[ES] El síndrome de Dravet es una epilepsia severa rara causada por mutaciones en el gen SCN1A, el cual codifica para la proteína Nav1.1, subunidad α de los canales de sodio regulados por voltaje. En esta tesis se ha generado mediante recombinación homóloga, una nueva mutación en el gen para que hemos denominado paraKO, el cual cumple la misma función en Drosophila melanogaster. Estas moscas han mostrado un fenotipo epiléptico inducido por altas temperaturas, y muerte súbita en el caso de las crisis de larga duración. También se han observado alteraciones musculares en ensayos de geotaxis negativa, vuelo y locomoción. Del mismo modo, han presentado problemas cognitivos como la ansiedad y dificultades en el aprendizaje. El uso de imanes como terapia contra el fenotipo epiléptico ha tenido buenos resultados retrasando la aparición de las crisis y disminuyendo su duración y la cantidad de moscas que las padecen. El perfil metabolómico de las cabezas de estas moscas mostró un incremento en la concentración de aminoácidos, succinato y lactato, alteraciones que se pueden relacionar con la epilepsia y la disfunción mitocondrial. El neurotransmisor GABA, principal implicado en el síndrome de Dravet, mostró niveles superiores en el modelo generado. El análisis electrofisiológico de las corrientes de sodio de las motoneuronas aCC en estadío de larva señaló aumentos en las corrientes persistentes de sodio y su ratio con las transitorias, lo cual podría justificar las crisis epilépticas. Además, la excitabilidad y el tamaño de estas células fueron menores. Todos estos cambios presentes en los mutantes KO generados hacen de estas moscas un buen modelo para estudio de la epilepsia en general, y del síndrome de Dravet en particular. Este modelo ofrece nuevas herramientas para entender la patofisiología de la enfermedad y la búsqueda de biomarcadores y tratamientos. Finalmente la búsqueda de modificadores genéticos a través de ensayos de supervivencia, tiempo de recuperación a crisis y vuelo empleando el modelo parabss1 obtuvo buenos resultados con los genes nAchRα4 y KCNQ. El gen toy por el contrario resultó ser intensificador. La variabilidad en los resultados obtenidos en este apartado cuestiona la manera de llevar a cabo este tipo de estudios en modelos animales y pacientes del síndrome de Dravet. / [CA] La síndrome de Dravet és una epilèpsia severa rara causada por mutacions en el gen SCN1A, el qual codifica para la proteïna Nav1.1, subunitat α dels canals de sodi regulats por voltatge. En aquesta tesis s'ha generat, mitjançant recombinació homòloga, una nova mutació en el gen para, anomenada paraKO, el qual té la mateixa funció en Drosophila melanogaster. Aquestes mosques han mostrat un fenotip epilèptic induït por altes temperatures, y mort súbdita en el cas de les crisis de llarga duració. També s'han observat alteracions musculars en assajos de geotaxis negativa, vol y locomoció. De la mateixa manera, han presentat problemes cognitius como l'ansietat i dificultats en l'aprenentatge. L'ús d'imants com teràpia contra el fenotip epilèptic ha tingut bons resultats endarrerint l'aparició de les crisis i disminuint la seua durada i la quantitat de mosques que les pateixen. El perfil metabolòmic dels caps d'aquestes mosques mostrà increments en la concentració d'aminoàcids, succinat i lactat, alteracions les quals es poden relacionar amb l'epilèpsia y la disfunció mitocondrial. El neurotransmissor GABA, principal implicat en la síndrome de Dravet, mostrà nivells superiores en el model generat. L'anàlisi electrofisiològic de las corrents de sodi de les motoneurones aCC en estadi de larva assenyalà augments en les corrents persistents de sodi y el seu ràtio amb las transitòries, lo qual podria justificar las crisis epilèptiques. A més a més, l'excitabilitat y el tamany d'aquestes cèl·lules va ser menor. Todos aquests canvis presents en els mutants KO generats fan d'aquestes mosques un model per a l'estudi de l'epilèpsia en general, i de la síndrome de Dravet en particular. Aquest model ofereix noves ferramentes per a entendre la patofisiología de la malaltia i la recerca de biomarcadors y tractaments. Finalment la recerca de modificadors genètics a través d'assajos de supervivència, temps de recuperació a crisis y vol mitjançant el model parabss1 va obtindre bons resultats amb els gens nAchRα4 y KCNQ. El gen toy pel contrari resultà ser intensificador. La variabilitat en els resultats obtinguts en aquest apartat qüestiona la manera de fer aquest tipus d'estudis en models animals i pacients de la síndrome de Dravet. / [EN] Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. In this thesis we have made a new mutation in a gene called paraKO through homologous recombination, the single Drosophila melanogaster gene encoding this type of protein. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight and locomotion tests. Moreover, they also manifested some cognitive alterations such as anxiety and difficulties in learning. Using magnets as a therapy for epileptic phenotype, seizures start was delayed, and its duration and the quantity of flies affected was lower. Metabolomic profile of these flies' brains showed an increase in the amount of aminoacids, succinate and lactate, alterations that could be related with epilepsy and mitochondrial dysfunction. GABA, the main neurotransmitter involved in Dravet syndrome, was higher in the paraKO model. Electrophysiological sodium current analysis from aCC motoneurons in larvae stage revealed an increase in persistent currents and their ratio with transients, which is a symptom for epileptic seizures. Cell size and excitability were lower in these cells too. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments. Finally, a search for genetic modifiers through survival, recuperation time and flight using parabss1 flies obtained good results with nAchR¿4 y KCNQ. Otherwise, toy gene was an enhancer. However, variability observed in these type of assays dispute how modifiers search is made with model animals and Dravet syndrome patients. / Tapia González, A. (2022). Generación de nuevos modelos y búsqueda de modificadores para el Síndrome de Dravet en Drosophila Melanogaster [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/186189 / TESIS

No description available.

Thesis (MScMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) occurs when the cardiomyocytes in the left ventricle become enlarged by increasing in mass in response to haemodynamic pressure overload. This can either be attributed to a normal physiological response to exercise or can be the result of a maladaptive process or disease state, such as chronic hypertension. Hypertrophic cardiomyopathy (HCM) is the most common form of Mendelian-inherited cardiac disease. A defining characteristic thereof is primary LVH that occurs when there are no other hypertrophy-predisposing conditions present. Therefore, HCM provides a unique opportunity to study the molecular determinants of LVH in the context of a Mendelian disorder, instead of in more complex disorders such as hypertension. Over 1000 HCM-causing mutations in 19 genes have been identified thus far, most of them encoding sarcomeric proteins residing in the sarcomeric C-zone. However, for many HCM patients no disease-causing genes have been identified. Moreover, studies have shown phenotypic variation in presentation of disease in, as well as between, families in which the same HCM-causing mutation segregates. This has led many investigators to conclude that genetic modifiers of hypertrophy exist. The aim of the study was to identify novel plausible HCM-causing or modifier genes by searching for interactors of a known HCM-causing protein, namely titin. The hypothesis was that genes encoding proteins, which interact with proteins that are encoded by known HCM-causative genes, may also be considered HCM-causing or may modify the HCM phenotype. To this end, the aim was to identify novel interactors of the 11-domain super-repeat region of titin, which resides within the sarcomeric C-zone, using yeast two-hybrid analysis. Five putative interactors of the 11-domain super-repeat region of titin were identified in this study. These interactions were subsequently verified by colocalisation in H9C2 rat cardiomyocytes, providing further evidence for possible interactions between titin and these proteins. The putative interactor proteins of titin determined from the Y2H library screen were: filamin C (FLNC), phosphatidylethanolamine-binding protein 4 (PEBP4), heart-type fatty acid binding protein 3 (H-FABP3), myomesin 2 (MYOM2) and myomesin 1 (MYOM1). The FLNC gene could be a candidate for cardiac diseases, especially cardiomyopathies that are associated with hypertrophy or developmental defects. The putative interaction of titin and PEBP4 is speculated to be indicative of the formation of the interstitial fibrosis and myocyte disarray seen in HCM. Heart-type fatty acid-binding protein 3 has prognostic value to predict recurrent cardiac events. Its suggested interaction with titin is speculated to play a role in inhibiting its functional abilities. Myomesin 2 is jointly responsible, with MYOM1, for the formation of a head structure on one end of the titin string that connects the Z and M bands of the sarcomere. This is speculated to be linked to a developmental error with the result being a defect in sarcomeric structure formation, which could result in pathologies such as HCM. Therefore, these identified proteins could likely play a functional role in HCM due to their interactions with titin. This research could thus help with new insights into the further understanding of HCM patho-aetiology. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) ontstaan wanneer die kardiomyosiete in die linkerventrikel vergroot as gevolg van 'n verhoging in massa in reaksie op hemodinamiese drukoorlading. Dit kan toegeskryf word aan 'n normale fisiologiese respons op oefening of kan die gevolg wees van 'n wanaangepaste of siektetoestand, soos chroniese hipertensie. Hipertrofiese kardiomiopatie (HKM) is die mees algemene vorm van Mendeliese oorerflike hartsiekte. 'n Bepalende eienskap daarvan is primêre LVH, wat plaasvind wanneer daar geen ander hipertrofie-predisponerende voorwaardes teenwoordig is nie. Gevolglik bied HKM 'n unieke geleentheid om die molekulêre derterminante van LVH te bestudeer, in die konteks van 'n Mendeliese oorerflike siekte, in plaas van om dit in die meer komplekse siektes soos hoë bloeddruk te bestudeer. Meer as 1000 HKM-veroorsakende mutasies is tot dusver in 19 gene geïdentifiseer. Die meeste van hulle kodeer vir sarkomeriese proteïene wat in die C-sone voorkom. Egter, vir baie HKM-pasiënte is geen siekte-veroorsakende gene al geïdentifiseer nie. Daarbenewens het studies getoon dat variasie in fenotipiese aanbieding van die siekte in, sowel as tussen, families voorkom wat dieselfde HKM-veroorsakende mutasie het. Dit het daartoe gelei dat baie navorsers tot die gevolgtrekking gekom het dat genetiese wysigers van hipertrofie wel bestaan. Die doel van die studie was om nuwe moontlike HKM-veroorsakende of wysiger-gene te identifiseer deur te soek vir interaktors van 'n bekende HKM-veroorsakende proteïen, naamlik titin. Die hipotese was dat gene wat vir proteïene kodeer, wat in wisselwerking is met proteïene wat geïnkripteer word deur bekende HKM-veroorsakende gene, ook oorweeg kan word om HKM te veroorsaak. Dit kan ook die HKM fenotipe verander. Dus was die doel om nuwe interaktors van die 11-domein super-herhaalstreek van titin, soos gevind binne die sarkomeriese C-sone, te identifiseer deur middel van gis-twee-hibried-analise. Vyf vermeende interaktors van die 11-domein super-herhaalstreek van titin is in hierdie studie geïdentifiseer. Hierdie interaksies is later geverifieer met behulp van ko-lokalisering in H9C2-rotkardiomyosiete, wat verdere bewyse vir moontlike interaksies tussen titin en hierdie proteïene verskaf. Die vermeende interaktor-proteïene van titin wat bepaal is vanaf die gis-twee-hibried-biblioteeksifting was as volg: filamin C (FLNC), phosphatidylethanolamine-bindingsproteïen 4 (PEBP4), hart-tipe-vetsuur bindingsproteïen 3 (H-FABP3), myomesin 2 (MYOM2) en myomesin 1 (MYOM1). Die FLNC-geen kan 'n kandidaat vir kardiale siektes, veral kardiomiopatieë, wees wat geassosieer word met hipertrofie of ontwikkelingsafwykings. Die vermeende interaksie van titin en PEBP4 dui daarop om 'n aanduiding te wees vir die vorming van die interstisiële fibrose en miokardiale wanorde, soos gesien in HKM. Hart-tipe-vetsuur bindingsproteïen 3 het prognostiese waarde om herhalende kardiale gebeure te voorspel. Verder dui sy voorgestelde interaksie met titin moontlik daarop dat dit 'n rol kan speel in die inhibering van sy funksionele vermoëns. Myomesin 2 tesame met MYOM1 is verantwoordelik vir die vorming van 'n kopstruktuur aan die een kant van die titinstring wat dan die Z- en M-bande van die sarkomeer verbind. Daar word vermoed dat dit gekoppel is aan 'n ontwikkelingsfout, met die gevolg dat daar 'n defek is in sarkomeriese struktuurvorming, wat weer kan lei tot patologieë soos HKM. / Mrs Wendy Ackerman / Prof Paul van Helden / National Research Foundation (NRF) / Stellenbosch University

M. Tech. (Civil Engineering, Faculty of Engineering and Technology), Vaal University of Technology) / Modified asphalt concrete is one of the important construction materials for flexible pavements. The addition of polymers and natural hydrocarbon modifiers to enhance the properties of asphalt concrete over a wide temperature range in paving applications has been the common practice. Currently these modified asphalt mixtures are relatively expensive. However, recycled polymers and rubber added to asphalt have also shown similar results in improving the performance of road pavements. In this study, an attempt has been made to use low density polyethylene (LDPE) obtained from plastic waste and crumb rubber obtained from worn out vehicle tyres. The aim was to optimise the proportions of LDPE in the bitumen binder using the ‘wet process’ and crumb rubber aggregates in the hot mix asphalt (HMA) using the ‘dry process’. The Marshall method of bituminous mix design was carried out for varying percentages of LDPE namely 2%, 4%, 6%, 8% and 10% by weight of bitumen binder and 1%, 2%, 3%, 4% and 5% crumb rubber by volume of the mineral aggregates. The characteristics of bitumen modified with LDPE were evaluated. The modified asphalt mix was also evaluated to determine the different mix characteristics. The results from laboratory studies in terms of the rheological properties of the LDPE modified bitumen binder showed an increase in viscosity, softening point and stiffness of the binder. The optimum Marshall stability values for HMA mixtures containing 2% crumb rubber tyre and 4% LDPE were found to be 30% higher than the conventional asphalt concrete mix. The wheel tracking test done at 50ºC was 9.81mm rut depth showing a good rutting resistance of the optimized mixture compared to the conventional asphalt mixes. The Modified Lottman test gave a Tensile Strength Ratio value of 0.979 which indicates a low degree of moisture susceptibility of the modified asphalt mix. The above results showed improved properties of the asphalt mixture. The economic assessment done using the present worth of costs indicated a reduction in maintenance cost due to the extended service life of the modified asphalt pavement.

Glass production has historically occurred at around 50 glassworks in Sweden, in a region known as the Kingdom of Crystals (Glasriket). Today, most of these sites are no longer active and left behind is glass waste of different forms (both as fragments of finished glass as well as unrefined glass melts). Consequently, increased concentrations of different metals, especially arsenic, lead and cadmium, have been found around the sites, both in soil as well as in ground and surface water. Between 2016 and 2019, the Geological Survey of Sweden (SGU) assigned Golder Associates AB (Golder) to evaluate the environmental risks at three different glassworks: Flerohopp, Åryd and Alsterbro. The results, based on humidity cell tests (HCT) conducted on glass samples from each site, showed that glass itself leached to a surprisingly high extent. Based on this, the aim of this master thesis has been to explain trends in glass leaching by a thorough literature review and through the analysis of HCT data of glass samples. Additionally, the speciation of different metals in the leachate was investigated based on geochemical modelling using PHREEQC. Results from the literature review show that one of the possible mechanisms for the leaching of glass in contact with water is ion exchange, which occurs at the surface of the glass, namely between glass components and H+ ions in water. Additionally, the literature also argues that glass with higher silica content form a more resilient structure, in contrast to glass which contains a large amount of modifiers, such as Na and Ca. Researchers speculate that adding such modifiers to the glass mass opens up the structure, making it more vulnerable upon contact with water. Looking at the total concentration of elements from the three glassworks, the results show a variation in silica content in relation to other elements. In line with this hypothesis, the sample from Åryd, which contained a higher proportion of modifiers, showed a high leaching rate of both Na and Si. Furthermore, the result shows that the leaching of Na and As follows the same pattern over the HCT period for all glassworks. This is, to some extent, also the case for Pb although the correlation is not as significant. This could be explained by the result from geochemical modelling, showing that As tends to dissolve into the leachate while Pb is more prone to forming secondary minerals. Hence explaining their differences in leaching behavior. The result from this study showed no clear correlation between Ca and either As or Pb which could potentially be explained by the formation of precipitates. However, another approach to describe the difference in the behavior between Na and Ca is based on the glass structure itself as well as the hypothesis that Na+ participate in ion exchange to a larger extent than Ca2+. Consequently, the leaching of Na+ makes the surface structure more vulnerable, thereby promoting the leaching of other components such as As and Pb. / Produktion av glas har historiskt skett på cirka 50 glasbruk i Sverige i ett område som kallas Glasriket. I dag är produktionen vid majoriteten av dessa glasbruk avvecklad och kvar på platserna finns glasavfall i olika former, både som skärvor av färdigt glas och som ej färdigställd glasmassa. Som en konsekvens av detta har förhöjda halter av olika metaller, särskilt arsenik, bly och kadmium, påträffats i jorden såväl som i grund- och ytvattnet kring glasbruken. Mellan åren 2016 och 2019 gav Sveriges geologiska undersökning (SGU) i uppdrag till Golder Associates AB (Golder) att uträtta huvudstudier och bedömma risker vid tre olika glasbruk, Flerohopp, Åryd och Alsterbro. Resultaten, baserade på fuktkammarförsök på glassavfall, påvisade att glas lakade till en överraskande hög utsträckning. Detta resultat lade grunden till detta examensarbete med frågeställningar i syfte att förklara lakning av glas baserat på en genomgående litteraturstudie samt analys av resultat från fuktkammarförsöken. Vidare har även geokemisk modellering med programmet PHREEQC gjorts för att identifiera olika specifieringar av metaller som kan förväntas påträffas i lakvätskan. Resultat från litteraturstudien visar att en möjlig process som kan förklara lakning av glas vid kontakt med vatten är jonbyte mellan glasets beståndsdelar och H+-jonerna i vattnet. Tidigare studier påvisar att ett högre kiselinnehåll i glaset skapar en mer motståndskraftig struktur än glas som innehåller en förhållandevis hög andel modifierare, såom Na och Ca. Forskare spekularar kring huruvida tillsatsen av modifierare till glasmassan bidrar till att öppna upp glasstrukturen och som en konsekvens av detta göra strukturen mer sårbar. Vid analys av prover tagna vid de tre olika glasbruken påvisade resultaten ett varierat kiselinnehåll i förhållande till övriga ämnen. I linje med denna hypotes påvisade provet från Åryd den högsta andelen modifierare och samtidigt även den högsta lakningen av Na såväl som Si. Vidare påvisar resultatet att lakningen av Na och As följer samma mönster över hela fuktkammarförsöket. Detta kan delvis ses för Pb men korrelationen är inte lika signifikant som för As. En förklaring till detta baseras på resultat från geokemisk modellering, där As tenderar att gå i lösning medan Pb kan förväntas forma sekundära mineral vilket därmed kan antas kontrollera lakningen. Resultatet från denna studie visade ingen korrelation mellan varken Ca och As eller Ca och Pb vilket också skulle kunna förklaras av utfällningar i form av Ca-mineral i lakvätskan. En annan utgångspunkt för att beskriva den skillnad som kan ses mellan Na och Ca baseras på själva glasstrukturen och hur Na+ deltar i jonbyte till en högre grad än vad Ca2+ gör. Som en konsekvens av detta bidrar lakningen av Na+ till att ytan på glaset blir mer sårbar och på så sätt gör att ämnen som As och Pb blir mer lättåtkomliga. Detta resulterar i en större möjlighet för dessa att delta i reaktioner på ytan och därmed laka ut från strukturen.

Neste trabalho foi medida a tenacidade à fratura de quatro ligas fundidas com composição química base do aço AISI M2 – uma de composição química convencional (liga I), e as demais modificadas por adições de nitrogênio (liga II), cério (liga III) e antimônio (liga IV) – submetidas a tratamentos térmicos visando a decomposição do carboneto M2C, a esferoidização e engrossamento dos carbonetos produto M6C e MC, em altas temperaturas e por diversos tempos. A metodologia empregada nesta avaliação da tenacidade à fratura foi a dos corpos de prova curtos com entalhe chevron segundo ASTM E 1304-97, de forma a superar a necessidade do pré-trincamento por fadiga, procedimento de difícil controle e custoso em materiais como os aços rápidos temperados e revenidos. Verificou-se que a metodologia utilizada para obtenção e ensaio de corpos de prova chevron foi de fácil execução (comparada à metodologia convencional) permitindo grande número de experimentos. Para verificar a consistência dos resultados, em algumas condições, também se utilizou a metodologia convencional segundo a ASTM E 399-90, cujo pré-trincamento foi feito utilizando os procedimentos propostos por Harris e Dunegan. Os resultados obtidos para os aços fundidos foram correlacionados com os obtidos para outros aços rápidos convencionais (VM2, M2 Thyssen) e um aço rápido sinterizado (SINTER 23). A microestrutura foi caracterizada utilizando-se técnicas de ataques metalográficos diferenciais, metalografia quantitativa manual e computadorizada e microscopia eletrônica de varredura. A avaliação microestrutural indica que não ocorreu precipitação eutética do carboneto M6C, em nenhuma das ligas fundidas. O carboneto M2C apresenta morfologia tanto irregular (plaquetas – tipo 1) quanto regular-complexa (lamelas – tipo 2). As ligas I, III e IV, apresentaram a predominância da morfologia tipo 1 enquanto que a liga II modificada pelo nitrogênio, apresentou apenas a morfologia tipo 2. O carboneto MC apresentou-se com morfologia regular-complexa. Medidas do espaçamento interdendrítico indicam que não houve influência significativa dos elementos modificadores sobre este parâmetro. Ensaios de resistência à flexão, indicam pouca influência dos elementos modificadores, mas forte influência dos tratamentos térmicos sobre o limite de resistência à ruptura transversal do aço fundido. Em todas as ligas, a resistência à flexão cresceu com o tempo de tratamento a 1200°C, bem como com a temperatura de decomposição em tratamentos por 2 horas. Análise das fraturas por microscopia eletrônica de varredura indicou que o crescimento das trincas se deu na região interdendrítica. O aço convencional apresentou resistência à ruptura transversal muito superior à dos aços fundidos. Os ensaios de tenacidade à fratura apresentaram resultados compatíveis com a literatura para os aços AISI M2 convencional e SINTER 23. Os resultados obtidos para o aço fundido, indicam queda nos valores de tenacidade à fratura nos materiais tratados a 1050°C com o avanço do tempo de tratamento; pouca variação dos valores com o tempo nas amostras tratadas a 1150°C; e aumento significativo da tenacidade à fratura com o tempo de tratamento a 1200°C. Os valores de tenacidade obtidos para os aços rápidos fundidos foram mais elevados que os obtidos para os materiais trabalhados e para o material sinterizado. / Fracture Toughness of four cast alloys with chemical composition based on the High-Speed Steel AISI M2 were measured. One of the alloys (alloy I) had the conventional AISI M2 composition, while the other three were modified by the addition of N (alloy II), Ce (alloy III) and Sb (alloy IV). The cast alloys were heat-treated in order to promote the decomposition of the M2C carbide as well as spheroidize and coarsen the product M6C e MC carbides. The method chosen for measuring fracture toughness was based on the use of short rod and bar chevron notched samples, according to ASTM E1304 – 97, in order to evade the need for fatigue pre-cracking, notoriously difficult for High Speed Steels quenched and tempered. The chevron-notch method proved straightforward and allowed for successful testing a great number of specimens. Conventional compact sample fracture toughness, according to ASTM E 399-90, with pre-cracking obtained using Harris-Dunegan drop-weight procedure, was used to validate the results. The results for cast alloys were compared with conventionally produced High Speed Steels (VM2, M2 Thyssen) and with a powder metallurgy High Speed Steel (SINTER 23). Microstructural characterization was performed using selective etching of polished surfaces, manual and automated quantitative metallography and SEM. Microstructural evaluation of as-cast alloys showed that there was no eutectic precipitation of M6C carbides. The M2C carbides show an irregular eutectic morphology (Type 1- plates) as well as a regular-complex eutectic morphology. Measurements of interdendritic spacing did not detect any effect of the modification. The bending test rupture strengths did not vary with the addition of modifying elements, but increased with the time and temperature of decomposition, spheroidization and coarsening of carbides. Rupture strengths increased with the heat-treatment time at 1200°C as well as with increasing temperatures for 2 h heat-treatments. SEM examination of the fracture surfaces showed that crack preferential growth path was interdendritical. Conventional High Speed Steels tested in bending presented better results for the rupture strength than cast steels. Fracture toughness results for M2 conventional steels and for the SINTER 23 steel were similar to the results from the literature. Fracture toughness results obtained for cast steels diminished with increasing decomposition time at 1050°C, did not change much with increasing decomposition time at 1150°C, increased markedly withy increasing decomposition times at 1200°C. The fracture toughness results for the as-cast steels were higher than the results obtained for the wrought steels and for the powder metallurgy steel.

Esta tese investiga o modo de organização dos domínios nominal, verbal e dos adjetivos em Português do Brasil (PB), tendo como guia a aceitabilidade de sentenças com todo. Para o inglês, a natureza do parâmetro orienta a seleção de argumentos por operadores; já para o PB, o que importa é a oposição entre tipos de escala. O PB não tem determinantes que distingam entre nome contável e massivo, como much e many. O operador aspectual progressivo não modifica estados em inglês, mas em PB sim. Em inglês, very seleciona adjetivos de parâmetro relativo. Em PB, muito + adjetivo tem parâmetro relativo, e todo + adjetivo tem parâmetro absoluto. Todo é um operador interdomínios, sensível aos tipos de escala. Todo modifica a relação de predicação. Todo impõe condições (quantitativas) sobre como a saturação de um predicado por certo argumento deve ocorrer. Todo não é nem um modificador nominal, nem um quantificador canônico como cada. Todo não cria, apenas modifica uma relação existente. A distribuição que ocorre em sentenças com todo é uma entre as muitas formas de saturação de um predicado por um argumento: uma relação incremental. Se o argumento for quantizado, o predicado necessariamente também se tornará quantizado. Analisamos uma descrição definida (DD) como um sintagma de medida (SM). O artigo definido torna um predicado nominal em denotação quantizada, mas todo não. Relacionamos ser quantizado a ser argumental, e ser cumulativo a ser predicativo. E associamos sentidos diferentes às posições de todo na sentença. / This thesis takes the distribution of todo as a probe for the structure of nominal, verbal and adjective domains in Brazilian Portuguese (BP). Todo is a Degree Modifier (DM) and is sensitive to scale structure. English DMs (e.g., very) select adjectives by their standards; the BP DMs select adjectives only by their scale structure. However, they produce phrases with standard specialization. Todo + adjective shows absolute standard interpretation. We claim that the domains show the same properties in both languages, but the nature of scale standard matters in a distinct level for each one. We claim that todo is neither a noun modifier nor a true quantifier. Todo is a relation modifier. Todo modifies the way the argument saturates the predicate. A quantized incremental argument will make the predicate quantized as well. Todo is not the true source of distributivity, since incremental relations occur even in its absence. Definite Descriptions are treated as measure phrases. The definite article relates noun predicates to situations. So it will change a bare noun into a quantized denotation, which todo cannot do. Each land site corresponds to a different meaning for floating todo.

A Neoplasia endócrina múltipla tipo 1 (NEM1; OMIM 131100) é uma síndrome endócrina hereditária, que envolve tumores nas glândulas paratireóides, pâncreas endócrino/duodeno e hipófise. Mutações germinativas no gene supressor de tumor MEN1 são identificadas em aproximadamente 80% dos casos familiais. Os casos restantes podem apresentar grandes deleções no gene MEN1 (raras), não identificáveis ao seqüenciamento direto, ou mutações em outros genes, ainda pouco conhecidos. Recentemente, mutações germinativas em genes que codificam quinases dependentes de ciclinas, como o gene supressor de tumor p27Kip1, foram identificadas em cerca de 1-2% dos pacientes NEM1 sem mutação no gene MEN1. Esses pacientes apresentam uma clínica similar à NEM1, sendo chamada de NEM-like ou NEM4. Estudos in vitro mostraram que a proteína codificada pelo gene MEN1, MENIN, controla a expressão gênica de p27Kip1, indicando que ambos os genes fazem parte da mesma via celular supressora de tumor. Devido à correlação genótipo-fenótipo ser muito fraca nessa síndrome e à grande variabilidade fenotípica encontrada em pacientes com NEM1 (mesmo entre indivíduos/familiares que possuem mesma mutação no gene MEN1), no presente estudo investigamos a hipótese do envolvimento do gene p27Kip1, e de outro gene supressor de tumor recentemente associado com um fenótipo tumores hipofisários famílias, o gene AIP, como possíveis moduladores de fenótipo entre os pacientes com NEM1 de uma extensa família brasileira com a mutação germinativa MEN1 c.308delC e ampla variabilidade fenotípica. Dentre uma série de variáveis clínicas investigadas, observamos um possível papel modulador de fenótipo do gene p27Kip1 nesta família com NEM1. Foi encontrada associação significante entre o genótipo do polimorfismo p.V109G do gene p27Kip1, localizado em um domínio de ligação com a proteína p38 (que é um regulador negativo de p27 por levar à degradação dessa proteína), com os seguintes aspectos clínicos: maior agressividade do tumor hipofisário (macro vs. microadenomas), precocidade no desenvolvimento do tumor pancreático, e presença de carcinóides e metástases nos pacientes analisados (p< 0,05). Não foi observada nenhuma associação do gene AIP e o fenótipo dos pacientes com NEM1. O presente estudo investigou, pela primeira vez, o status germinativo do gene p27Kip1 em pacientes com mutação MEN1 e identificou uma associação significante em relação à susceptibilidade e agressividade dos tumores na coorte estudada / Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumoral syndrome that involves tumors in the parathyroids, anterior pituitary and in the pancreatic islet(s) cells. Germline mutations in the tumor suppressor gene MEN1 are detectable through direct sequencing in the majority (80%) of the patients with familial MEN1. The remaining patients may present large MEN1 gene deletions, not detectable through direct sequencing, or mutations in other genes, so far largely unknown. Recently, rare mutations in genes that encode cyclin-dependent kinases, as p27Kip1, have been reported in approximately 1-2% of the patients without a MEN1 mutation. These patients were reported as presenting a MEN1-like (or the MEN4) syndrome phenotype. In vitro studies have demonstrated that the protein encoded by the MEN1 gene, MENIN, controls the expression of the p27Kip1 gene and, therefore, these two genes seem to act in the same intracellular tumor suppressor pathway. Due to the lack of genotype-phenotype correlation in MEN1 and the large clinical variability usually observed within unrelated patients carrying the same MEN1 mutation, we hypothesized that p27Kip1 (as well as AIP gene, recently associated with familial predisposition to pituitary tumors) may act as phenotypic modifying gene(s) in the MEN1 syndrome. Herein, we analyzed possible correlations between p27Kip1 genotype and a number of clinical features. We identified significant statistic associations between the p.V109G p27Kip1 polymorphism and phenotype manifestations, indicating a potential role of p27Kip1 in modifying MEN1 phenotype, as follows: pituitary tumor size; early development of pancreatic tumors, and presence of carcinoids and metastasis (p< 0,05). In addition, a possible association with the AIP gene was excluded. The present study analyzed, for the first time, the germline status of p27Kip1 gene in MEN1-mutated patients and identified a potential interaction between the genotype of this tumor suppressor gene in regulating susceptibility and the tumor aggressiveness in MEN1 patients

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Esta tese tem como foco os efeitos da desigualdade de renda na saúde bucal e as tendências em desigualdades socioeconômicas em saúde bucal. Qualquer injustiça social, pelo caráter moral é digna de estudo, porém nem toda desigualdade de renda é socialmente injusta. Ela se torna injusta quando as pessoas com menos recursos são aquelas que permitem que as desigualdades econômicas afetem direitos humanos, como o direito a um nível de vida que assegure ao indivíduo e a sua família uma vida saudável. As desigualdades de renda foram estudadas em duas vertentes:a) efeitos contextuais da desigualdade de renda na saúde bucal ; b) tendências na diferença de saúde bucal entre pessoas com maior e menor renda. A primeira parte contém quatro artigos originais que estudaram a associação e os mecanismos contextuais p elos quais a desigualdade de renda afeta a saúde bucal. Para isso, foram utilizados dados do inquérito em saúde bucal SBBrasil de 2002. Os resultados mostraram que: a) a associação entre desigualdade de renda e saúde bucal é mais forte em relação à cárie dental do que outras doenças bucais (e.g. doenças periodontais e maloclusões); b)seus efeitos estão mais fortemente associados à doenças bucais de menor latência; c) os efeitos associados à cárie dental afetam pobres e ricos igualmente; e d) a ausência de políticas públicas parece ser a melhor explicação para os efeitos da excessiva desigualdade de renda no Brasil. Ainda em relação às políticas públicas, foi encontrados que os ricos beneficiam-se mais de políticas públicas municipais do que os pobres. A segunda parte desta tese contém dois artigos originais que descrevem as tendências em saúde bucal e o uso dos serviços odontológicos em grupos de maior e menor renda, no Brasil e na Suécia. Para essas análises, foram usados dados dos inquéritos em saúde bucal no Brasil dos anos de 1986 e 2002, e para Suécia foram obtidos dados do "Swedish Level of Living Survey" para 1968, 1974, 1981, 1991 e 2000. As tendências relacionadas à prevalência de edentulismo mostraram que houve uma redução das desigualdade em percentuais absolutos nos dois países, porém, no Brasil houve um aumento das diferenças quando o desfecho foi a prevalência de nenhum dente perdido. As reduções das disparidades em edentulimo estiveram associadas à presença de uma diferença inicial significativa ,já o aumento das desigualdade na prevalência de nenhum dente perdido esteve relacionado a uma pequena desigualdade no início da coleta de dados. Em relação às desigualdades de uso dos serviços, ressalta-se que o grupo mais pobre permanece utilizando menos os serviços odontológicos em ambos os países e as diferenças continuam significantes através dos tempos. Entretanto, tanto no Brasil como na Suécia, essas diferenças reduziram levemente nas coortes jovens em função do declínio no percentual de pessoas mais ricas que visitam o dentista. Nossos dados permitem concluir que as desigualdades, em saúde bucal, mesmo em países altamente igualitários, como a Suécia. / This thesis focuses on the effect of income distribution on oral health and trends on socioeconomic disparities in oral health. Any social injustice, because of moral issues, is worth studying, though not all inequality of is unfair. Income inequality is unfair when people with less economic resources are penalized with poor health because of their condition of poverty. Unjust societies are those that allow economic inequalities to affect human rights as the right to a standard of living that ensures the individuals and their family a healthy life. Income inequalities were studied in two aspects: a) the contextual effects of income inequality in oral health, and; b) trends in the difference in oral health among people with higher and lower income. The first part contains 4 original articles that studied the association and the contextual mechanism by which income inequality affects oral health. For this we used data of the oral health survey SSBrasil in 2002. The results showed that: a) the association between income inequality and oral health is stronger in relation to dental caries than other oral diseases (e.g. periodontal diseases and malocclusions); b) the effects of inequality of income are more strongly associated with oral diseases of a shorter latency: c) that the effects associated with dental caries affect equally the rich and the poor. The second part of this thesis contains two original articles that described the trends in oral health and in the use of dental services into groups of higher and lower income, in Brazil and Sweden. For this analysis data were obtained from the Brazilian oral health surveys for the year 2002, while for Sweden were used data from the "Swedish Level of Living Survey" for the years 1968, 1974, 1981, 1991 and 2000. Trends in the prevalence of edentulismo showed a reduction in absolute disparities in both countries, but in Brazil trends in the prevalence of "no missing tooth" increased. Reductions in disparities in edentulismo were associated with the presence of a significant initiak difference, while the increase in inequality for outcome "no missing tooth" was related to small inequalities in the begining of data collection. Trends in the use of dental services highlighted that the poorer have been using less the dental services in both countries and the difference remain saignificant over time. however, in Brazil and Sweden, these differences decrease slightly in the cohort of young people because there was a decline in the percentage of rich people who visit the dentist. Our data show that income inequalities in oral health and use of dental serviceshave historically favored the more affluent population even in highly egalitarian countires as Sweden.