Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 89-117).

Mammalian cell types and tissues have diverse functional roles within an organism but can be derived by the differentiation of the embryonic stem cells (ESCs). ESCs are pluripotent cells with self-renewal properties. During development subsets of genes in ESCs are activated or silenced for manifestation of the cell type specific function. Gene expression changes occur transiently in early developmental stages, through signals received and executed by a variety of transcription factors (TFs), regulatory elements (promoters, enhancers) and epigenetic modifications of chromatin. Post-translational modifications of the histone tails are regulated by chromatin modifiers and transform the chromatin architecture. Polycomb (PcG) and Trithorax (TrxG) group proteins are the most commonly studied histone modifiers. They were first discovered as repressors (H3K27me3) and activators (H3K4me3) respectively of Homeobox (Hox) genes in Drosophila and they are conserved in mammals. Bivalent chromatin is defined as the simultaneous presence of silencing (H3K27me3) and activating (H3K4me3) histone marks and was first discovered as a feature of many developmental gene promoters of ESCs. Bivalent promoters are thought to be in a ‘poised’ state for later activation or repression during differentiation due to the presence of the two counter-acting histone modifications and a pausing variant of RNA polymerase II (RNAPII) accompanied with intermediate-low levels of expression. By integrative analysis of publicly available ChIP sequencing (ChIP-seq) datasets in murine and human ESCs, we predicted 3,659 and 4,979 high–confidence (HC) bivalent promoters in mouse and human ESCs respectively. Using a peak-based method, we acquire a set of bivalent promoters with high enrichment for developmental regulators. Over 85% of Polycomb targets were bivalent and their expression was particularly sensitive to TF perturbation. Moreover, murine HC bivalent promoters were occupied by both Polycomb repressive component classes (PRC1 and PRC2) and grouped into four distinct clusters with different biological functions. HC bivalent and active promoters were CpG rich while H3K27me3-only promoters lacked CpG islands. Binding enrichment of distinct sets of regulators distinguished bivalent from active promoters and a ‘TCCCC’ sequence motif was specifically enriched in bivalent promoters. Using the recent technology of single cell RNA sequencing (scRNA-seq) we focused on gene expression heterogeneity and how it may affect the output of differentiation. We collected single cell gene expression profiles for 32 human and 39 murine ESCs and studied the correlation between diverse characteristics such as network connectivity and coefficient of variation (CV) across single cells. We further characterized properties unique to genes with high CV. Highly expressed genes tended to have a low CV and were enriched for cell cycle genes. In contrast, High CV genes were co-expressed with other High CV genes, were enriched for bivalent promoters and showed enrichment for response to DNA damage and DNA repair. Bivalent promoters in ESCs grouped in four distinct classes of variable biological functions according to Polycomb occupancy and three RNAPII variants. To study the dynamics of epigenetic and transcription control at promoters during development, we collected ChIPseq data for two chromatin modifications (H3K4me3 and H3K27me3) and RNAPII (8WG16 antibody) as well as expression data (RNA-seq) across 8 cell types (ESCs and seven committed cell types) in mouse. Hierarchical clustering of 22,179 unique gene promoters across cell types, showed that H3K4me3 peaks are in agreement with the expression data while H3K27me3 and RNAPII peaks were not highly consistent with the hierarchical tree of gene expression. Unsupervised clustering of ChIP-seq and RNA-seq profiles has resulted in 31 distinct profiles, which were subsequently narrowed down to nine major profile groups across cell types. TF enrichment at individual clusters using ChIP sequencing data did not fully agree with the classification of 8 major profile groups. Considering all the above results, three major epigenetic profiles (active, bivalent and latent) seem to be conserved across the species and cell types in our study. These states could recapitulate only a fraction of the transcriptional information - adding other chromatin marks could enrich it - since they are seemingly unaffected by their respective expression profiles. H3K27me3 only state has low CpG density and shows stronger signatures at differentiated cell types. Transcriptional control is tighter in active than bivalent promoters and the different occupancy levels of PcG subunits and RNAPII can be reflected at the expression variance of bivalent genes, where a fraction of them are involved in developmental functions while others are more tissue-specific. Last, there is a striking similarity in the pausing patterns of RNAPII in the progenitor cell types, which suggests that RNAPII pausing is correlated with the developmental potential of the cell type. Finally, this analysis will serve as a resource for future studies to further understand transcriptional regulation during development.

Medical information must be available for all people in the world. Therefore it is important to translate medical research articles into foreign languages. The aim of this essay was to translate a German medical research article called “Troponinerhöhung und EKG-Veränderungen bei Schlaganfall und Subarachnoidalblutung” into Swedish and to analyse how problems that appeared during the translation process could be solved. The analysis was based on Vinay and Darbelnets, Kollers and Ingos translation theories and dealt with the question how to translate German noun phrases into Swedish. Special attention was paid to noun phrases consisting of medical terms and noun phrases containing extended modifiers. The medical terms in the source text were divided into three categories depending on their origin, Greek and Latin terms, German terms and English terms. The translation of a large number of Greek and Latin terms was based on the translation procedure called borrowing. Calque was represented especially in the translation of terms of German origin, whereas borrowing or paraphrasing was preferred when translating English terms. There were 63 noun phrases with extended modifiers in the source text. Two fifths of these corresponded to Swedish noun phrases with extended modifiers, whereas the rest must be translated into Swedish noun phrases with adjective premodifiers or relative clauses or into verbal expressions.

Propelentes sólidos são materiais energéticos que produzem gases em alta pressão por meio de uma reação de combustão. Qualquer propelente sólido inclui dois ou mais dos seguintes componentes: oxidante (nitratos e percloratos); combustível (resinas orgânicas ou polímeros); compostos químicos combinando oxidantes e combustíveis (nitrocelulose ou nitroglicerina); aditivos para facilitar processos de produção ou alterar a taxa de queima e inibidores (fita de etilcelulose), para restringir superfícies de combustão. Pequenas percentagens de aditivos são usadas para modificar diversas propriedades mecânicas, químicas e balísticas dos propelentes sólidos: acelerar ou desacelerar a velocidade de combustão (catalisadores e inibidores de combustão, respectivamente); assegurar a estabilidade química para prevenir a deterioração durante a estocagem; controlar as propriedades de processamento durante a produção de propelente (tempo de cura, fluidez para extrusão ou moldagem, etc.); controlar as propriedades de absorção de radiação no propelente em combustão; aumentar a resistência mecânica e diminuir a deformação elástica; e, finalmente, minimizar a sensibilidade térmica. No caso de propelentes sólidos Base Dupla (mistura de duas bases ativas: a nitrocelulose e a nitroglicerina), é possível alterar sua velocidade de queima principalmente pelo emprego de pequenos teores de modificadores balísticos, em geral sais orgânicos de cobre e chumbo. Neste trabalho, estudou-se a aceleração da velocidade de queima de uma formulação conhecida de propelente Base Dupla - BD, alterando o teor total dos modificadores balísticos cromato de cobre e estearato de chumbo (ou plastabil - nome comercial) na receita original, bem como a proporção entre eles. Estas alterações na formulação original devem, idealmente, preservar os parâmetros de desempenho estabelecidos para as propriedades químicas (estabilidade química) e mecânicas (densidade da massa e ensaios de tração), ao mesmo tempo otimizando o desempenho balístico, pelo aumento da velocidade de queima. Os resultados experimentais mostram que para os parâmetros de qualidade elongação e velocidade de queima a interação entre os fatores, Proporção Sal de Chumbo/Sal de Cobre (Fator A) e Teor de Modificadores Balísticos (Fator B) foram significativos, ou seja, quanto maior os fatores pior o resultado com as propriedades. Com os parâmetros de resistência a tração e densidade da massa, o fator A e B respectivamente influenciam negativamente quando aumentado em sua concentração. Para o parâmetro estabilidade química não houve nenhum sinal de melhora ou influencia dos fatores. No caso da velocidade de queima a interação AB é o que mais influencia. Melhorando significativamente a velocidade de queima. / Solid propellants are energetic materials which produce a considerable amount of high-pressure gases by means of a combustion reaction. Any solid propellant formulation includes at least two of the following items: oxidizer (nitrates and perchlorates); fuel (organic resins or polymers); chemical compounds combining oxidizers and fuels (nitrocellulose or nitroglycerine); additives to easy production operations or to modify the burning rate and inhibitors (tape ethyl-cellulose), to restrict the combustion surfaces. Small amounts of additives are employed to modify the mechanical, chemical and ballistic features of the solid propellants: to accelerate or diminish the burning rate (catalysts and inhibitors of burning, respectively); to assure the chemical stability in order to prevent the deterioration during stocking; to control the processing properties during propellant production (curing time, extrusion or casting rheology); to control the radiation absorption in the burning propellant; to enhance the mechanical resistance and to reduce the strain; and, finally, to get the thermal sensitivity to a minimum level. In the case of Double-Base solid propellants (blend of two energetic bases: nitrocellulose and nitroglycerine), it\'s possible to control its burning rate mainly by the use of small amounts of ballistic modifiers, generally copper and lead organic salts. This work has studied the burning rate acceleration of a known Double-Base propellant formulation, by changing the total amount of the ballistic modifiers copper chromate and lead stearate (commercially known as plastabil) in the original formulation, as well as the proportion between them. These changes at the original recipe should preserve, ideally, the performance levels required for the chemical (chemical stability) and mechanical properties (density and stress-strain evaluation), optimizing, at the same time, the ballistic performance, through the burning rate enhancement. Results show that for the parameters of quality and elongation rate of burning the interaction between factors, Proportion of Lead Salt / Salt Copper (Factor A) and content Ballistic Modifiers (Factor B) were significant, ie, the higher the worst factors result with the properties. With the parameters of tensile strength and mass density, the factor A and B respectively negatively influence increased when its concentration. For the chemical stability parameter there was no sign of improvement or influences of factors. In the case of burning rate AB interaction is what most influences. Significantly improving the speed of burning.

This essay deals with translation issues arising when translating a German source text – situated within the field of media communication and political science – into Swedish. More specifically, it focuses on translation problems and solutions in regard to extended participial modifiers and metaphorical expressions.From a translation perspective, complex German pre-nominal participial modifiers are known to pose a challenge to Swedish translators. This depends on language-specific restrictions within the nominal domain. In linguistic translation literature, it is commonly held, that complex pre-nominal participial modifiers cause – in Vinay & Darbelnet’s (1977) terminology – 'transpositions', yielding a Swedish relative clause. This widely held assumption again proved to be right. In some cases, however, other structural options were made use of such as abbreviated (participial) clauses. Also, depending on the complexity of the modifier, transpositions were involved which crossed one or more sentence boundaries. In contrast to complex nominal phrases with pre-nominal participial modifiers, metaphors are usually considered to be stylistically inappropriate in academic discourse. However, a closer examination of the metaphorical expressions appearing in the source text showed that they are almost without exception lexicalized or conventionalized and, therefore, not particularly artistic or daring. The analysis of the translation procedures involved when translating metaphorical expressions was limited to metaphors linked to the area of politics and career, mainly stemming from the conceptual domains: POLITICS IS WAR/A GAME and CAREER IS A JOURNEY. The analysis shows that German and Swedish have similar metaphors, building on those exact concepts. Still, literal translation was not applied in each and every case. In some cases, a neutral periphrasis or a formal equivalent was employed which resulted in a loss or change of some of the semantic aspects inherent to the original metaphor. Keywords: translation, nominal phrases, extended modifiers, metaphors

The following essay is an analysis of a translation from English into Swedish of two articles concerning tourism, travelling and the environment. The language of the articles is expressive and rich in metaphors, which evokes images in the mind of the reader. The translation was performed with the aim to transfer this effect into the translated texts and the aspects to be examined in the analysis were chosen with this in mind.One of the three aspects to be examined is the use of metaphors and how they are translated into Swedish. Many of the metaphors bear reference to travelling and the environment which gives them a function of enforcing the message and engaging the reader in the text. In order to obtain the same effect in the Swedish translations several translation strategies had to be used.The second aspect to be examined is the terminology used within tourism and the environment.  The environmental concern is a growing trend which inevitably influences the language and requires a new set of useful and understandable terms. This becomes clear when reading and translating the articles at hand. The environmental terms are fairly new and sometimes hard to distinguish. In this study focus is set on the translation strategies and the procedures used in order to find the Swedish equivalents of the terms in this context.The third aspect is the translation of hyphenated pre-modifiers. This aspect is particularly interesting, since the phenomenon is more or less unknown in Swedish. Of the fifteen hyphenated pre-modifiers in the source texts none were translated into hyphenated pre-modifiers in Swedish although five of them were translated into regular pre-modifiers. The analysis is based on the translation strategies applied and the comparison of syntactic structures of the expressions in English and Swedish.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-07-12T15:39:14Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Juan Luiz Coelho da Silva.pdf: 2693101 bytes, checksum: b946d507d9f21698d6349e8ecf91e259 (MD5) / Made available in DSpace on 2017-07-12T15:39:14Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Juan Luiz Coelho da Silva.pdf: 2693101 bytes, checksum: b946d507d9f21698d6349e8ecf91e259 (MD5) Previous issue date: 2016-03-11 / FACEPE / Algumas evidências destacam mutações no gene ASXL1 como um evento importante na evolução clínica de pacientes com neoplasias hematológicas, particularmente em leucemias mieloides agudas e síndrome mielodisplásicas. Contudo, seu impacto prognóstico em neoplasias mieloproliferativas (NMP) ainda é pouco explorado. Aqui, nós caracterizamos 208 pacientes com NMP cromossomo Filadélfia (Ph) negativo (policitemia vera, PV; trombocitemia essencial, TE; mielofibrose primária, MFP), de acordo com mutações no gene ASXL1, e correlacionamos esses achados com características clinico-laboratoriais desses pacientes. A pesquisa das mutações foi realizada por sequenciamento sanger, em que polimorfismos germinativos e mutações sinonímias foram excluídas das análises. Mutações no ASXL1 foram detectadas em 22/208 pacientes (10%), das quais quatro foram observadas em pacientes com PV (4/54; 7%), onze em pacientes com TE (11/123; 9%) e sete com MFP (7/31; 22%). As características clínicas e laboratoriais foram similares entre pacientes com ASXL1 mutado e não mutado. Quando as entidades foram avaliadas individualmente (PV, TE e MFP), observou-se associação entre mutações no ASXL1 e idade mais avançada em pacientes com TE (P = 0,049) e desenvolvimento de esplenomegalia em pacientes com MFP (P = 0,026). Com uma mediana de seguimento de 5,1 anos (IC95%: 4,5 a 7,3 anos), 136 pacientes (65%) desenvolveram algum tipo de manifestação clínica, sendo o desenvolvimento de complicações vasculares o mais frequente (n=54; 26%), seguido por esplenomegalia (n=47; 22%), eventos hemorrágicos (n=30; 14%) e trombose (n=21; 10%). Mutações no gene ASXL1 não foram associadas com o desenvolvimento das referidas manifestações. Dentro deste seguimento, apenas dois pacientes evoluíram para síndrome mielodisplásica e um para leucemia mieloide aguda, todos sem mutações no gene ASXL1. / Accumulating evidences report mutation in ASXL1 as an important predictor to clinical outcomes of patients with hematological malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome. However, the prognostic impact in myeloproliferative neoplasm (MPN) remains underexplored. Here, we evaluated clinical and laboratory features of 208 Philadelphia negative MPN patients (polycythemia vera, PV; essential thrombocythemia, ET; primary myelofibrosis, PMF), according to mutations in ASXL1. Screening for ASXL1 mutations were performedby Sanger sequencing. Germline variations were excluded. ASXL1 mutations were detected in 22/208 patients (10%), of which four in PV patients (4/54-7%), 11 in ET patients (11/123-9%) and seven in PMF (7/31-22%). Baseline features were similar between ASXL1-mutated and non-mutated patients. Evaluated individually (PV, ET, PMF), we observed that ET patients harboring ASXL1 mutations were older (P = 0,049) than ASXL1 non-mutated patients. Similarly, PMF patients presented higher frequency of splenomegaly in ASXL1mutated group (P = 0,026). No other features were associated with ASXL1mutations. The median follow-up was 5,1 years (CI95%: 4,5-7,3 years). One hundred and thirty six patients (65%) developed some of the clinical common manifestations, which the most frequent was vascular complications (n=54; 26%), followed by splenomegaly (n=47; 22%), bleeding (n=30;14%) and thrombosis (n=21;10%). ASXL1 mutations were not associated with development of such events. In our cohort, only two patients have evolved for myelodysplastic syndrome and one for acute myeloid leukemia, all of them without mutations in ASXL1.

This thesis is focused on determining the durability characteristics of asphalt mixtures containing bio-based additives for the purpose of more effective use of recycled materials. Fifty mixtures were evaluated by Cantabro Mass Loss testing in their virgin state, after 1 year of field aging, and after laboratory conditioning to determine the effectiveness of bioditives in dense graded asphalt and sand asphalt mixtures. Key findings from this work demonstrated that considerable amounts of recycled asphalt shingles (i.e. 5% of the total mixture) significantly affect the brittleness of dense graded asphalt mixtures when used in conjunction with reclaimed asphalt pavement (RAP). Furthermore, brittleness was not improved with the use of bioditives at high dosages (e.g. greater than 7.5% of the total binder content), but was improved in some cases at lower dosage rates (e.g. 2.5-5%). Additional testing of similar mixtures and bioditives evaluated in this thesis are recommended.

Yes / The presence of lubricant droplets in the gas that flows through the piston assembly and crankcase of an internal combustion engine (generically termed oil misting) has important implications for performance, particularly lubricant supply to the upper piston assembly, oil consumption and lubricant degradation. A significant source of these droplets is thought to be oil shearing and blow-through by blow-by gas flows in the piston assembly. An experimental rig was developed to simulate the high velocity gas and lubricant film interactions at a top piston ring gap where the flow conditions are most severe. Flows of lubricant droplets were produced and characterised in terms of the proportion of the oil flow that formed droplets in the gas flow and the size distribution of the droplets produced. Considering various aspects of a commercial automotive crankcase formulation, the effect of lubricant viscosity was found to be particularly important. Of the lubricant additives evaluated, viscosity modifiers were found to have the greatest effect on the tendency to form droplets: Detailed study on a range of viscosity modifiers identified that the influence of their molecular architectures on viscoelasticity was the key mechanism.

Yes / This mini-review highlights the latest advances in the chemistry and biology of Pluronic® triblock copolymers. We focus on their applications in medicine, as drug delivery carriers, biological response modifiers, and pharmaceutical ingredients. Examples of drug delivery systems and formulations currently in clinical use, clinical trials or preclinical development are highlighted. We also discuss the role that Pluronic® copolymers may play in the innovative design of new nanomedicines in the near future. / We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB) and EPSRC (EP/G004897/1 to APB) for support.