Islamophobia is a phenomenon that has developed very dramatically since the beginning of the 21st century due to several different factors. This has given rise to negative consequences for many individuals around the world who identify with the religion of Islam (Muslims). It has led several researchers to study Islamophobia from different perspectives based on their scientific disciplines, which has resulted in various definitions, theories, results, and solutions. The purpose of this study has been to analyze existing research over time that defines the term Islamophobia as a phobia, in order to understand the definition and development of the concept. Additionally, the study aims to critically examine the concept and the included definition factors. Through a qualitative literature review, eight psychological research papers were examined to answer the purpose of this study. All of the scientific studies that were examined based their definition on Islamophobia being a phobia (fear) towards Muslims. The difference between the definitions lies in what people are afraid of at the core and how this fear spills over onto Muslims. Upon critical examination, it has been found in this study that the term "phobia" is not a suitable term for defining discrimination towards Muslims, because a phobia is often defined as an unfounded and exaggerated fear. Moreover, the psychological research studies examined in this study contradict this definition, as they consider the fear to be strong. Based on the critical examination of scientific works in this study, it is suggested that a new term should be used to define all psychological feelings that have an essence in this research field.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s B- cell lymphoma, accounting for about 30% of these lymphomas in the United States. Large-scale genome analyses of DLBCL have identified mutations in the related histone acetyltransferases (HATs) p300 and CBP in approximately 15% of patient samples and patient-derived cell lines. The research presented herein characterizes two human DLBCL cell lines, RC-K8 and SUDHL2, which express C-terminally truncated HAT domain-deficient p300 proteins, p300ΔC-1087 and p300 p300ΔC-820, respectively. It is shown that p300ΔC-820 localizes to sites of active transcription in the nucleus, interacts with NF-κB transcription factor REL, weakly enhances REL-dependent transactivation, and has a half-life similar to wild-type p300. Results demonstrate that knockdown of p300ΔC-820 in SUDHL2 cells reduces cell proliferation in vitro. In RC-K8 cells, p300ΔC-1087 suppresses expression of the NF-κB target genes A20 and IκBα, both of which are cytotoxic when overexpressed in RC-K8 cells. Microarray analysis of p300ΔC1087 knockdown compared to wild-type RC-K8 cells indicated that p300ΔC-1087 suppresses an NF-κB gene expression program and activates a MYC gene expression program in RC-K8 cells. Bioinformatic analysis demonstrated that cancer cell lines— regardless of tissue type—with truncating p300 mutations have altered expression of a MYC target gene set as compared to cancer cell lines with wild-type p300/CBP. Taken together, this research indicates that p300 truncations contribute to cell growth in DLBCL by modifying the transcriptional output of two lymphoid cell-specific oncoproteins, NF- κB and MYC, to optimal levels and suggests that p300 truncating mutations similarly modify the activity of oncogenic drivers in other cancer cell types. Based on this work, p300 truncation is proposed to represent a new class of oncogenic mutation that serves to optimize the activity of context-specific oncogenic transcription factors, and it is suggested that such oncogenic mutations be termed “cancer modifying” mutations. / 2017-09-30T00:00:00Z

This dissertation is concerned with the relationships of prehistoric lithic technology to past subsistence and settlement systems operative at upper elevations in the Southern Interior Plateau of British Columbia. It has both a methodological and a substantive aspect. From a methodological perspective, the research applies a linear model of chipped-stone tool manufacturing processes and multivariate data reduction techniques to a series of lithic assemblages from surface sites located in Upper Hat Creek Valley in order to study intersite variability of stone tool manufacture and use. In order to efficiently study differences in tool manufacturing sequences, potential attributes that may measure such technological variability were evaluated by a R-mode factor analysis of a small sample of the assemblages; This enabled the selection of a reduced number of attributes that measure the underlying patterns of relationships present in the sample. Tool classes based on overall morphology and working edge characteristics were employed to describe artifact use. Two site classifications, one based on lithic waste patterning and the other on tool assemblage variability, were established by cluster analysis and multidimensional scaling of the assemblages. The relative effectiveness of each site classification as a means of delineating settlement types was evaluated by the ability to interpret the results of the analyses with respect to such variables as the nature and intensity of occupation, and environmental relationships. Interpretations of each analysis tend to be in general agreement with each other, although some differences are present. In some cases, the debitage analysis provides a more detailed and complex perspective of the type of occupation.- Also, a larger amount of patterning with environmental variables is evident among the site groups based on technological variability. Nevertheless, interpretations of site utilization based on results of both analyses were much more comprehensive relative to those possible from the examination of each analysis separately. In addition to studying interassemblage variability, the analysis of debitage provided some insight into the quantitative patterning of technological attributes and their significance as measures of variation in manufacturing steps. In two specific instances, observed attribute patterning is opposite to that expected by present knowledge of lithic technology. The explanation of these differences indicates some directions to be pursued by future experimental studies. The empirical validity of each site classification was also investigated. A series of Kruskal-Wallis analysis of variance tests was run on general lithic assemblage data and technological attributes to determine if the site groups defined are statistically significant. The tool-based site classification differentiates general lithic assemblage variability better than debitage however, this tends to reflect site size rather than technological processes. Both analyses support expectations based on ethnography that Upper Hat Creek Valley was likely utilized for seasonal hunting and plant gathering. These activities are reflected by the two main settlement types defined: 1) staging sites for hunting and butchering activities and 2) plant gathering and processing sites. Considerable variation with respect to the emphasis on extractive and maintenance activities is present within each type. This study has major implications for the future study of interassemblage variability where the predominant artifact class is lithic debitage. It has demonstrated that technological patterning is observable at the intersite level and that this can be accounted for in terms of subsistence-settlement activities. / Arts, Faculty of / Anthropology, Department of / Graduate

UHRF1 est une protéine nucléaire responsable du maintien et de la régulation de l'épigénome des cellules. Elle favorise la prolifération cellulaire et est surexprimée dans la plupart des cancers. TIP60, l'un des partenaires le plus important d’UHRF1, est impliqué dans le remodelage de la chromatine et la régulation transcriptionnelle grâce à son activité acétyltransférase. Ensemble, les deux protéines régulent la stabilité et l'activité d'autres protéines telles que la DNMT1 et la p53. Le but de cette étude était d'explorer le mécanisme d'interaction entre UHRF1 et TIP60 en visualisant cette interaction dans les cellules. La microscopie par imagerie à temps de vie de fluorescence et d'autres techniques de biologie moléculaire ont été utilisées. Les résultats ont montré que UHRF1 interagit directement avec le domaine MYST de TIP60 et cette interaction se produit dans la phase S du cycle cellulaire. Les deux protéines ont également montré une réponse similaire aux dommages à l'ADN, ce qui prédit une cohérence dans leur fonction dans le mécanisme de réparation de l'ADN. La surexpression de TIP60 a également induit la baisse du niveau d’UHRF1 et de DNMT1 ainsi qu’une induction d'apoptose dans les cellules ce qui suggère un rôle de TIP60 dans la régulation des fonctions oncogéniques d’UHRF1. / UHRF1 is a nuclear protein maintaining and regulating the epigenome of cells. Its promotes proliferation and is found upregulated in most of cancers. TIP60 is one of the important interacting partner of UHRF1 and is involved in chromatin remodeling and transcriptional regulation through its acetyltransferase activity. Together they regulate the stability and activity of other proteins such as DNMT1 and p53. The aim of this thesis was to explore the mechanism of interaction between UHRF1 and TIP60 by visualizing this interaction in cells. Fluorescent lifetime imaging microscopy and other molecular biology techniques were employed for this purpose. Results of this study showed that UHRF1 interacts directly to the MYST domain of TIP60 and this interaction prevails in the S-phase of cell cycle. Both proteins also showed a similar response to DNA damage predicting a coherence in their function in DNA repair mechanism. Overexpression of TIP60 also downregulated UHRF1 and DNMT1 and induced apoptosis in cells suggesting a role of TIP60 in regulation of oncogenic functions of UHRF1.

Tip60 is a 60 kDa nuclear protein which exists in three isoforms, belongs to the MYST/HAT family of proteins and was discovered after its interaction with the Human HIV-1 Tat. As a nuclear protein, Tip60 can act as a coactivator or repressor. To understand the HAT action of Tip60, two possible catalytic models exist; the ping-pong and the ternary complex formation models. In correlation with the exploration of HAT catalytic action, mutations of a Cys to Ala and a Glu to Gln on Esa1 (yeast homolog of Tip60 and MYST/HAT prototype), was reported to show wild type-like and decreased acetylating properties, respectively. In this work, Tip60 HAT action was explored. In Tip60, the Cys in the active site is important for acetylation of the H4(1-20) substrate and the Glu showed semi loss in acetylating the H4(1-20) peptide substrate. These data highlight a unique mechanism of Tip60 catalysis.

No description available.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In Brazil, the economic potential of the germplasm of medicinal species is a treasure to be preserved and utilized, increasingly becoming a form of alternative therapy available for the population to use. However, the indiscriminate and uncontrolled use can, cause more harm than benefits to health and it is important to understand these plants, from cellular levels and the action on living organisms. The medicinal species Echinodorus grandiflorus and Sagittaria montevidensis belong to the family Alismataceae, known respectively as leather hat and false leather hat in Brazil. For E. grandiflorus the attributed medicinal potentials are depurative, diuretic, anti-inflammatory, antiophidic and anti-rheumatic action, were leaves are the main part of the plant used, either as a tea or infusion. S. montevidensis has no known medicinal properties and having a wide range of leaf morphologies, leading to population confused with leather hat . The present study evaluated the genotoxic and antiproliferative extracts of the dried leaves of E. grandiflorus and S. montevidensis using the cell cycle of Allium cepa, and performing analysis by high performance liquid chromatography (HPLC-DAD) for the quantification of the extracts of the compounds. The test system is well suited for the analysis of genotoxicity, being validated by the International Programme on Chemical Safety (IPCS, WHO) and can alert on the possible damages that can be caused to organisms exposed to the substances in the plants. For the test, plant material was collected in the field in Rio Grande do Sul, in the municipalities of: Santa Maria, São Sepé, Silveira Martins and Pinhal Grande and in the commercial form of E. grandiflorus, separated into two experimental groups. The extracts were prepared, by infusing dry leaves for 15 min., at two concentrations, 6g.L-1 e 24g.L-1, and two controls, water (negative control) and glyphosate 15% (positive control). The chromatographic analysis (HPLC-DAD), revealed the presence of flavonoids and phenolic acids for both species, higher concentrations of caffeic acid and flavonoid glycoside in E. grandiflorus and phenol glycoside in S. montevidensis. This study showed that extracts of E. grandiflorus and S. montevidensis show genotoxic potential and when used in high concentrations, antiproliferative potential. / No Brasil, o potencial econômico de germoplasma de espécies medicinais é uma riqueza a ser preservada e utilizada, tornando-se cada vez mais uma forma de terapia alternativa acessível para o uso da população. No entanto, o uso indiscriminado e sem controle pode causar mais danos à saúde do que benefícios, sendo importante o conhecimento dessas plantas, desde os níveis celulares bem como ação sobre os organismos vivos. As espécies medicinais Echinodorus grandiflorus e Sagittaria montevidensis pertencem à família Alismataceae, conhecidas respectivamente como chapéu-de-couro e falso chapéu-de-couro. Para E. grandiflorus é atribuído potencial medicinal como ações depurativa, diurética, antiinflamatória, antiofídica e antirreumática, sendo as folhas a principal parte utilizada da planta, seja na forma de chá ou infusão. S. montevidensis não apresenta suas propriedades medicinais conhecidas e tendo uma grande variedade morfológica das folhas, isso leva a população a confundi-la com chapéu-de-couro . O presente estudo teve o objetivo de avaliar o potencial genotóxico e antiproliferativo de extratos das folhas secas de E. grandiflorus e S. montevidensis, sobre o ciclo celular de Allium cepa, bem como realizar análise por cromatografia líquida de alta eficiência (CLAE-DAD) para quantificação dos compostos dos extratos. O sistema teste A. cepa é bem aceito para a análise da genotoxicidade, sendo validado pelo Programa Internacional de Segurança Química (IPCS, OMS), podendo vir a alertar sobre possíveis danos que substâncias podem causar aos organismos a elas expostos. Para o teste foi coletado material vegetativo no habitat natural no Rio Grande do Sul, nos munícipios de: Santa Maria, São Sepé, Silveira Martins e Pinhal Grande e na forma comercializada de E. grandiflorus, separados em 2 grupos experimentais. Os extratos preparados, por infusão de 15 min. das folhas secas, em duas concentrações 6g. L-1 e 24g.L-1, para cada espécie e 2 controles, água (controle negativo) e o glifosato 15% (controle positivo). A análise cromatográfica (HPLC-DAD) revelou a presença de flavonóides e ácidos fenólicos para ambas as espécies. Sendo, maiores teores de ácido cafeico e flavonóide glicosídeo em E. grandiflorus e glicosídeo fenol em S. montevidensis. Este estudo mostrou que os extratos de E. grandiflorus e S. montevidensis apresentam potencial genotóxico e quando usadas em elevadas concentrações, potencial antiproliferativo.

L’utilisation chronique des glucocorticoïdes conduit généralement au développement d’une résistance aux glucocorticoïdes impliquant une modulation de l’expression de gènes impliqués dans l’inflammation ou la progression tumorale comme celui codant la MMP-9. L’expression de la MMP-9 est régulée par des mécanismes épigénétiques notamment l’acétylation des histones gouvernée par la balance HDAC/HAT (histone deacetyltransferase/histone acetyltransferase) et les micro-ARNs (miRs), mécanismes également impliqués dans les phénomènes de cortico-résistance. Cependant, les altérations épigénétiques survenant suite à un traitement chronique aux glucocorticoïdes et leurs répercutions sur l’expression de la MMP-9 ne sont pas encore clairement élucidés. L’objectif de notre étude consiste donc à déterminer le rôle des mécanismes épigénétiques dans le phénomène de résistance aux glucocorticoïdes à travers leur implication dans la régulation de l’expression de la MMP-9. Nous avons montré que l’exposition chronique aux glucocorticoïdes a perturbé, à la fois, la balance HDAC/HAT (favorisant une hyperacétylation des histones) et l’expression des miRs conduisant ainsi à une surexpression de la MMP-9. De plus, nous avons montré qu’en inhibant les HDACs par le MS-275 amplifiant ainsi le phénomène d’hyperacétylation des histones, le profil d’expression des miRs a été davantage perturbé, une perturbation qui s’est répercuté sur l’expression et la sécrétion de la MMP-9. En conclusion, nous avons montré que l’acétylation des histones et la modulation de l’expression des miRs pourraient agir en harmonie pour contrôler l'expression de la MMP-9 dans un contexte de résistance aux glucocorticoïdes. / Chronic use of glucocorticoids generally leads to the development of glucocorticoid resistance which involves a modulation of the expression of genes involved in inflammation or tumor progression as that encoding the MMP-9. MMP-9 expression is regulated by epigenetic mechanisms including histone acetylation governed by the balance HDAC / HAT (histone deacetyltransferase / histone acetyltransferase) and microRNAs (miRs). These mechanisms could be involved in the phenomena of cortico-resistance. However, epigenetic alterations occurring after chronic treatment with glucocorticoids and their repercussions on MMP-9 expression are not yet clearly understood. The aim of our study is to determine the role of epigenetic mechanisms in the phenomenon of glucocorticoid resistance through their involvement in the regulation of MMP-9 expression. We demonstrated that chronic exposure to glucocorticoids disrupted both the balance HDAC / HAT (favoring a histone hyperacetylation) and expression of miRs thus leading to an overexpression of MMP-9. In addition, we have shown that inhibiting HDACs by MS-275 thereby amplifying the phenomenon of histone hyperacetylation, the expression profile of miRs was more disturbed. This disturbance has affected MMP-9 expression and secretion. In conclusion, we have shown that histone acetylation and modulation of miRs expression of harmony miRs could act to control the expression of MMP-9 in a glucocorticoid resistance context.

Les acides aminés ont de nombreuses fonctions dans l’organisme en plus de leur rôle comme constituants élémentaires des protéines. Ils peuvent par exemple servir de neurotransmetteur ou de signal pour l’activation de voies de signalisation intracellulaires. Leur passage à travers la membrane plasmique est facilité par des transporteurs de la famille des protéines SLC. Les transporteurs hétérodimériques d’acides aminés HAT appartiennent aux SLC. Les HAT sont constitués d’une chaîne légère SLC7 assurant la spécificité de transport et d’une chaîne lourde SLC3 impliquée dans l’adressage du complexe protéique à la membrane. Ma thèse a porté sur l’étude du rôle d’un homologue de SLC7 chez la drosophile, Minidiscs (Mnd), dans le fonctionnement du système nerveux. Mnd appartiendrait aux transporteurs du système L, principalement connus pour leur rôle dans la prolifération cellulaire. Mes travaux de thèse ont permis de mettre en évidence la localisation de Mnd dans le cerveau de drosophile dans certains neurones (corps pédonculés, neurones dopaminergiques) et dans certaines cellules gliales (glie corticale). La présence de Mnd dans le cerveau semble intervenir dans la modulation de certains comportements, tels que le réflexe de géotaxie négative. Ces travaux ont aussi montré que, comme les HAT de mammifères, Mnd s’associe de façon covalente à un partenaire protéique. Les expériences de transport semblent par ailleurs confirmer l’appartenance de Mnd au système L.Ces résultats suggèrent que Mnd est probablement impliqué dans la régulation de l’activité neuronale et donc dans le fonctionnement du système nerveux, ce qui n’avait encore jamais été décrit pour un transporteur du système L. / Amino acids have many functions in the body in addition to their role as basic constituents of proteins. They can for example serve as a neurotransmitter or signal for the activation of intracellular pathways. Carriers of the SLC protein family facilitate their path through the plasma membrane. The heterodimeric amino acid transporters HAT belong to SLC proteins. HAT are composed of a light chain SLC7 ensuring the specificity of transport and a heavy chain SLC3 involved in the addressing of the protein complex to the plasma membrane. My thesis focused on studying the role of a SLC7 homologue in drosophila, Minidiscs (Mnd), in the functioning of the nervous system. Mnd might belong to system L carriers, mainly known for their role in cell proliferation. My thesis work led to highlight the location of Mnd in the drosophila brain in some neurons (mushroom bodies, dopaminergic neurons) and some glial cells (cortical glia). The presence of Mnd in the brain seems to be involved in the modulation of some behaviors such as negative geotaxis reflex. This work also showed that, as for mammal HAT, Mnd is associated covalently to a protein partner. Transport experiments seem also to confirm the belonging of Mnd to the system L. These results suggest that Mnd is probably involved in the regulation of neuronal activity and thus in the functioning of the nervous system, which had never been described for a system L carrier.

Hat sections, single and double, made of steel are frequently encountered in automotive body structural components such as front rails, B-Pillar, and rockers of unitized-body cars. These thin-walled components can play a significant role in terms of crashworthiness and impact energy absorption, through a nonlinear phenomenon called as progressive dynamic buckling. As modern vehicle safety design relies heavily on computer-aided engineering, there is a great need for analysis-based predictions to yield close correlation with test results. Although hat sections subjected to axial loading have been studied widely in the past, there is scanty information in published literature on modeling procedures that can lead to robust prediction of test responses. In the current study, both single-hat and double-hat components made of mild steel are studied extensively experimentally and numerically to quantify statistical variations in test responses such as peak load, mean load and energy absorption, and formulate modeling conditions for capturing elasto-plastic material behavior, strain rate sensitivity, spot-welds, etc. that can lead to robust predictions of force-time and force-displacement histories as well as failure modes. In addition, keeping initial stages of vehicle design in mind, the effectiveness of soft computing techniques based on polynomial regression analysis, radial basis functions and artificial neural networks for quick assessment of the behaviors of steel hat sections has been demonstrated. The study is extended to double-hat sections subjected to eccentric impact loading which has not been previously reported. A lightweight enhancement of load carrying capacity of steel hat section components has been investigated with PU (polyurethane) foam-filled single and double hat sections, and subjecting the same to quasi-static and axial impact loading. Good predictions of load-displacement responses are again obtained and shortening of fold lengths vis-à-vis hollow sections is observed. Finally, the performance of hat sections made of glass fiber-reinforced composites is studied as a potential lightweight substitute to steel hat section components. The challenging task of numerical prediction of the behaviors of the composite hat sections has been undertaken using a consistent modeling and analysis procedure described earlier and by choosing an appropriate constitutive behavior available in the popular explicit contact-impact analysis solver, LS-DYNA.