Individuals and the significance of affect : foreign policy variation in the Middle East

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    This dissertation seeks to expand our understanding of variation in foreign policy. Although we have a series of large, extant literatures dealing with the sources of foreign policy, there has been less attention paid over the last decade to understanding why states change their behavior. At the same time, the thesis argues that foreign policy change is best understood as a result of the role of individual decision-makers and the role that emotion plays in their foreign policy calculations.Foreign policy depends on the decisions made by individual leaders. The type of individual thus determines the specific policy. Here individuals are categorized as ideological or adaptable. Ideological individuals are more rigid in their belief structures, are more likely to select policies that fit with their extant understandings of the world and the position of their state in it, and more likely to rely on the emotional or affective appeal an object or issue holds for them. Adaptable leaders are more flexible, not tied to specific ideologies or reliant on emotion to guide their thinking, and thus more likely to choose or learn ideas that best respond to changing environmental conditions. At the same time, how a state's decision-making institutions are structured tells us how likely it is that an individual's own predilections matter. In polities where decision-making is centralized (e.g., in the office of the prime minister), individuals have greater leeway to put their ideas (whether based on their ideological outlooks or shifting environmental circumstances) into practice, while in de-centralized polities other actors constrain the leader from autonomous decision-making. In such cases, it is likely that an individual's ideas will conform to those of the constraining actors. Finally, the role of ideas is taken into consideration, as the dominant national ideas about foreign policy regarding a specific issue-area help us better understand the context in which individuals make (or change) foreign policy.This model is tested against alternate explanations---systemic imperatives, Constructivism, public opinion, poliheuristic theory, and prospect theory---in two case studies: the Israeli decision to pursue and sign the 1993 Oslo Accords, and the 2002 decision by the Islamist government in Turkey to actively lobby for membership in the European Union. Both foreign policies represent significant variation, and both provide important theoretical and empirical puzzles for scholars

    Immobilization, characterization and use of fish protease

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    Enzyme immobilization as a technique attaches free forms of enzyme molecules to stationary support materials to permit enzymes to be reused several times. Bovine trypsin as a model enzyme was immobilized onto controlled pore glass (CPG) beads to investigate the optimum conditions for immobilization, as well as the physico-chemical properties of the immobilized enzyme versus the free form of the enzyme. At pH 9, about 60% of the enzyme protein incubated with CPG was immobilized onto the CPG, and immobilized bovine trypsin activity was determined as 0.265 BAPNA U/g CPG beads. The immobilized bovine trypsin showed lower affinity for its substrate, lower susceptibility to inhibition by soybean trypsin inhibitor and higher thermal stability, while the optimum pH and optimum temperature values were shifted to higher values compared to those of the free enzyme. The immobilized enzyme was evaluated for its capacity to extract carotenoproteins from shrimp shell. After 11 re-uses, the immobilized enzyme retained about 77% of its initial activity, and the total yield of the product from the same immobilized trypsin was 4.3 times higher than a single use of the same amount of the free enzyme. Cunner fish is a cold water adapted, stomachless teleost fish. Cunner fish trypsin possesses some unique properties compared with homologous trypsins from (i) species acclimated to warm temperature regimes, and (ii) species with functionally distinct-stomachs. Cunner fish trypsin was extracted from pancreatic tissue, and immobilized onto CPG beads using glutaraldehyde as cross-linking reagent. The influence of enzyme loading, the properties of the immobilized enzyme in terms of specific activities, and responses to pH and temperature were investigated. The kinetic properties and operational stability of the immobilized cunner trypsin were studied as well. The pH optimum of the immobilized fish trypsin shifted from pH 8.5 to pH 9, and the temperature optimum also increased from 45ºC to 50ºC versus the free form of the cunner enzyme. The catalytic efficiencies (Vmax/Km) of the immobilized fish trypsin were determined for both amidase and esterase reactions, using BAPNA and TAME as substrates and were found to be greater than those of immobilized bovine trypsin. Thus, the immobilized cunner fish trypsin had a higher catalytic capacity for the hydrolysis of both the amide and ester substrates. The operational stability of immobilized fish trypsin was studied by extracting carotenoprotein from shrimp shell. The immobilized fish trypsin retained 75% of its initial hydrolytic capacity after 11 re-uses, and the yield obtained was over 20% higher than that of immobilized bovine trypsin. When the immobilized cunner fish trypsin was applied to digest native pectin methylesterase (PME), it exhibited greater capacity to inactivate the PME than immobilized bovine trypsin. The inactivation efficiency of the immobilized fish trypsin was 20% higher than that of the immobilized bovine trypsin. The inactivation of PME was influenced by PME concentration, incubation time and temperature. In general, higher temperature, longer incubation period, and lower initial PME concentration produced more PME inactivation. PME inactivated by immobilized fish trypsin and bovine trypsin regained part of its activity during storage at 4ºC. The initial PME concentration affected the reactivation period. The kinetic studies indicated that the inactivation rate constants increased and D-values (time to inactivate 90% of the enzyme) decreased with increasing temperature for both immobilized fish trypsin and bovine trypsin. The activation energy (Ea) of PME inactivation by the immobilized fish trypsin was lower than that by the immobilized bovine trypsin, which explains why the immobilized fish trypsin had higher catalytic capacity at various temperatures than immobilized bovine trypsin

    A time-based approach for multi-GHz embedded mixed-signal characterization and measurement /

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    The increasingly more sophisticated systems that are nowadays implemented on a single chip are placing stringent requirements on the test industry. New test strategies, equipment, and methodologies need to be developed to sustain the constant increase in demand for consumer and communication electronics. Techniques for built-in-self-test (BIST) and design-for-test (DFT) strategies have been proven to offer more feasible and economical testing solutions.Previous works have been conducted to perform on-chip testing, characterization, and measurement of signals and components. The current thesis advances those techniques on many levels. In terms of performance, an increase of more than an order of magnitude in speed is achieved. 70-GHz (effective sampling) on-chip oscilloscope is reported, compared to 4-GHz and 10-GHz ones in previous state-of-the-art implementations. Power dissipation is another area where the proposed work offer a superior solution compared to previous alternatives. All the proposed circuits do not exceed a few milliWatts of power dissipation, while performing multi-GHz high-speed signal capture at a medium resolution. Finally, and possibly most importantly, all the proposed circuits for test rely on a different form of signal processing; the time-based approach. It is believed that this approach paves the path to a lot of new techniques and circuit design skills that can be investigated more deeply. As an integral part of the time-based processing approach for GHz signal capture, this thesis verifies the advantages of using time amplification. The use of such amplification in the time domain is materialized with experimental results from three specific integrated circuits achieving different tasks in GHz high-speed in-situ signal measurement and characterization. Advantages of using such time-based approach techniques, when combined with the use of a front-end time amplifier, include noise immunity, the use of synthesizable digital cells, and circuit building blocks that track the technology scaling in terms of area and speed

    Origin of DNA methylation patterns in the male germ line : roles of the novel DNA methyltransferases in male germ cells

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    Formation of gametes capable of supporting development is dependent on a number of genetic and epigenetic events. DNA methylation is an epigenetic modification catalyzed by enzymes named DNA methyltransferases (DNMTs). In the mouse, methylation of DNA is associated with the control of gene expression and proper embryo development. Methylation patterns are established in a sex- and sequence-specific manner during male and female germ cell development and further modified during early embryonic development. Even though new DNMTs have recently been identified, little information is known on the origin of the methylation marks during male germ cell development (spermatogenesis). The main goal of the work presented in this thesis was to gain a better understanding of the enzymes involved in creating the epigenetic program of the male genome. The first step in doing so involved comparing the temporal expression profiles of DNA methyltransferases in the developing testis and ovary. The expression profiles obtained indicated that in the male, DNMT3a and DNMT3L could be involved in de novo methylation while DNMT3b and DNMT1 could be responsible for maintaining methylation patterns following DNA replication. Next, characterization of Dnmt3a and Dnmt3b expression in isolated postnatal male germ cells revealed how tightly regulated the expression of these genes is during spermatogenesis: specific transcript variants and protein isoforms of each DNMT are differentially expressed during male germ cell development. Finally, assessing the effect of Dnmt3L inactivation on the male germ line exposed the presence of a mitotic defect in germ cells lacking this protein. DNA methylation analyses revealed that many loci throughout the genome are marked for methylation by DNMT3L, indicating a more global role for this enzyme than that previously reported in genomic methylation patterning in the male germ line. As methylation patterns instituted during spermatogenesis have to be properly established for accurate transmission of epigenetic information to the next generation, the studies presented here contribute to our knowledge of the events leading to the creation of the epigenetic program necessary for the formation of healthy gametes

    The handling of iron by erythroid and erythrophagocytic cells /

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    Iron is not a trace element in mammalian physiology. Using textbook values for blood volume (5.5 L), red blood cell (RBC) count (5 million/muL), and a lifespan of 120 days for red blood cells, the equilibrium value for the erythrocyte generation/death rate in the average adult male human is over 2 million/sec. It follows that the amount of iron required for hemoglobin synthesis in one day amounts to about 25 mg. Virtually every atom of that 25 mg is recycled by macrophages of the reticuloendothelial system (RES) that provide iron to the plasma for its subsequent delivery back to the erythron (with a small fraction going to other tissues). In light of the certain toxicity of unprotected iron, both erythroid precursors and RES macrophages perform remarkable tasks in handling such copious amounts of the catalytic metal. In my studies, I have examined specific aspects of iron metabolism in these two tissues.Iron is taken up by nearly every cell through a mechanism of receptor-mediated endocytosis, whereby the plasma iron binding protein transferrin (Tf) binds to its cognate receptor (TfR) on the cell surface, followed by internalization of the complex into a membrane bound organelle. Subsequent to endocytosis, the endosome is acidified by a v-ATPase proton pump, facilitating the release of iron from Tf. Through an unknown mechanism, iron is targeted to the inner membrane of the mitochondria, where the enzyme that inserts Fe2+ into protoporphyrin IX, ferrochelatase, resides. Although it has been demonstrated that the divalent metal transporter, DMT1, is responsible for the egress of reduced Fe from the vesicle, the immediate fate of the iron atoms after their transport across the vesicular membrane remains unknown. Therefore, we have investigated the uptake of iron in reticulocytes, cells that are taking up large amounts of iron for the synthesis of hemoglobin. Through both biochemical and imaging techniques, we have demonstrated that iron is transferred via a direct interorganellar relation between the endosome and mitochondria.The "haemoglobin-deficit" (hbd) mouse has an erythroid-specific mutation which is responsible for its microcytic, hypochromic phenotype. Previous studies have shown that these mice have normal dietary iron acquisition and normal to elevated serum iron levels. We therefore investigated the handling of iron in reticulocytes from these animals to determine whether the mutated gene possibly plays a role in the trafficking of transferrin-iron-containing organelles. A systematic examination of the steps in the transferrin pathway revealed that the intracellular trafficking of the protein is compromised in the hbd mice.The rapid turnover of iron by macrophages of the RES requires heme oxygenase-1 (HO-1), which catalyzes the rate-limiting step in heme degradation. This highly inducible enzyme, besides its major role in erythrocyte iron recycling, has been demonstrated to confer astonishing cytoprotectivity to cells and tissues in which its expression is elevated (either through chemical induction or genetic manipulation). In addition to, reportedly protective, carbon monoxide and biliverdin, the HO-1 catalyzed reaction releases ferrous iron, which itself is a potent pro-oxidant. Also, it is unlikely that there exists a significant amount of free heme in most tissues (i.e., non-erythroid, non-erythrophagocytic), to provide significant amounts of substrate to this enzyme. Hence, it is tempting to speculate that the mechanism of heme oxygenase cytoprotection is removed from its function of heme catabolism. Therefore, we investigated whether increased expression of heme oxygenase will, in and of itself, alter iron metabolism in cultured cells. My experiments show that in the absence of exogenous hemin, elevation of HO-1 protein levels does not have any effect on cellular iron metabolism in cultured cells

    The diverse roles of collapsin response mediator protein 4 in mitosis and nerve regeneration

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    Microtubule-actin interactions underlie a diverse number of biological processes including cell motility, neuronal outgrowth, cellular wound healing, cell division and cortical flow. CRMPs (Collapsin Response Mediator Proteins) are a family of cytosolic phosphoproteins that play roles in regulating both actin and microtubule dynamics. The roles of the CRMP family of proteins in regulating these cellular processes have only been partially described. Our lab has been particularly interested in the function of the CRMP4 isoform because of its unique ability to complex with RhoA, a master regulator of the actin cytoskeleton. In this thesis we explore the function of CRMP4 in two biological processes that are dependent on actin and microtubule dynamics: mitosis (Chapter 2) and axon regeneration (Chapter 3 and 4). In Chapter 2, we identify CRMP4 as an important regulator of mitotic chromosomal alignment. We show that CRMP4 localizes to spindle microtubules during mitosis and that loss of CRMP4 disrupts chromosomal alignment, mitotic progression and spindle morphology. Furthermore, we demonstrate that these processes are dependent on CRMP4 phosphorylation, which may be important for recruitment of additional proteins to the mitotic machinery. In Chapter 3, we investigate the ability of an adeno-associated virus (AAV) encoding a CRMP4 antagonist C4RIP (CRMP4-RhoA inhibitory peptide) to enhance adult retinal ganglion cell (RGC) axon regeneration in an in vivo preclinical optic nerve injury model. We describe the inability of AAV-C4RIP to promote RGC regeneration and discuss the likelihood that AAV-mediated expression levels of C4RIP may be insufficient to promote regeneration. In Chapter 4, we describe the development and validation of cell permeable recombinant C4RIP (TAT-C4RIP) and discuss our data testing the effects of TAT-C4RIP on regeneration in vitro and in vivo. Together, these studies identify CRMP4 as an important regulator of mitosis, and describe our ongoing studies testing the effects of a CRMP4 antagonist on nerve regeneration.Les interactions entre l'actine et les microtubules sont sous-jacentes à divers processus biologiques incluant la motilité cellulaire, le guidage neuronal, la cicatrisation cellulaire, la division cellulaire et la circulation corticale. Les protéines CRMPs (Collapsin Response Mediator Protein) sont une famille de phosphoprotéines cytosoliques jouant un rôle dans la régulation de la dynamique de l'actine et des microtubules. Cependant, cette régulation du cytosquelette par les CRMPs n'a été que partiellement décrite. Notre laboratoire s'intéresse à la fonction de l'isoforme CRMP4 en raison de sa capacité unique d'interagir avec RhoA, un régulateur important du cytosquelette d'actine. Dans cette thèse, nous explorons la fonction de CRMP4 dans deux processus biologiques qui dépendent de la dynamique de l'actine et des microtubules: la mitose (chapitre 2) et la régénération des axones (chapitre 3 et 4). Dans le chapitre 2 sera présentée notre identification de CRMP4 en tant que régulateur important de l'alignement chromosomique durant la mitose. Nous démontrons que, pendant la mitose, CRMP4 se situe sur les fuseaux mitotiques formés de microtubules et que la perte de CRMP4 perturbe l'alignement chromosomique, la progression de la mitose et la morphologie des fuseaux. En outre, nous démontrons que ces processus sont dépendants de la phosphorylation de CRMP4. Ceci pourrait être crucial pour le recrutement de protéines supplémentaires nécessaire pour la mitose. Dans le chapitre 3, nous étudions la capacité d'un virus adéno-associé (AAV) codant pour l'antagoniste de CRMP4, nommé C4RIP (CRMP4-RhoA inhibitory peptide), de favoriser la régénération de l'axone de cellules ganglionnaires de la rétine (RGC) chez l'adulte. Pour cela, nous utilisons un modèle in vivo de traumatismes du nerf optique chez le rat adulte. Nous décrivons l'incapacité des virus AAV-C4RIP de favoriser la régénération des RGCs et discutons de la probabilité que les niveaux de AAV-C4RIP exprimés puissent être insuffisants afin de favoriser la régénération. Le chapitre 4, quant à lui, est consacré à la description du développement et de la validation de la protéine recombinante TAT-C4RIP qui a le potentiel de traverser la membrane cellulaire. Nous y discutons les données concernant les effets de TAT-C4RIP sur la régénération in vitro et in vivo. Dans l'ensemble, ces études caractérisent CRMP4 comme important régulateur de la mitose et décrivent une nouvelle méthode de purification pour des protéines perméables à la membrane cellulaire

    Willingness to pay for change : the use of contingent valuation and choice experiments in the Trinidad and Tobago water services sector

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    Financing water infrastructure has been increasingly identified as a constraint to reaching the Millennium Development Goals for developing countries' water sectors and a significant area in which potential exists to develop sustainable financing is through the design of appropriate tariff policies.This thesis examines in detail the demand for water service improvements by analysing the willingness to pay for such improvements in Trinidad and Tobago. The basis for the work is a household sample survey conducted in 2003 which assessed the current quality of service and attitudes towards changing the status quo situation. The survey of 1419 households showed that services are poorer than officially stated, and that in response many households have opted for private coping solutions to mitigate the poor service levels of the utility.Choice experiments, which have only limited previous application in the sector, are employed to develop attribute based utility models describing the welfare effects of service level changes, in addition to the more commonly used contingent valuation method. A rigorous comparison of the two methods is developed. It provides evidence that the choice experiment methodology has benefits for policy analysis around the willingness to pay for service changes in the water sector.An analysis of proposed marginal cost based tariffs in Trinidad, as a part of wider sector reforms, is used as a case study for the policy applications of the choice experiment based willingness to pay data. Consumers are willing to pay for investments in water infrastructure, provided that they impact upon the actual service received. Marginal cost based tariffs might be socially unacceptable given that whilst significant, the willingness to pay, given likely service changes associated with planned investments by the Trinidadian water utility, for service changes is not sufficient to cover this economically efficient level of tariff

    Effect of particle size and natural organic matter on the transport and fate of latex nanoparticles in saturated porous media

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    Colloid filtration experiments were performed using latex particles (50 nm, 110 nm and 1500 nm) in both the presence and absence of 5.0 mg/L humic acid (HAs). At low ionic strengths (1 -- 10 mM KCl), an increase in attachment efficiency (alpha) with increasing particle size was observed, which contrasts with predictions based on DLVO theory. The presence of HAs generally resulted in a decrease in alpha. Characterization experiments to better understand this behaviour included particle sizing using dynamic light scattering (DLS) and zeta potential using laser Doppler velocimetry (LDV). The particles' hydrodynamic diameters were unchanged in the presence of HAs. HAs lead to an increase in absolute zeta potential for the 50 nm and 110 nm colloids and a decrease in zeta potential for the 1500 nm particles. A discussion of the apparent deviations from Derjaguin-Landau-Verwey-Overbeek (DLVO) theory and explanations for the observed behaviour are provided

    Depression, medication use, and cognitive functioning in older medical patients

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    The inter-relationship between depression, medication use and cognitive decline in older persons has potentially important clinical and public health implications, yet research findings on the nature of this relationship remain inconclusive. This thesis presents a systematic investigation into this topic in a sample of 281 medical inpatients aged 65 and over, who were followed for up to 12 months after admission.In the first three chapters, the concept, population burden and measurement of depression and cognitive function in the elderly population are described. The relevant literature is reviewed, and the rationale and approaches of this thesis are presented.In the fourth chapter (1st manuscript), the short-term temporal relationship between depression and cognitive functioning was explored using an interviewer-rated depression severity scale. Based on competing mixed effects models under alternative temporal assumptions, the severity of depression symptoms appeared to have a concurrent rather than prospective relationship with cognitive functioning.In the fifth chapter (2nd manuscript), diagnostic criteria were used to define depression. After adjusting for covariates, both major and minor depression were significantly predictive of subsequent cognitive decline, and the strength of the association appeared to increase with the duration of "exposure".In the sixth chapter (3rd manuscript), using a provincial prescription database, the effects of medication exposure on cognitive function were evaluated. Antidepressant use was not associated with cognitive decline in general, but interacted with depression diagnoses. In exploratory analyses, antidepressant use appeared to be associated with improved cognitive function over time in the minor depression group, independent of comorbid diseases, current depression symptoms and concomitant medications. Both major and minor depression were independently predictive of subsequent cognitive decline, especially in those not prescribed antidepressants.In summary, this thesis demonstrates that, in this sample of older medical inpatients, both major and minor depression are independent risk factors for 12-month cognitive decline. The potentially beneficial effects of antidepressants for patients with minor depression should be investigated

    Mucosal immunizations in a humanized transgenic mouse model and development of novel multimeric tools for detection of cellular immunity towards an HIV vaccine

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    Viral vector-based vaccines represent an effective means of in vivo antigen expression and the ensuing generation of a sustained immune response in the host. These new generation vaccines are deemed promising against pathogens for which researchers have so far failed to put forth preventive strategies and/or effective, accessible, treatment modalities. HIV-1 stands at the foremost of this list. In the current study, we have evaluated the use of two different viral vector-based vaccines against Clade A of HIV-1, namely recombinant modified vesicular stomatitis virus (VSV-AV3) and Adenovirus serotype 5 (Ad5) expressing the Gag protein from subtype A. These viral vectors, which are also inherently endowed with adjuvant properties, were delivered via a mucosal immunization strategy in a humanized transgenic mouse model. Transgenic mice expressing both HLA-A*0201 and HLA-DR*0101 represent a versatile model in which HIV-specific immunogenic epitopes and the resulting T cell receptor (TCR) specificity can be determined. We show that following mucosal delivery of vaccine, there is induction of antigen-specific systemic T cells against epitopes which were previously shown to be immunogenic in humans. We next developed novel multimeric reagents for the detection of CD4 + T cells, namely dodecameric HLA-DR1 molecules using a murine immunoglobulin M (IgM) scaffold. These reagents aim at increasing the overall avidity of peptide-MHC Class II complexes to detect low-affinity TCRs. These multimers were able to activate in vitro a Jurkat T cell line in an antigen-specific manner. The identification and characterization of the molecular requirements boosting the qualitative and quantitative features of the immune response to HIV vaccines, in addition to the development of novel state-of-the-art immune monitoring tools, will be crucial in better understanding of the mechanisms of interaction between the virus and the host immune system, leading to rational strategies in the fight against the AIDS epidemic
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