Hepatitis C Virus (HCV) is a global health problem, with over 170 million infected individuals worldwide. 70-80% of infected individuals develop progressive disease, and approximately 2% of these acquire hepatocellular carcinoma (HCC). HCV entry is dependent on tetraspanin CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Tetraspanins are involved in multiple biological functions including cell-ECM adhesion and motility. An actin polymerization-dependent cell spread was observed upon ligation of CD81 on hepatoma cells. Importantly, HCV infection perturbed CD81-dependent cell spread, suggesting HCV infection may modulate CD81 function in hepatoma cells. Functional assays demonstrated that CD81 expression and HCV infection promote hepatoma cell motility. These findings allude to a link between HCV infection and associated HCC development. Establishment of a chronic infection demonstrates that HCV can escape from the host adaptive immune responses. We developed an in vitro cell culture system to monitor viral transmission in the presence of neutralizing antibodies (nAb). Separation of producer and target cells ablated nAb resistant transmission, suggesting that cell-cell contact was essential. Furthermore nAb resistant transmission was dependent upon all four co-receptors. These observations confirm HCV immune evasion by cell-to-cell transfer and have major implications for anti-glycoprotein targeted therapies.

Magnesium alloys are widely used in engineering applications, including aerospace and automobile industries, due to their desirable properties, such as lower density, high damping capacity, relatively high thermal conductivity, good machinability, and recyclability. Researchers have, therefore, been developing new magnesium materials. However, mechanical and corrosion properties are still limiting many commercial applications of magnesium alloys. In this Ph.D. thesis research, I developed Mg-Ti composite materials to offer some solutions to further improve the mechanical behavior of magnesium, such as titanium-magnesium (Ti-Mg) claddings, Mg-Ti multilayers, and Ti particle enforced Mg alloys. Low cost manufacturing processes, such as hot roll-bonding (RB) and accumulative roll-bonding (ARB) techniques, were used to produce Mg-Ti composites and sheets. The microstructural evolution and mechanical properties of composites were investigated using optical microscopy (OM), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), electron backscatter diffraction (EBSD), nanoindentation, and tensile tests. In the first part of this study, I investigated the bonding strength of the AZ31/Ti to understand the mechanical properties of Mg/Ti composites. Using a single pass RB process, I fabricated AZ31/Ti multilayers with the thickness reduction in a range of 25% to 55%. The hot-rolled AZ31/Ti multilayers were heat-treated at 400 °C for 6, 12, and 24 hours, respectively, in an argon atmosphere. Tensile-shear tests were designed to measure the bonding strength between AZ31/Ti multilayers. Furthermore, the experimental results revealed good bonding of the AZ31/Ti multilayers without forming any intermetallic compounds in the as-rolled and heat-treated AZ31/Ti multilayers. The good bonding between Ti and AZ31 is the result of diffusion bonding whose thickness increases with increasing heat-treatment time and thickness reduction. The shear strength of the Ti/AZ31 multilayer increases with increasing bonding layer thickness. In the second part of this study, I characterized the microstructure and texture of three-layered Ti/AZ31/Ti clad sheets which were produced by single-pass hot rolling with a reduction of thickness 38% (sheet I) and 50% (sheet II). The AZ31 layer in sheets I and II exhibited shear bands and tensile twins {1012}⟨1001⟩ . The shear bands acted as local strain concentration areas which led to failure of the clad sheets with limited elongation. Heat treatment caused changes in the microstructure and mechanical properties of clad sheets due to static recrystallization (SRX) on twins and shear bands in the AZ31 layer. Recrystallized grains usually randomize the texture which causes weaken the strong deformed (0001) basal texture. Twins served as nucleation sites for grain growth during SRX. Tensile tests at room temperature showed significantly improved ductility of the clad sheets after heat treatment at 400°C for 12h. The results showed that the mechanical properties of clad sheets II are better than clad sheet I: The clad sheet II shows elongation 13% and 35% along the rolling direction (RD) for as-rolled and annealed clad sheet, respectively whereas the clad sheet I shows elongation 10% and 22% along RD for as-rolled and annealed clad sheet, respectively. In the final part of this study, I examined the effects of dispersed pure titanium particles (150 mesh) with 0, 2.3, 3.5, 4.9, and 8.6 wt. % on the microstructure and mechanical properties of AZ31-Mg alloy matrix. Mg-Ti composites were processed through three accumulative roll bonding (ARB) steps using thickness reductions of 50% in each pass followed by heat treatment at 400 °C for 12 h in an argon atmosphere. ARB is an efficient process to fabricate Mg-Ti composites. Mechanical properties of Mg- 0Ti and Mg-2.3Ti composite were enhanced by ~ 8% and 13 % in yield strength and ~ 30% and 32 % in ultimate tensile strength, respectively. Meanwhile, the elongation of the composites were decreased by 63% and 70%, respectively. After heat treatment, the results showed a decrease in yield strength and increase in elongation to fracture. The mechanical properties of the Mg-0 and Mg-2.3Ti composite were enhanced: ultimate tensile strength by 9% and 7%, and elongation by 40% and 67%, while the yield strength was decreased by 28% and 36% compared with the initial AZ31. Enhancements of strength and ductility were the results of two mechanisms: a random matrix texture by ARB and ductile titanium particle dispersion.

The interaction between thermal convection and magnetic field is of interest in geophysical and astrophysical problems as well as in metallurgical processes such as casting or crystallization. A magnetic field may act in such a way to damp the convective velocity field in the melt or to reorganize the flow aligned with the magnetic field. This ability to manipulate the flow field is of technological importance in industrial processes. In this work, a direct numerical simulation of three-dimensional Boussinesq convection in a horizontal layer of electrically conducting fluid confined between two perfectly conducting horizontal plates heated from below in a gravitational and magnetic field is performed using a spectral element method. Periodic boundary conditions are assumed in the horizontal directions. The numerical model is then used to study the effects of imposing magnetic field. Finally, a low dimensional representation scheme is presented based on the Karhunen-Loeve approach.

This dissertation details the development and experimental implementation of single-photon atomic cooling. In this scheme atoms are transferred from a large-volume magnetic trap into a small-volume optical trap via a single spontaneous Raman transition that is driven near each atom's classical turning point. This arrangement removes nearly all of an atomic ensemble's kinetic energy in one dimension. This method does not rely on a transfer of momentum from photon to atom to cool. Rather, single-photon atomic cooling achieves a reduction in temperature and an increase in the phase-space density of an atomic ensemble by the direct reduction of the system's entropy. Presented here is the application of this technique to a sample of magnetically trapped ⁸⁷Rb. Transfer efficiencies between traps of up to 2.2% are demonstrated. It is shown that transfer efficiency can be traded for increased phase-space compression. By doing so, the phase-space density of a magnetically trapped ensemble is increased by a factor of 350 by the single-photon atomic cooling process. / text

<p>Control of E2F transcription factor activity, regulated by the action of the retinoblastoma tumor suppressor, is critical for determining cell cycle entry and cell proliferation. However, an understanding of the precise determinants of this control, including the role of other cell cycle regulatory activities, has not been clearly defined. </p><p>Recognizing that the contributions of individual regulatory components could be masked by heterogeneity in populations of cells, we made use of an integrated system to follow E2F transcriptional dynamics at the single cell level and in real time. We measured and characterized E2F temporal dynamics in the first cell cycle where cells enter the cell cycle after a period of quiescence. Quantitative analyses revealed that crossing a threshold of amplitude of E2F transcriptional activity serves as the critical determinant of cell-cycle commitment and division. </p><p>By using a developed ordinary differential equation model for Rb/E2F network, we performed simulations and predicted that Myc and cyclin D/E activities have distinct roles in modulating E2F transcriptional dynamics. Myc is critical in modulating the amplitude whereas cyclin D/E activities have little effect on the amplitude but do contribute to the modulation of duration of E2F transcriptional activation. These predictions were validated through the analysis of E2F dynamics in single cells under the conditions that cyclin D/E or Myc activities are perturbed by small molecule inhibitors or RNA interference. </p><p>In an ongoing study, we also measured E2F dynamics in cycling cells. We provide preliminary results showing robust oscillatory E2F expression at the single-cell level that aligns with the progression of continuous cell division. The temporal characteristics of the dynamics trajectories deserve further quantitative investigations.</p><p>Taken together, our results establish a strict relationship between E2F dynamics and cell fate decision at the single-cell level, providing a refined model for understanding the control logic of cell cycle entry.</p> / Dissertation

It is a widely debated subject whether a patient with a diagnosis of major depression and a history of psychosis is able to use and comprehend metaphors. There are a number of studies that indicate that metaphor comprehension with this population is very reduced. However, within the context of psychotherapy metaphor is poorly defined and the concept is often applied inconsistently in academic literature. This thesis examines a commonly reported occurrence of metaphor formation in art psychotherapy and in particular, examines a type of metaphor that offers a novel perspective about interpersonal relationships called the creative relationship metaphor. This thesis aims to develop a definition of a form of metaphor that is helpful in clinical practice and understand the clinical formation of this metaphor in art psychotherapy. The first part of the thesis develops a new metaphor type, called the ‘creative relationship metaphor’ (CRM), beginning with a psycholinguistic perspective. 2 3 In summary, the key characteristics of the CRM being developed is that it is: • An interpersonal event • An image based representation which is cognitively mapped • Context dependent • A novel way of perceiving the person, thing or event The hypothesis that patients diagnosed with severe mental health issues can produce CRMs is tested through two analyses. The first analysis focuses on the defining features of the creative relationship metaphor and the second analysis focuses on the therapist’s influence on metaphor formation. In the clinical examples, the increased capacity to reflect on significant relationships is linked to the formation of the CRM. These results offer preliminary evidence suggesting that there are specific in-session interventions that support the development of the CRM in the assessment context.

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Der erste Teil dieser Arbeit konzentriert sich auf die systematische Synthese von Informationen über Anpassung, Anpassungsstrategien, Einschränkungen und Grenzen auf globaler Ebene durch die Aufarbeitung der wissenschaftlichen Literatur und mit Hilfe von Techniken des maschinellen Lernens. In einem zweiten Schritt werden mittels einer Online-Umfrage und halbstrukturierter Interviews die Wahrnehmungen von Einschränkungen der Anpassungsmöglichkeiten in den kleinen Inselstaaten der Karibik bewertet, wobei der Schwerpunkt auf den Wechselwirkungen zwischen verschiedenen Arten von Einschränkungen und dem erheblichen Einfluss der fehlenden Anpassungsfinanzierung liegt. Schließlich wird ein zukunftsorientierter Ansatz verfolgt, bei dem Bottom-up- und Top-down-Daten kombiniert werden, um zu veranschaulichen, wie sich sozioökonomische Dimensionen im Zusammenhang mit Einschränkungen bis zum Jahr 2100 unter verschiedenen Szenarien der künftigen sozialen und wirtschaftlichen Entwicklungen entfalten könnten. Die Ergebnisse zeigen, dass die Anpassung derzeit schrittweise und weitgehend fragmentiert erfolgt. Die Erkenntnisse über die Anpassungspolitik nehmen rasch zu, aber es bestehen weiterhin geografische Ungleichheiten. Finanzen und Regierungsführung sind weltweit die größten Einschränkungen, wobei die kleinen Inselstaaten sowie Mittel- und Südamerika die meisten Einschränkungen und Grenzen melden. Die Wechselwirkungen zwischen den Einschränkungen können zu Grenzen und zusätzlichen Verlusten und Schäden führen. Dies unterstreicht die Notwendigkeit, die Einschränkungen parallel anzugehen und eine nachhaltige und gezielte Anpassungsfinanzierung zu gewährleisten. Mögliche Szenarien für die künftige Entwicklung zeigen, dass selbst in den optimistischsten Szenarien sozioökonomische Schlüsseldimensionen wie schwache Regierungsführung die Anpassung bis weit in die zweite Hälfte des 21. Jahrhunderts hinein erschweren werden. / The first part of this thesis focuses on systematically synthesising information on adaptation, adaptation policies, constraints and limits on the global level by reviewing scientific literature and with the support of machine learning techniques. Secondly, through an online-survey and semi-structured interviews, perceptions of constraints in Caribbean Small Island Developing States are assessed, by focusing on the interactions between different types of constraints and the significant influence of the lack of adaptation finance. Finally, a forward-looking approach combining bottom-up and top-down data is taken to illustrate how socio-economic dimensions related to constraints could evolve by 2100, under various scenarios of future development. The results show that adaptation is currently incremental and largely fragmented. Evidence on adaptation policy is rapidly growing but geographic inequalities persist. There is negligible data on adaptation reducing climate change risks. Finance and governance are found to be the most prominent constraints globally, with Small Island Developing States and Central and South America reporting most constraints and limits. Indeed, Caribbean Small Island Developing States face large financial constraints which in turn closely interact with governance, human capacity and information constraints and result in vicious circles. Interactions between constraints can lead to limits and additional losses and damages. This highlights the need to address constraints in parallel and for sustained and dedicated adaptation finance. Potential scenarios of future development show that, even under the most optimistic scenarios, key socio-economic dimensions such as weak governance will challenge adaptation well into the second half of the 21st century. The persistence of constraints, in particular in the most vulnerable regions, calls for stringent mitigation, improved adaptation and increased efforts to address losses and damages.

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