, synthesis of C3 and susceptibility to C-attack. Few differences were observed between lines of different genotypes though expression of terminal pathway regulator CD59 was observed in C3"7" lines only. Re-inoculation of WT and C3 lines showed no differences between the groups with comparable tumour incidence and growth rates observed. Additionally, the effect of C on progression of a pre-characterised WT fibrosarcoma line was tested by inoculation into WT and C-deficient mice. Tumours inoculated into C1q"7", C3"7" and CD55"7'.CD59"7" mice were shown to exhibit comparable growth characteristics to those in WT controls. However, depletion of the terminal pathway component C5 using a monoclonal antibody (mAb) was shown to inhibit tumour progression. Treatment of mice with anti- C5 mAb conferred a statistically significant protective effect to these mice and suggests a role for C in driving tumour pathology. In conclusion, work in this thesis demonstrates an important pro-tumour role for C whereby activation of C can result in enhanced tumour progression. Additionally, expression of the CRegs CD55 and CD59 on host cells rather than tumour cells contributes to tumour proliferation. A pro-tumour role for C is contrary to current dogma but supports an alternative hypothesis whereby cell activating effects may provide a selective advantage to tumour cells following C-activation.
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Pijoan-Mas, Josep. „The role of habit formation in general equilibrium macroeconomics“. Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271028.
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Taylor, Amanda Faith. „The role of glutamate in bone formation in vitro“. Thesis, University of York, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341824.
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Migues, Paola Virginia. „Role of neurosteroids on memory formation in the chick“. Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367225.
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Blagden, Christopher Simon. „The role of sonic hedgehog in slow muscle formation“. Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312763.
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Xiao, Nan. „Role of PICK1 in acrosome formation and male fertility /“. View abstract or full-text, 2009. http://library.ust.hk/cgi/db/thesis.pl?BICH%202009%20XIAO.
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James, Nathalie. „The role of subjective input in causal category formation“. Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1781954331&sid=6&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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32
Mugele, Dorothee. „Role of neuro-mesodermal progenitors in neural tube formation“. Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10057534/.
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It has long been thought that neural tube and somites derive from different germ layers, namely the ectoderm and mesoderm. This paradigm was challenged by the discovery of a dual-fated cell population in the mammalian tail bud, the so-called neuro-mesodermal progenitors (NMPs), which give rise to both neuroepithelium and paraxial mesoderm beyond the gastrulation stage. The aim of this PhD thesis was to characterise how NMPs contribute to neural tube formation using mouse embryos as a model system. First, the colonisation of the neural tube by NMPs and related cell populations was studied by labelling with the green fluorescent dye DiO followed by whole-embryo culture. Cells labelled caudal to the node (the NMP location) predominantly colonised the dorsal and dorso-lateral neural tube, but not the ventral domain, which was populated from the node, the node-streak border, and anterior to the node. Next, laser-ablation was used to study the developmental requirement for NMPs. As expected, ablation of the NMP location considerably disturbed the formation of paraxial mesoderm and neuroepithelium, although this effect was only transient, as adjacent cells rapidly re-populated the ablated region. A prevailing assumption is that NMPs co-express the neural marker Sox2 and the mesodermal marker T. However, lineage tracing experiments revealed that the contribution of Sox2-expressing cells to the paraxial mesoderm at post-epiblast stages is very infrequent, whereas descendants of T-expressing cells extensively colonise both neural tube and somites. This suggested that NMPs are actually Sox2-negative. Indeed, when Sox2 was specifically depleted in the T-expressing lineage, the resulting embryos had no mesoderm defect, but substantially reduced Sox2 mRNA and protein levels in the neural tube with otherwise normal morphology and gene expression domains. This indicates that Sox2 is not specifically required for neural tube formation and that bi-potent NMPs likely do not express Sox2.
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Love, Katie. „Investigating the Role of Disulfide Bond Formation in FABP5“. Thesis, Boston College, 2016. http://hdl.handle.net/2345/bc-ir:107265.
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Thesis advisor: Abhishek ChatterjeeThesis advisor: Eranthie Weerapana
EGF signaling activates multiple pathways within the cell that lead towards proliferation, rendering this pathway of interest for cancer therapy. Recent studies focused on triple-negative breast cancer have shown that EGF-induced tumorigenesis strongly correlates with the up-regulation of FABP5, which shuttles fatty acids from the cytoplasm of cells to the nucleus. Our work began with the identification of redox active cysteine residues upon EGF activation in situ using a caged electrophile to perform live cell labeling. In these studies, the C120 residue of FABP5 was identified as a cysteine with high redox activity and thus became a subject of further interest. The characterization of redox active cysteine residues yields important information about protein structure and function. We have confirmed these results via in-gel fluorescence and developed fluorescence assays to probe the significance of C120 and C127 in FABP5. Two fatty acids were chosen based on their conformation in the FABP5 binding pocket. Upon the addition of a fatty acid, wild type protein showed a decrease in fluorescence indicating that the fatty acids were outcompeting the fluorophores used. Future studies will investigate both wild type and mutant versions of FABP5 with emphasis on determining potential disulfide bond formation via phosphoproteomics and western blotting techniques
Thesis (MS) — Boston College, 2016
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Martini, Nicholas Fred. „The role of ideology in foreign policy attitude formation“. Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3347.
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I examine the formation of a "foreign policy" ideology and how it shapes the preferences and decisions of individuals during foreign policy events. Following from earlier research on the structure of a foreign policy ideology, two dimensions are identified as important determinants of individual preferences: a militant dimension and a cooperative dimension. To understand the determinants of an individual's ideology, a bottom-up, value driven approach is employed that explores influences that are both psychological (values, beliefs, traits) and sociological (groups, environment). As to the impact of ideology on preferences, I explore how ideology influences preferences in the context of support for military intervention, leader evaluation during times of war, and casualty tolerance. Beyond simply shaping preferences, one novel aspect of my research is exploring if ideology can modify the impact of external stimuli, such as elite cues and environmental context, on individual preferences. Following from research on "motivated reasoning" my theory argues that ideology colors the way new information is interpreted and accepted. In essence, ideology can filter the influence exerted by partisan/elite cues and environmental context (i.e. casualties, mission purpose).
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Ghosh, Joydeep. „The Role of Virginia Tech in Human Capital Formation“. Thesis, Virginia Tech, 2001. http://hdl.handle.net/10919/34075.
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Virginia Tech contributes significantly to social and economic progress at the regional, state and national levels through its teaching, research and public service activities. The study is motivated by the current debate on the appropriate level of support for higher education in Virginia's largest university. This study measures the benefits of the university's undergraduate teaching mission. The results suggest that a VT undergraduate degree significantly increases the lifetime earnings of the graduates and also leads to several other benefits to the graduate, to his/her family, and to society. This study can help policy-makers to better understand the important contribution of Virginia Tech's teaching mission to society, and thus make more-informed decisions regarding the appropriate level of support for higher education.Master of Science
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Parthasarathy, Varadarajan. „The role of tetraspanins in multinucleated giant cell formation“. Thesis, University of Sheffield, 2005. http://etheses.whiterose.ac.uk/14486/.
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Bray, Andrew William. „Mineral weathering and soil formation : the role of microorganisms“. Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/6848/.
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Mycorrhizal fungi play a significant role in primary mineral weathering and soil formation. Due to their direct access to solar energy through symbiotic plant partners, fungi are able to extend into soils, acting as biosensors for nutrients which they subsequently uptake and supply to their plant partners. Mycorrhizal fungi operate at the individual hypha scale, mechanically forcing and chemically altering minerals to extract nutrient elements. The hyphae acidify their local environment by exuding organic acids, which are also involved in mineral breakdown. To extend the work on mycorrhizal fungal biotite weathering completed as part of the Weathering Science Consortium the mechanisms and kinetics of biotite dissolution were investigated. This was done by characterising the biotite surface as a function of fluid composition and measuring dissolution rates. During contact with dilute solutions, the chemical composition of the biotite surface changed dramatically as a function of pH. The rapid release of elements during these experiments was not stoichiometric but was highly pH dependent. A combination of electrokinetic measurements and potentiometric titrations further highlighted the variable composition of the biotite surface by yielding two values for zero points of charge, separated by ~7 pH units. Abiotic dissolution of biotite progressed by the formation of a dissolution front depleted in K Mg, Fe and Al, the extent of which varies spatially and with pH. The presence of the organic ligands, citric acid, oxalic acid and DFOB (desferrioxamine B) slightly enhanced the overall biotite dissolution rate in lightly acidic and near neutral pH conditions. The growth rate of mycorrhizal fungi over the surface of biotite was quantified at two levels of atmospheric CO2, 350 ppm and 1500 ppm. Initial growth rate calculations in the 1500 ppm experiments revealed hyphae to grow at an average of 10 μm d-1. Finally, changes in the biochemistry of fungal hypha were observed using μ-FTIR. Results suggested that biochemical changes present could be related to changes in fungal functionality spatially in future work.
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Biewers, Sandra Maria. „Sepallata genes and their role during floral organ formation“. Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/8965/.
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Charles Darwin called the ability and success of angiosperms to colonise various parts of the earth even under unfavorable conditions an abominable mystery. This mystery is still not solved but one idea to explain the success of angiosperms is the development of the flower. SEPALLATA genes are common across angiosperms and play a major role in the development of all four floral organs and meristem determinacy. SEP genes occurred via Whole Genome Duplication (WGD) and are described as redundantly acting genes in the model organism A. thaliana. However, this study shows non-redundant functions affecting all floral organs for all four genes, especially under elevated growth conditions affecting the robustness and reproductive fitness of the plant, suggesting a diversification. SEPALLATA4 in particularly has a specific role within this gene family based on its early expression pattern compared to the other SEPs and its effect on flowering time, floral meristem maintenance, floral organ identity and organ number. The identification of genome wide targets of SEP4 and expression analysis revealed a bi-functional role for this transcription factor during flower development. Comparison between SEP3 and SEP4 targets revealed a large number of common but also independent targets, indicating that flower development is regulated to a large degree redundantly but also has independent ways of regulation. This suggests that maintenance of multiple genes after a WGD event in angiosperms causes diversification in-between these genes and contributes to the robustness of the plant to environmental perturbations and has influenced their ability to radiate and occupy different ecological niches. This might be one explanation to explain the tremendous success of flowering plants.
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Arstikaitis, Pamela. „The role of filopodia in the formation of spine synapses“. Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/32688.
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In the mammalian brain, excitatory (glutamatergic) synapses are mainly located on dendritic spines; bulbous protrusions enriched with F-actin. Dendritic filopodia are thin protrusions thought to be involved in the development of spines. However, limited evidence illustrating the emergence of spines from filopodia has been found. In addition, the molecular machinery required for filopodia induction and transformation to spines is not well understood. Paralemmin-1 has been shown to induce cell expansion and process formation and is concentrated at the plasma membrane, in part through a lipid modification known as palmitoylation. Palmitoylation of paralemmin-1 may also serve as a signal for its delivery to subcellular lipid microdomains to induce changes in cell morphology and membrane dynamics making it a candidate synapse-inducing molecule. Using live imaging as well as loss and gain-of-function approaches, our analysis identifies paralemmin-1 as a regulator of filopodia induction, synapse formation, and spine maturation. We show neuronal activity-driven translocation of paralemmin-1 to membranes induces rapid protrusion expansion, emphasizing the importance of paralemmin-1 in paradigms that control structural changes associated with synaptic plasticity and learning. Finally, we show that knockdown of paralemmin-1 results in loss of filopodia and compromises spine maturation induced by Shank1b, a protein that facilitates rapid transformation of newly formed filopodia to spines.
To investigate the role of filopodia in synapse formation, we contrasted the roles of molecules that affect filopodia elaboration and motility, versus those that impact synapse induction and maturation. Expression of the palmitoylated protein motifs found in growth associated protein 43kDa, enhanced filopodia number and motility, but reduced the probability of forming a stable axon-dendrite contact. Conversely, expression of neuroligin-1 (NLG-1), a synapse inducing cell adhesion molecule, resulted in a decrease in filopodia motility, but an increase in the number of stable axonal contacts. Moreover, siRNA knockdown of NLG-1, reduced the number of presynaptic contacts formed. Postsynaptic scaffolding proteins such as Shank1b, a protein that induces the maturation of spine synapses, reduced filopodia number, but increased the stabilization of the initial contact with axons. These results suggest that increased filopodia stability and not density may be the rate-limiting step for synapse formation.
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Krisantini. „The role of auxin in adventitious root formation of grevillea /“. [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe.pdf.
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Dass, Sajith. „The role of Cornichon (Cni) in axis formation in Drosophila“. [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974321753.
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Metcalf, Talibah U. „The role of SP85 in spore coat formation in Dictyostelium“. [Gainesville, Fla.] : University of Florida, 2002. http://purl.fcla.edu/fcla/etd/UFE1001168.
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Uggla, Claes. „New perspectives on the role of auxin in wood formation /“. Umeå : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1998. http://epsilon.slu.se/avh/1998/91-576-5342-9.gif.
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Walawender, Joshua Michael. „Quantifying the role of protostellar outflows in star formation feedback“. Diss., Connect to online resource, 2006. 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:3207734.
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Shin, Jong Ho. „Role of nucleation and growth in two-phase microstructure formation“. [Ames, Iowa : Iowa State University], 2007.
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Liu, Dan. „The role of senescent fibroblasts in tumor formation : a dissertation /“. San Antonio : UTHSC, 2006. http://proquest.umi.com/pqdweb?did=1257790121&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Houston, Karen Grace. „The role of membrane lipids in Weibel Palade body formation“. Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17253/.
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The Weibel Palade body (WPB) is the major regulated secretory organelle of endothelial cells. The WPB is used here as a model system to investigate the formation and acquisition of membrane identity of regulated secretory organelles. Heterologous expression of von Willebrand (VWF), the main secretory cargo of WPBs, in cells lacking endogenous VWF, is able to induce the formation of structures that are not only morphologically indistinguishable from WPBs but also recruit the appropriate membrane components resulting in the correct membrane identity. The question arises as to how VWF acts within the lumen of the secretory pathway to do this. The working hypothesis is that VWF drives the formation of WPB and the acquisition of membrane identity by direct interaction with specific lipids on the lumenal face of the lipid bilayer. This thesis describes attempts to test this hypothesis both directly, by looking for putative interactions of VWF with membrane lipids and indirectly, by studying the role of glycosphingolipids in WPB formation. To look for direct interaction of VWF with membrane lipids, attempts were made to produce recombinant, enzymatically tagged VWF probes and develop an overlay assay. Glycoarrays were also probed with VWF to identify potential glycan binding partners. VWF was found to bind to a class of fucosylated glycans on the array. In order to look for the influence of glycosphingolipids on WPB formation two distinct approaches were taken The effect of drug-mediated inhibition of membrane glycosphingolipid synthesis on WPB formation in cultured human endothelial cells was investigated. Inhibition of glucosylceramide synthesis, and hence complex glycosphingolipids, by N-butyldeoxygalactonojirimycin had no apparent effect on VWF trafficking. Trafficking of heterologously expressed VWF was studied in two epithelial cell lines, known to have distinct glycosphingolipid compositions. The two cell lines were shown to differ in VWF trafficking both morphologically and biochemically. VWF was also shown to be differentially glycosylated between the two cell lines, suggesting a link between VWF glycosylation and trafficking.
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Smith, Gregory Robert. „Unraveling the Role of Cellular Factors in Viral Capsid Formation“. Research Showcase @ CMU, 2015. http://repository.cmu.edu/dissertations/475.
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Understanding the mechanisms of virus capsid assembly has been an important research objective over the past few decades. Determining critical points along the pathways by which virus capsids form could prove extremely beneficial in producing more stable DNA vectors or pinpointing targets for antiviral therapy. The inability of current experimental technology to address this objective has resulted in a need for alternative approaches. Theoretical and computational studies offer an unprecedented opportunity for detailed examination of capsid assembly. The Schwartz Lab has previously developed a discrete event stochastic simulator to model virus assembly based upon local rules detailing the geometry and interaction kinetics of individual capsid subunits. Applying numerical optimization methods to learn kinetic rate parameters that fit simulation output to in vitro static light scattering data has been a successful avenue to understand the details of virus assembly systems; however, information describing in vitro assembly processes does not necessarily translate to real virus assembly pathways in vivo. There are a number of important distinctions between experimental and realistic assembly environments that must be addressed to produce an accurate model. This thesis will describe work expanding upon previous parameter estimation algorithms for more complex data over three model icosahedral virus systems: human papillomavirus (HPV), hepatitis B virus (HBV) and cowpea chlorotic mottle virus (CCMV). Then it will consider two important modifications to assembly environment to more accurately reflect in vivo conditions: macromolecular crowding and the presence of nucleic acid about which viruses may assemble. The results of this work led to a number of surprising revelations about the variability in potential assembly rates and mechanisms discovered and insight into how assembly mechanisms are affected by changes in concentration, fluctuations in kinetic rates and adjustments to the assembly environment.
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Brown, L. E. „Dissecting the structural role of GABAA receptors in synapse formation“. Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1476757/.
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GABAergic synapse formation involves the establishment of specific cellcell contacts between the presynaptic GABAergic neurones and their postsynaptic targets. Postsynaptic GABAA receptors (GABAARs) themselves have been shown to play a direct structural role in the initiation of functional synapses (Fuchs et al., 2013). Yet, characterisation of the molecular mechanisms underlying their structural involvement remains sparse. As the large N-terminal extracellular domains (ECDs) of the GABAAR subunits reside within the synaptic cleft, we hypothesised that these domains participate in trans-synaptic interactions with cleft-spanning presynaptic proteins. To investigate our hypothesis, a baculovirus/Sf9 cell expression system was used to express and purify the ECDs of the α1, β2 and γ2 GABAAR subunits. These ECDs were utilised in proteomics and mass spectrometry experiments to identify candidate trans-synaptic interacting proteins. To dissect the structural role(s) played by individual GABAAR subunits in synapse formation, a co-culture model system incorporating GABAergic medium spiny neurones and HEK293 cells expressing different combinations of GABAARs was developed. The results indicated that the γ2 subunit was necessary for contact formation and that its 'synaptogenic' effects were influenced by the subtype of α and β GABAAR subunits that were incorporated within the receptor. To elucidate whether the synaptogenic effects of the GABAAR subunits were directly mediated by their ECDs, the purified α1, β2 and γ2 ECDs were added to HEK293-MSN co-cultures at 14 Day in vitro (DIV). Contact formation was reduced in the presence of each of the exogenous ECDs. In parallel, the ECDs were added to pure cultures of MSNs to analyse their structural effects on GABAAR cluster size and number. The results demonstrated that synapsespecific effects were observed for each ECD. In summary, the synaptogenic effects of GABAARs depend on their individual subunit composition, with the ECDs structurally contributing towards the initial cell-cell contacts.
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Al, Shammari Basim Raddam K. „Defining the role of matrix metalloproteinases in TB granuloma formation“. Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/43938.
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Tuberculosis (TB) remains a global health emergency and one third of the global population harbour latent infection. A central tenet of TB pathology is that caseation of TB granuloma leads to matrix degradation and pulmonary cavitation, resulting in Mtb transmission and disease progression. However, lung destruction must involve activity of MMPs which are emerging as key proteases contributing to lung tissue pathology in TB. MMP-1 is the dominant collagenase in human pulmonary TB, but mice do not express an orthologue of human MMP-1 in the lung. The precise relationship between the formation of caseous necrosis and lung matrix destruction has not been systematically examined, nor how the extracellular matrix (ECM) regulates the host-pathogen interaction. I investigated the effect of transgenic expression of human MMP-1 and -9 in the mouse on TB pathology and studied lung matrix integrity in human TB granulomas by ECM stains. In cell culture systems, I developed a standard in vitro granuloma model and then progressed to 3D and engineered models of TB granuloma and investigated the effect of modulating cell-matrix interaction by introducing matrix components. In the mouse model, transgenic expression of human MMP-1 caused collagen destruction and caseous necrosis, suggesting that the initial event in caseation is collagen breakdown. In human granulomas, ECM destruction and caseous necrosis co-localise, with loss of collagen fibres in areas of caseous necrosis. Consistent with the hypothesis that matrix degradation is a key initial event in TB pathogenesis, I demonstrated that in cell culture models collagen improves survival of Mtb-infected cells. I have re-considered the sequence of events underlying TB immunopathology and demonstrated that collagen destruction driven by MMP-1 is a critical initial event. This challenges current paradigms of disease pathology. These data demonstrate that the ECM regulates the host-pathogen interaction in TB.