Many irreversible antagonists are known to bind irreversibly to pharmacological receptors. However, few studies suggest that these irreversible antagonists may also display irreversible non-specific antagonism by binding irreversibly to non-syntopic binding sites on the receptor macromolecule, whereby they modulate the signal transduction of these receptors or reduce the agonist binding affmity. The aim of this study was to investigate whether the classical irreversible antagonists phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible nonspecific antagonism at various G protein-coupled receptor (GPCR) types. In addition, the subcellular mechanism whereby benextramine displays irreversible non-specific antagonism was investigated. Three cell lines were employed to investigate the antagonism by these irreversible antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine a2A-adrenoceptor (a2A-AR) at higher (a2A-H) or lower (a2A-L) numbers, human neuroblastoma (SH-SY5Y) cells that endogenously express muscarinic acetylcholine receptors (mACh-Rs), and SH-SY5Y cells transfected (5HT2A-SH-SY5Y)o express the human 5HT2A-serotonirne ceptor (5HTZA-R).C ells of the appropriate cell line were pre-treated at the appropriate concentrations and incubation times with an appropriate irreversible antagonist, with or without an appropriate reversible competitive antagonist at a sufficient concentration to protect the specific receptors. This was followed by washing procedures with drug-free media to rinse any unbound or reversibly bound drugs from the cells. When appropriate, cell membranes were prepared. Receptor function was evaluated by measuring whole-cell [3H]-cAMP or [3H]-IPx acumulation, or the binding of [35S]-GTPyS to membraness. Receptor concentrations were determined from radioligand-binding assays. In addition, the constitutive [35S]-GTPyS binding to Go protein before and after pre-treatment with benextramine was investigated. Results suggest that phenoxybenzamine (100 uM, 20 minutes) and benextramine (10 uM, 20 minutes) display irreversible non-specific antagonism at a2A-ARs when measuring Gi-mediated effects in a2A-L cells, but the affinity for a2A-ARs in a2A-H cells was not changed. In addition, it was found that the observed irreversible nonspecific antagonism by benextramine appears to be time- and concentration-dependent. When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35S]-GTPyS to a2A-H membranes with protected a2A-ARs, but did not modulate the constitutive binding of [35S]-GTPyS to Go. In addition, benextramine displays irreversible non-specific antagonism by inhibiting the G,-mediated effects of a2A-ARs in a2A-H cells and the Gq-mediated effects of mACh-Rs or 5HT2A-Rs in SH-SY5Y or 5HT2A-SH-SY5Y cells respectively. 4-DAMP mustard (100 uM, 20 minutes) did not display irreversible non-specific antagonism at mACh-Rs in SH-SY5Y cells, but irreversible non-specific antagonism was observed when the incubation time was increased (100 uM, 60 minutes). In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non-specific antagonism at typical experimental conditions. These findings confirm concerns in literature and supports the possibility that more irreversible antagonists could display irreversible non-specific antagonism, and that could influence the interpretation of data obtained with such drugs. In addition, benextramine may prove to be a useful experimental drug in studying GPCR signalling. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

The aim of this study is to examine social workers’ experiences of how the ADHD-diagnosis affects their work with children and youths living in foster care and how it affects the individuals and families themselves. The study is built upon five qualitative interviews and the results are analyzed through a theoretical framework that constitutes ADHD as not only the symptoms and the medical disorder but also as a social phenomenon where the disorder is socially constructed by the current society, norms, and knowledge. The study shows that the social workers’ do not rely on the sole ADHD-diagnosis in the understanding and guidance of the children and their foster parents, but rather see the individual needs of each children. The social workers’ experiences shows that the diagnosis can act as a relief and explanation for both children and their foster parents but can also be a stigma. My overall conclusions are that the diagnosis seems to have only minor significance for these social workers’ daily work and is rather more relevant for obtaining medical treatment or extra support in school for the children. / Syftet med den här studien är att undersöka socialsekreterares erfarenheter av hur ADHD hos barn och unga som är familjehemsplacerade påverkar socialsekreterarnas arbete och hur diagnosen påverkar barnen och de unga samt familjehemmen. Studien bygger på fem kvalitativa intervjuer och resultaten är analyserade genom ett teoretiskt ramverk som betraktar ADHD som inte bara symtomen och den medicinska störningen utan också som ett socialt fenomen där diagnosen är socialt konstruerad genom samhället, normer och aktuell kunskap. Studien visar att socialsekreterarna inte förlitar sig enbart på ADHD-diagnosen för att förstå och hjälpa barnen och deras familjehemsföräldrar utan snarare ser varje barns individuella behov. Socialsekreterarnas erfarenheter visar att diagnosen kan ge lättnad och förklaring för både barnet och familjehemsföräldrarna men att den också kan vara stigmatiserande. Mina slutsatser är att diagnosen tycks spela mindre roll för socialsekreterarnas dagliga arbete med barnen utan är mer relevant för att erhålla medicinsk behandling eller för att få extra stöd i skolan.

Many irreversible antagonists are known to bind irreversibly to pharmacological receptors. However, few studies suggest that these irreversible antagonists may also display irreversible non-specific antagonism by binding irreversibly to non-syntopic binding sites on the receptor macromolecule, whereby they modulate the signal transduction of these receptors or reduce the agonist binding affmity. The aim of this study was to investigate whether the classical irreversible antagonists phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible nonspecific antagonism at various G protein-coupled receptor (GPCR) types. In addition, the subcellular mechanism whereby benextramine displays irreversible non-specific antagonism was investigated. Three cell lines were employed to investigate the antagonism by these irreversible antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine a2A-adrenoceptor (a2A-AR) at higher (a2A-H) or lower (a2A-L) numbers, human neuroblastoma (SH-SY5Y) cells that endogenously express muscarinic acetylcholine receptors (mACh-Rs), and SH-SY5Y cells transfected (5HT2A-SH-SY5Y)o express the human 5HT2A-serotonirne ceptor (5HTZA-R).C ells of the appropriate cell line were pre-treated at the appropriate concentrations and incubation times with an appropriate irreversible antagonist, with or without an appropriate reversible competitive antagonist at a sufficient concentration to protect the specific receptors. This was followed by washing procedures with drug-free media to rinse any unbound or reversibly bound drugs from the cells. When appropriate, cell membranes were prepared. Receptor function was evaluated by measuring whole-cell [3H]-cAMP or [3H]-IPx acumulation, or the binding of [35S]-GTPyS to membraness. Receptor concentrations were determined from radioligand-binding assays. In addition, the constitutive [35S]-GTPyS binding to Go protein before and after pre-treatment with benextramine was investigated. Results suggest that phenoxybenzamine (100 uM, 20 minutes) and benextramine (10 uM, 20 minutes) display irreversible non-specific antagonism at a2A-ARs when measuring Gi-mediated effects in a2A-L cells, but the affinity for a2A-ARs in a2A-H cells was not changed. In addition, it was found that the observed irreversible nonspecific antagonism by benextramine appears to be time- and concentration-dependent. When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35S]-GTPyS to a2A-H membranes with protected a2A-ARs, but did not modulate the constitutive binding of [35S]-GTPyS to Go. In addition, benextramine displays irreversible non-specific antagonism by inhibiting the G,-mediated effects of a2A-ARs in a2A-H cells and the Gq-mediated effects of mACh-Rs or 5HT2A-Rs in SH-SY5Y or 5HT2A-SH-SY5Y cells respectively. 4-DAMP mustard (100 uM, 20 minutes) did not display irreversible non-specific antagonism at mACh-Rs in SH-SY5Y cells, but irreversible non-specific antagonism was observed when the incubation time was increased (100 uM, 60 minutes). In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non-specific antagonism at typical experimental conditions. These findings confirm concerns in literature and supports the possibility that more irreversible antagonists could display irreversible non-specific antagonism, and that could influence the interpretation of data obtained with such drugs. In addition, benextramine may prove to be a useful experimental drug in studying GPCR signalling. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Increasing evidence implicates the presence of bacteria in intrauterine tissues as an important risk factor for spontaneous preterm labor. Epigenetic alterations of innate immunity genes may increase the mother’s sensitivity to subclinical levels of bacteria. This study examined the presence of TET2, TLR-2, and TLR-9 in intrauterine tissue, and evaluated whether epigenetic alterations of these genes, as well as IL-8, changed their expression in human decidual tissue and a macrophage cell culture. Immunohistochemicalstaining was used to detect the presence of these proteins in intrauterine tissue. Gene expression changes were evaluated in stimulated monocytes and macrophages. Fluorescence immunohistochemistry was used to track translocation of TET2 in stimulated monocytes and macrophages. Secreted IL-8 concentration was detected with ELISA. Decidual expression of TET2, TLR-2, and TLR-9 increased in the order TNL < TL < sPTL < iPTL. This study found that TET2, TLR-2, TLR-9, and IL-8 are regulated by epigenetic mechanisms. This study was the first to report activation of TET2 involves its translocation from the cytosol to the nucleus in macrophages.

Untersuchungsgegenstand dieser Arbeit ist die Degradation flexibler Dünnschichtsolarzellen auf Basis von Cu(In,Ga)Se2 Absorbern. Zur beschleunigten Alterung unter Laborbedingungen wurden unverkapselte Solarzellen in Klimaschränken Wärme und Feuchte ausgesetzt. Die Auswirkungen von Wärme und Feuchte auf die Solarzellen wurden zunächst durch Messung von Strom–Spannungs–Kennlinien (IV) und Kapazitäts–Spannungs–Charakteristiken (CV) erschlossen. Mittels in–situ Messungen der IV–Kennlinien der Solarzellen unter Wärme und Feuchte konnte die Degradationskinetik untersucht werden. Es gelang zwei Phasen der Alterung, eine anfängliche Verbesserung und die eigentliche Degradation, zu unterscheiden. Außerdem war es dadurch möglich Degradationsraten zu bestimmen. Die Untersuchung der Stabilität der Flächenkontakte erfolgte im Schichtverbund der Solarzelle und separat. Dann wurde der Einfluss von Natrium, einem Bestandteil der Cu(In,Ga)Se2 Solarzellen, untersucht. Schichtzusammensetzung, Elementprofile und Oberflächenbeschaffenheit wurden mittels Laser–induzierter Plasmaspektroskopie (LIBS), Sekundärionen–Massenspektrometrie (SIMS), Rasterelektronenmikroskopie (SEM) und 3D–Lasermikroskopie gemessen. Die Rolle von Natrium für den Degradationsprozess konnte für zwei unterschiedliche Methoden der Natriumeinbringung in den Absorber (Ko–Verdampfung, Nachbehandlung) beschrieben werden. Schließlich wurde mittels Elektrolumineszenz (EL), Thermographie (DLIT) und der Messung Lichtstrahl–induzierter Ströme (LBIC) die Degradation ortsaufgelöst untersucht und Inhomogenitäten detektiert. Aus spannungsabhängigen Elektrolumineszenzaufnahmen gelang es Serienwiderstandskarten zu errechnen. Die Kombination der genannten Messmethoden erlaubte eine Identifizierung dominanter Degradationsprozesse in den flexiblen Cu(In,Ga)Se2 Solarzellen unter Wärme und Feuchte. Unter anderen wurde die Degradation der Grenzfläche zwischen Absorber und Rückkontakt diskutiert. Die Degradationskinetik konnte beschrieben, Solarzelllebensdauern abgeschätzt, die für die Wärme–Feuchte–Stabilität nachteilige Wirkung von Natrium identifiziert und laterale Inhomogenitäten des Degradationsprozesses aufgezeigt werden. Aus der Diskussion der Ergebnisse wurden Vorschläge zur Verbesserung der Wärme–Feuchte–Stabilität abgeleitet.

This dissertation presents an edition of six poems from John Donne’s Songs and Sonets—“The Indifferent,” “Love’s Usury,” “The Will,” “The Funerall,” “The Primerose,” and “The Dampe”—and a digital edition of one additional poem, “To His Mistress Going to Bed.” Using the methodologies of The Variorum Edition of the Poems of John Donne, I have also adopted the edition’s principal goal—to recover and present Donne’s exact texts to the extent that this is possible. For each poem, I have selected a copy-text and emended it in accordance with the Variorum’s principles. A textual introduction for each poem explains how the copy-text was chosen and traces the circulation of the text in all seventeenth-century artifacts. I have also provided a textual apparatus for each poem, which, in addition to recording the texts collated, emendations to the copy-text, imperfections in the sources, and indentation patterns in the sources, also notes all verbal variants and variants of punctuation. Finally, I have created a stemma charting the transmissional history for each poem and giving a visual representation of how the textual artifacts relate to each other. The other major component of my dissertation, a digital edition of “To His Mistress Going to Bed,” is meant to serve as a prototype for what might usefully be done with Donne’s poems in a digital medium. While the actual digital edition of this poem cannot be fully represented on paper, my chapter on this edition outlines the process I used to create it and describes its major features. The digital edition itself can be found at <http://donnevariorum.tamu.edu/resources/tohismistress/tohismistress.html>.

The subject of the master´s is the construction and technological preparation of a house of culture reconstruction. For the construction project it is made a technical report, a estate road layout, a preliminary design of technological implementation, a site equipment, a time and financial schedule, a design of the main building machines and mechanism, technological specifications and test plan. The other topic is a contract of work, a project budget, a comparison of roof production technology and a special topic is a structural analysis of roof girder.

Untersuchungsgegenstand dieser Arbeit ist die Degradation flexibler Dünnschichtsolarzellen auf Basis von Cu(In,Ga)Se2 Absorbern. Zur beschleunigten Alterung unter Laborbedingungen wurden unverkapselte Solarzellen in Klimaschränken Wärme und Feuchte ausgesetzt. Die Auswirkungen von Wärme und Feuchte auf die Solarzellen wurden zunächst durch Messung von Strom–Spannungs–Kennlinien (IV) und Kapazitäts–Spannungs–Charakteristiken (CV) erschlossen. Mittels in–situ Messungen der IV–Kennlinien der Solarzellen unter Wärme und Feuchte konnte die Degradationskinetik untersucht werden. Es gelang zwei Phasen der Alterung, eine anfängliche Verbesserung und die eigentliche Degradation, zu unterscheiden. Außerdem war es dadurch möglich Degradationsraten zu bestimmen. Die Untersuchung der Stabilität der Flächenkontakte erfolgte im Schichtverbund der Solarzelle und separat. Dann wurde der Einfluss von Natrium, einem Bestandteil der Cu(In,Ga)Se2 Solarzellen, untersucht. Schichtzusammensetzung, Elementprofile und Oberflächenbeschaffenheit wurden mittels Laser–induzierter Plasmaspektroskopie (LIBS), Sekundärionen–Massenspektrometrie (SIMS), Rasterelektronenmikroskopie (SEM) und 3D–Lasermikroskopie gemessen. Die Rolle von Natrium für den Degradationsprozess konnte für zwei unterschiedliche Methoden der Natriumeinbringung in den Absorber (Ko–Verdampfung, Nachbehandlung) beschrieben werden. Schließlich wurde mittels Elektrolumineszenz (EL), Thermographie (DLIT) und der Messung Lichtstrahl–induzierter Ströme (LBIC) die Degradation ortsaufgelöst untersucht und Inhomogenitäten detektiert. Aus spannungsabhängigen Elektrolumineszenzaufnahmen gelang es Serienwiderstandskarten zu errechnen. Die Kombination der genannten Messmethoden erlaubte eine Identifizierung dominanter Degradationsprozesse in den flexiblen Cu(In,Ga)Se2 Solarzellen unter Wärme und Feuchte. Unter anderen wurde die Degradation der Grenzfläche zwischen Absorber und Rückkontakt diskutiert. Die Degradationskinetik konnte beschrieben, Solarzelllebensdauern abgeschätzt, die für die Wärme–Feuchte–Stabilität nachteilige Wirkung von Natrium identifiziert und laterale Inhomogenitäten des Degradationsprozesses aufgezeigt werden. Aus der Diskussion der Ergebnisse wurden Vorschläge zur Verbesserung der Wärme–Feuchte–Stabilität abgeleitet.

Both testate amoebae and fungi are common inhabitants of coniferous litter. Their interactions in this environment were rarely studied, although they reach high biodiversity and can play a significant role in nutrient cycling in this environment. In this study, a cultivation of litter needles in the damp chambers was used to investigate interactions between fungi and testate amoebae. Observation of spruce litter needles in environmental scanning electron microscope was used to better characterize testate amoebae communities directly on the needles. Additionally, two experiments changing the biotic conditions in the microcosm were used to follow a principle of the interactions. Three species of testate amoebae from litter needles were able to colonize the filter paper on the bottom of the damp chambers. Occurrence of Phryganella acropodia and Assulina muscorum on the filter paper was significantly fuelled by the presence of mycelium. Assulina muscorum was associated with the fungal spores and Arcella discoides was attracted by sporulating colonies of Cladosporium spp. in the damp chambers. By contrast, no association of putatively mycophagous Phryganella acropodia with fungal spores was observed. Arcella discoides was attracted both by live and death mycelium in additional experiment. Interestingly, the...

This thesis documents the development of a simulation strategy to model the behavior of geomembranes at large deformations using the explicit finite difference code FLAC3D. The geomembrane is represented by special shell elements and interfaces at both sides of the geomembrane duplicating the interaction with the overlying and underlying materials. Chapter 1 provides an introduction to geotextiles and geomembranes, and their use in geotechnical engineering. Special attention is paid to pull-out tests because of their importance to describe the behavior at large deformations. Chapter 2 describes the proposed ‘liner’ model concept to simulate the interaction of a geomembrane with the over- and underlying material. Furthermore, this chapter documents in detail the simulation of uniaxial pull-out tests for validation of the proposed ‘liner’ model concept and compares it with the FLAC3D built-in geogrid element. To clarify more clearly the potential failure (crack propagation and rupture process) of the geomembrane, the ‘liner’ model under biaxial loading was investigated in Chapter 3. Chapter 4 documents a detailed parameter study with a special focus on the stiffness and frictional behavior of the ‘liner’ element using a simplified waste dump. In chapter 5 a new constitutive model (“Femesalz”) is proposed to describe the visco-elasto-plastic behavior of crushed salt and waste rock salt, respectively. The “Femesalz” constitutive model together with the ‘liner’ model is applied to simulate the behavior of a rock salt waste dump (2.5-dimensional) to validate both, the new constitutive model “Femesalz” as well as the ‘liner’ model. Chapter 6 documents the use of the ‘liner’ element and the “Femesalz” constitutive model to simulate salt dump models in 2D and 3D on different terrain types (mountain, valley, plain) for a time of 100 years to generate large deformations. Chapter 7 contains the main conclusions and recommendations.:ABSTRACT AND STRUCTURE OF THESIS 2 ACKNOWLEDGMENTS 4 CONTENTS 5 LIST OF TABLES 7 LIST OF FIGURES 10 NOMENCLATURE 16 CHAPTER 1: INTRODUCTION AND STATE-OF-THE-ART 22 1.1 Geosynthetic for geoengineering projects (overview) 22 1.2 Pull-out tests (overview) 29 CHAPTER 2: “LINER” CONCEPT AND NUMERICAL SIMULATIONS OF UNIAXIAL PULL-OUT TESTS 39 2.1 Introduction 39 2.2 Numerical calculations 39 2.2.1 General considerations 39 2.2.2 Concept of the 'liner' element 40 2.2.3 'Geogrid' versus 'liner' element 41 2.2.4 Verification of ‘liner’ element 42 2.2.5 Conclusions 58 CHAPTER 3: BIAXIAL LOADING OF “LINER” MODEL 61 3.1 Introduction 61 3.2 Model set-up 61 3.3 Results of biaxial pull-out test simulation 63 3.4 Summary and Conclusions 71 CHAPTER 4: PARAMETER STUDY OF EMBEDDED GEOMEMBRANE 74 4.1 Introduction 74 4.2 Model set-up 74 4.3 Results 77 4.3.1 Influence of interface stiffness 80 4.3.2 Influence of interface friction 87 4.4 Conclusions 93 CHAPTER 5: CONSTITUTIVE MODEL FOR SALT DUMP 95 5.1 Introduction 95 5.1.1 Overview of constitutive models for rock salt 97 5.1.2 Overview of constitutive models for crushed salt 104 5.2 ‘Femesalz’ constitutive model for crushed salt 106 5.2.1 Introduction 106 5.2.2 Compaction test 111 5.2.3 Triaxial test and realistic waste dump simulation 114 5.2.4 Numerical salt dump simulations 115 5.3 Summary 122 CHAPTER 6: SIMULATIONS CONSIDERING TOPOGRAPHY OF UNDERLYING MATERIAL 123 6.1 Introduction 123 6.2 Model set-up 123 6.3 Model parameters and calculation sequence 131 6.4 Calculation results 132 6.5 Discussion of results and conclusions 139 CHAPTER 7: CONCLUSIONS 141 REFERENCE 143