The innate immune system is the first line of defence against viral infections. Conventionally, innate immune activation begins with the detection of foreign nucleic acids by pattern recognition receptors (PRRs), which triggers a signalling cascade that culminates in the production of interferon (IFN) and other inflammatory cytokines and chemokines. Over the past few years, a number of studies have shown that IFN innate immune responses can also be triggered by stressors, such as membrane perturbations, cytoskeletal perturbations, oxidative stress, and endoplasmic reticulum (ER) stress 1–3. One way that some viruses provoke such stress responses is through membrane and cytoskeletal distortions during enveloped virus particle entry. In some cases, the glycoproteins responsible for virus particle entry can also trigger cell-cell fusion. The potential of cell-cell fusion to induce stress-based IFN responses analogous to those triggered by virus-cell fusion has not been addressed until very recently. To investigate if and how cell-cell fusion may induce antiviral mechanisms and IFN responses we used the reptilian reovirus p14 fusion associated small transmembrane (FAST) protein as a model of cell-cell fusion. We found that p14-mediated cell fusion led to the production of low level IFN and upregulation of interferon stimulated genes (ISGs) in a stimulator of interferon genes (STING) and interferon regulatory factor 3 (IRF3) dependent manner. We also observed that multinucleated cells experienced extensive DNA-damage that led to the accumulation of cytosolic DNA in the form of micronuclei. Micronuclei can be detected by cytosolic DNA PRRs like cyclic GMP-AMP synthase (cGAS) and signal IFN production through the cGAS-STING signalling axis. Additionally, early syncytia formation restricted replication of vesicular stomatitis virus (VSV), herpes simplex virus-1 (HSV), and vaccinia virus (VSV) in an IFN and IRF3 independent, and STING dependent manner, suggesting involvement of either a novel antiviral mechanism or suppression of virus replication and spread by biological changes in syncytial cells, such as cell cycle arrest. This study highlights a key role of DNA sensing pathways in the immune response to cell fusion associated stress and points out the importance of fusion kinetics in the selective advantage of syncytial viruses. Understanding the potential of syncytial cells to induce IFN responses and influence viral replication at a mechanistic level is beneficial to the design of improved oncolytic immunotherapy. / Thesis / Master of Science (MSc) / Viruses and their hosts continuously fight each other for survival. The host tries to protect itself from the virus by activating various features of its immune system, while the virus tries to block and evade detection by the immune system. One way that some viruses attempt to bypass the immune system and enhance spread involves expressing proteins that can merge together infected cells with neighboring uninfected cells. Cell-cell fusion disrupts the balanced environment within the cell, which is a form of stress that may activate immune responses. This work investigates if and how host cells may activate the immune system to respond and protect themselves from the cell merging activity of select viruses. We found that the stress associated with existing as a large, fused cell caused DNA damage and fragmentation. These DNA fragments could stimulate key immune sensors and initiate immune responses. We also observed an impaired ability of viruses to infect fused cells, but this restriction was not associated with typical immune responses, suggesting that some other biological change in fused cells created an environment that is not suitable for viral spread. Further investigation is required to fully understand this phenomenon; however, this study highlights some protective mechanisms of the host immune system in response to the stress of viral fusion protein induced cell-cell fusion.

In this study, Thermomechanical properties of Ti-50.8 and 50.7 at% Ni alloy severely deformed using Equal Channel Angular Extrusion (ECAE) are investigated. The aim of this study is to reveal the effects of severe plastic deformation on shape memory, pseudelasticity, interplay between plastic deformation via dislocation slip and twinning, and forward and reverse martensitic transformation. The samples are processed at room temperature, i.e. slightly above the austenite finish temperature, and at 450 °C, i.e. well-above the austenite finish temperature. Transformation temperatures, microstructural evolution, and thermomechanical properties of ECAE processed samples are studied before and after low temperature annealing heat treatment and compared with conventional cold drawn and precipitation hardened material. The unique findings are: 1) the observation of a mixture of heavily deformed B2 (austenite) and B19’ (martensite) phases in the samples processed at room temperature although martensite stabilization was expected, 2) the observation of highly organized, twin-related nanograins in B2 phase of the samples deformed at room temperature which was attributed to B2 to B19' via SIM, and B19' to B2 via SPD (SIM: Stress Induced Martensitic transformation, SPD: Severe Plastic Deformation) transformation sequence, 3) simultaneous observation of B2 austenite and strain induced B19’ martensite in the samples deformed at 450 °C, and 4) perfect pseudoelasticity, small pseudoelastic stress hysteresis and excellent cyclic response with no irrecoverable strain up to 1000 cycles for ECAE at 450 °C processed sample. Strain induced martensite in NiTi alloys was reported for the first time. The formation of well-organized twin-related nanograins via severe plastic deformation opens a new opportunity for twinning induced grain boundary engineering in NiTi alloys which significantly improves the matrix strength and the cyclic response against degradation of shape memory and pseudoelasticity.

In this study, Thermomechanical properties of Ti-50.8 and 50.7 at% Ni alloy severely deformed using Equal Channel Angular Extrusion (ECAE) are investigated. The aim of this study is to reveal the effects of severe plastic deformation on shape memory, pseudelasticity, interplay between plastic deformation via dislocation slip and twinning, and forward and reverse martensitic transformation. The samples are processed at room temperature, i.e. slightly above the austenite finish temperature, and at 450 °C, i.e. well-above the austenite finish temperature. Transformation temperatures, microstructural evolution, and thermomechanical properties of ECAE processed samples are studied before and after low temperature annealing heat treatment and compared with conventional cold drawn and precipitation hardened material. The unique findings are: 1) the observation of a mixture of heavily deformed B2 (austenite) and B19’ (martensite) phases in the samples processed at room temperature although martensite stabilization was expected, 2) the observation of highly organized, twin-related nanograins in B2 phase of the samples deformed at room temperature which was attributed to B2 to B19' via SIM, and B19' to B2 via SPD (SIM: Stress Induced Martensitic transformation, SPD: Severe Plastic Deformation) transformation sequence, 3) simultaneous observation of B2 austenite and strain induced B19’ martensite in the samples deformed at 450 °C, and 4) perfect pseudoelasticity, small pseudoelastic stress hysteresis and excellent cyclic response with no irrecoverable strain up to 1000 cycles for ECAE at 450 °C processed sample. Strain induced martensite in NiTi alloys was reported for the first time. The formation of well-organized twin-related nanograins via severe plastic deformation opens a new opportunity for twinning induced grain boundary engineering in NiTi alloys which significantly improves the matrix strength and the cyclic response against degradation of shape memory and pseudoelasticity.

A finite element analysis approach is used to determine the susceptibility to wrinkles for thin sheets with clamped ends when subjected to tensile loading. The model problem chosen to do this analysis is the stretching of a thin sheet with clamped-ends. In the preliminary analysis, a stress analysis of thin sheets is done to study the stresses that develop under these boundary conditions. The analysis shows that there is a stretch-induced compressive stress in the transverse direction to the applied load that causes wrinkles. Then, the parametric study is conducted to determine the effect of aspect ratio and strain on the compressive stress. Based on the results of the parametric study, a critical strain value for each aspect ratio is determined for which the corresponding compressive stress is zero. Further buckling analysis is performed to find the buckling modes of the model problem that shows a limit of aspect ratio below which buckling is not possible under given conditions. Finally, post-buckling analysis shows the nature of wrinkles observed in the model problem for different aspect ratios. / text

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Crystal engineering has advanced the strategies of design and synthesis of organic solids with the main focus being on improving the properties of the developed materials. Research in this area has a significant impact on large-scale manufacturing as industrial processes may give rise, at various stages, to stress-induced transformations and product modification. This thesis investigates the solid-state properties at play in the case of the surface and structural reorganization which results from the stress within a crystal during the drying of labile multicomponent organic solids. Chapter 1 introduces various concepts in solid-state chemistry and explores their application in the manufacture of solid pharmaceuticals. The significance of stress-induced transformations during the drying process is illustrated by reactions associated with crystal decomposition processes such as dehydration, desolvation and sublimation. The chapter also introduces carbamazepine (CBZ) multicomponent materials as models for the studies of stress-induced transformations. Chapter 2 presents the experimental section of the work and describes the materials, methods and equipment used for the study. Chapter 3 presents the analysis of the various crystal structures of CBZ. The crystal forms are classified with an emphasis on a comparison of intermolecular interactions, coformer arrangement, crystal packing and the geometric parameters of slip/cleavage planes within the crystals. Chapter 4 details the experimental methods for preparation of the samples. Cooling solution crystallization was the standard method which has been selected, and crystal habit and surface variations have been studied as a function of the solution concentration and the crystallization environment. Attention is given, in particular, to the preparation of carbamazepine dihydrate and the specific cocrystals carbamazepine cocrystals formed with benzoquinone and oxalic acid. Chapter 5 is devoted to the dehydration of carbamazepine dihydrate for samples prepared and examined in approximate 1-gram laboratory scale quantities. It explores the effect of vacuum, temperature, humidity and seeding on the surface and bulk properties of the products. Chapter 6 presents the solid-state characterization results obtained for samples crystallized at a much larger scale (ca. kilogram quantities) with a particular emphasis placed on their mechanical properties. It explores the comparison of large scaled batches with laboratory scale samples in order to obtain a greater understanding of how small-scale laboratory studies may be extrapolated to more commercial processes. Chapter 7 present results on the stress-induced transformations of carbamazepine solvates and cocrystals. It details the effect of thermal decomposition on the surface and bulk properties of the products, possible seeding effects, and the interconversion between carbamazepine dihydrate and carbamazepine benzoquinone cocrystal. Chapter 8 combines the research findings concerning the structural analyses of the materials in the context of current literature. Limitations related to the use of carbamazepine as a model and to the experimental set-up are also explored. In the final chapter conclusions are presented which correlate observations made on the crystallization and decomposition of multicomponent materials operating at small-scale to effects appropriate to manufacturing of pharmaceuticals at large scale.

Commercially available polycrystalline Ni (Ni200; grain size: 32 μm) and electrodeposited nanocrystalline Ni (grain size: 57 nm), Ni-2.6%Fe (grain size: 25 nm) and Ni-8.5%Fe (grain size: 20 nm) were analyzed for the phenomena of stress-induced heat generation and strain localization during plastic deformation at room temperature (i.e. 250C). Tensile specimens according to ASTM E8 standard dimensions were tested at strain rates of 10-2/s and 10-1/s, respectively, to record the amount of heat dissipated and the change of localized strain using a high resolution infrared (IR) detector and digital image correlation (DIC) camera, respectively. Results have shown that the maximum temperatures that were recorded in nanocrystalline Ni and Ni-Fe alloys were at least 300C lower than the onset temperatures for subgrain coalescence previously measured through differential scanning calorimetry. It can be concluded that thermally activated grain growth during tensile testing of nanocrystalline Ni and Ni-Fe alloys is not likely to occur.

Commercially available polycrystalline Ni (Ni200; grain size: 32 μm) and electrodeposited nanocrystalline Ni (grain size: 57 nm), Ni-2.6%Fe (grain size: 25 nm) and Ni-8.5%Fe (grain size: 20 nm) were analyzed for the phenomena of stress-induced heat generation and strain localization during plastic deformation at room temperature (i.e. 250C). Tensile specimens according to ASTM E8 standard dimensions were tested at strain rates of 10-2/s and 10-1/s, respectively, to record the amount of heat dissipated and the change of localized strain using a high resolution infrared (IR) detector and digital image correlation (DIC) camera, respectively. Results have shown that the maximum temperatures that were recorded in nanocrystalline Ni and Ni-Fe alloys were at least 300C lower than the onset temperatures for subgrain coalescence previously measured through differential scanning calorimetry. It can be concluded that thermally activated grain growth during tensile testing of nanocrystalline Ni and Ni-Fe alloys is not likely to occur.

Stress cardiomyopathy can cause significant morbidity in the functional life of patients. The most common finding is apical ballooning of the left ventricle on cardiac catheterization. Some cases present with atypical imaging findings. This report presents a case of atypical stress cardiomyopathy with midventricular hypokinesis.

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