Nucleotide synthesis is a conserved and highly regulated response to DNA damage, required for the efficient repair of DNA double strand breaks (DSB) by homologous recombination (HR). This is essential to prevent loss of heterozygosity (LOH) and maintain genome stability. The aim of this study was to identify new genes important for HR through roles in damage-induced nucleotide synthesis. A screen was performed to identify S. pombe gene deletion strains whose DSB sensitivity was suppressed by deleting the ribonucleotide reductase (RNR) inhibitor spd1⁺ to promote nucleotide synthesis. The screen identified a number of genes including ddb1⁺, cdt2⁺, rad3⁺ and csn1⁺ which have known roles in nucleotide synthesis. Distinct roles were identified for the DNA damage checkpoint in suppressing LOH. rad3⁺, rad26⁺, rad17⁺ and the rad9⁺, rad1⁺ and hus1⁺ genes encoding the 9-1-1 complex were required for DNA damage-induced nucleotide synthesis through Cdt2 induction to promote Spd1 degradation. The HR repair defect of rad3⁺ and rad26⁺ deletion strains was partially suppressed by spd1⁺ deletion. However, the HR repair defect of rad17⁺, rad9⁺, rad1⁺ and hus1⁺ deletion strains was not suppressed. An additional role was confirmed for Rad17 and the 9-1-1 complex in preventing LOH by promoting DSB resection. A role was identified for the Gcn5 histone acetyl transferase (HAT) protein module, consisting of Gcn5, Ngg1, Ada2 and Sgf29, in suppressing DSB sensitivity by promoting nucleotide synthesis. This was independent of Cdt2 or RNR protein levels. The Gcn5 HAT module was also found to regulate DSB repair pathway choice consistent with previous observations. Deletion of gcn5⁺, ngg1⁺ or ada2⁺ decreased HR and increased non-homologous end joining. Surprisingly, deletion of spd1⁺ in a gcn5∆, ngg1∆ or ada2∆ background also promoted HR. This predicts a role for nucleotide pools in regulating DSB repair pathway choice. Eleven other candidates showed repeatable suppression of DSB sensitivity following spd1⁺ deletion. However many of these candidates did not show reduced nucleotide levels. This suggests deleting spd1⁺ may also suppress DSB sensitivity by a different mechanism.

Compte tenu des attentes en termes de développements durables, de nouvelles solutions technologiques sont adoptées dans les bâtiments à basse consommation énergétique permettant de réduire considérablement les déperditions par ponts thermiques. Il s’agit des rupteurs thermiques, nouvelles jonctions entre porteurs verticaux et horizontaux constituées de matériaux innovants. Parallèlement à l’évolution des réglementations thermiques dans les bâtiments, la nouvelle définition de l’aléa sismique en France oblige les concepteurs à intégrer le cas de chargement sismique dans les dimensionnements de bâtiments dans une grande majorité du territoire métropolitain. Ces innovations technologiques nécessitent donc des études approfondies de leur comportement mécanique lors d’événements accidentels tels que les tremblements de terre. Au regard des enjeux sociétaux et économiques, il est d’une grande importance d’être capable d’apprécier la contribution de nouvelles solutions techniques à la vulnérabilité du bâti aux séismes. Pour cela, il est nécessaire de procéder à des analyses probabilistes pour la construction, par exemple de courbes de fragilité de structures sous sollicitations sismiques: structures étant composées ou non de rupteurs thermiques. L’objectif de ce travail est donc de proposer l’ensemble d’une méthodologie notamment les outils numériques, en termes de modèles mécaniques, susceptibles de répondre aux attentes de l’ingénierie dans la quantification de l’évolution des marges de résistance en intégrant différents types de rupteurs thermiques dans les bâtiments. Pour cela, différentes étapes, combinant modélisations numériques et expérimentations sont abordées afin d’élaborer un modèle numérique simplifié. Ce dernier doit être riche en termes de phénomènes mécaniques et efficace numériquement pour réaliser rapidement un nombre important de calculs nonlinéaires à l’échelle de bâtiment en tenant compte des aspects aléatoires. / Nowadays sustainable constructions imply an objective of energetic performances by reducing the level of thermal conduction. The thermal-break elements, an innovative technological element is under study in several countries in Europe. If the thermal benefits have already been proved, the mechanical effects of such a wall-slab connection in a building for the seismic risk have not been assessed. To evaluate the building seismic vulnerability modifications due to these thermal breaks, experimental and numerical developments have to be performed. An experimental campaign is proposed to evaluate the seismic ability of such structural elements and a simplified modelling is proposed aiming at developing numerical framework able to handle parametrical and probabilistic approaches for structural analysis. This model is also validated in dynamic case by using the Pseudodynamic testing.

This thesis examines the relationship between the distribution of structural breaks within a data sample and the estimated parameter of long memory. We use Monte Carlo simulations to generate data from processes with specific values of parameters. Subsequently we join the data with various shifts to mean and examine how the estimates of the parameters vary from their true values. We have discovered that the overestimate of the long memory parameter is higher when the breaks are clustered together. It further increases when the signs of the shifts are positively correlated within the clusters while negative correlation reduces the bias. Our findings enable the improvement of robustness of estimators against the presence structural breaks. Powered by TCPDF (www.tcpdf.org)

This thesis examines the implications of Euro on current account balances of countries using it. First, we summarize the main theoretical and empirical findings about determinants of current account deficits and possible implications of monetary union. Second, an empirical analysis of possible effects of single currency is presented. We employ time-specific fixed-effect estimator, corrected for possible endogeneity between fiscal policy stance and current account deficits. Our results do not support the hypothesis of any impact on current account balances as such, however we document positive role of single currency for gross saving and investment rates. We further examined eventual break in the relationship between fiscal and current account balances. Our regression indicates that the role of fiscal balance as determinant of current account transactions increased with introduction of single currency therefore implying less Ricardian behaviour of private sector in Eurozone. Keywords current account, monetary union, fiscal balance, shift Author's e-mail tomas.olesnanik@gmail.com Supervisor's e-mail jaromir.baxa@centrum.cz

<p>To ensure genomic integrity, dividing cells implement multiple checkpoint pathways during the course of the cell cycle. In response to DNA damage, cells may either halt the progression of the cycle (cell cycle arrest) or undergo apoptosis. This choice depends on the extent of damage and the cell's capacity for DNA repair. Cell cycle arrest induced by double-stranded DNA breaks relies on the activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell cycle effectors (e.g., Chk2 and p53) to inhibit cell cycle progression. ATM is an S/T-Q directed kinase that is critical for the cellular response to double-stranded DNA breaks. Following DNA damage, ATM is activated and recruited to sites of DNA damage by the MRN protein complex (Mre11-Rad50-Nbs1 proteins) where ATM phosphorylates multiple substrates to trigger a cell cycle arrest. In cancer cells, this regulation may be faulty and cell division may proceed even in the presence of damaged DNA. We show here that the RSK kinase, often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that RSK disrupts the binding of the MRN complex to DSB DNA. RSK can directly phosphorylate the Mre11 protein at Ser 676 both in vitro and in intact cells and can thereby inhibit loading of Mre11 onto DSB DNA. Accordingly, mutation of Ser 676 to Ala can reverse inhibition of the DSB response by RSK. Collectively, these data point to Mre11 as an important locus of RSK-mediated checkpoint inhibition acting upstream of ATM activation.</p><p>The phosphorylation of Mre11 on Ser 676 is antagonized by phosphatases. Here, we screened for phosphatases that target this site and identified PP5 as a candidate. This finding is consistent with the fact that PP5 is required for the ATM-mediated DNA damage response, indicating that PP5 may promote DSB-induced, ATM-dependent DNA damage response by targeting Mre11 upstream of ATM.</p> / Dissertation

Denna studies syfte var att undersöka lärare och lärarstudenters kunskaper och uppfattningar om fysisk aktivitet för ökad inlärning. Vilka möjligheter som skolor ges till fysisk aktivitet var också ett av studiens syfte. Studien har en kvalitativ forskningsansats genom att enkäter med slutna frågor har använts tillsammans med uppföljande semistrukturerade intervjuer som metod för att besvara studiens forskningsfrågor. Arton lärare har genomfört enkät via skolbesök och sex av dem har deltagit i uppföljande intervjuer. Dessutom har 246 respondenter besvarat enkäten via länk i sociala medier. Resultatet visar på att lärare och lärarstudenter har uppfattningen om att fysisk aktivitet är en viktig faktor för inlärning. Resultatet visar även att den fysiska aktiviteten har positiva bieffekter inte bara på hjärnans funktioner utan även på elevernas sociala utveckling. Respondenterna i studien är eniga om att fysisk aktivitet påverkar elevers inlärning vilket borde motivera ännu fler till att använda och utforska metoden.

O objetivo do trabalho foi analisar os efeitos da exportação de soja pelo Porto de Santarém (PA) no processo de formação de preços no mercado interno avaliando a integração tradicional entre os mercados no porto de Paranaguá (PR) e no município de Sorriso (MT). O período analisado foi de 2004 a 2013, com valores diários, dividido em dois subperíodos tomando como base para a divisão o potencial ponto de quebra estrutural no nível das diferenças relativas (percentuais) de preços entre Sorriso (MT) e Paranaguá (PR). O primeiro subperíodo considerou os preços de janeiro/04 a março/07, caracterizado pela ausência ou pela adaptação do mercado às novas oportunidades surgidas com a entrada em operação efetiva do porto de Santarém (PA). Já o segundo foi de março/07 a dezembro/13, considerando volumes mais expressivos e consolidados de exportações pelo porto paraense. Os testes de cointegração mostraram que as séries de preços se mantiveram cointegradas nos dois períodos analisados, porém o resultado interessante foi que as estimativas dos coeficientes da regressão da relação de equilíbrio de longo prazo apresentaram elasticidades de transmissão de preços estatisticamente diferentes. Considerando a modelagem VEC, foi observada pela análise de decomposição da variância que houve relativa redução da influência de Paranaguá (PR) nas mudanças de preços em Sorriso (MT) no segundo subperíodo, porém, sua importância permaneceu elevada. Já através da análise de impulsos, constatou-se que as mudanças de preços em Paranaguá (PR) são transmitidas integralmente (elasticidade unitária) a Sorriso (MT) no primeiro período e em torno de 80% no segundo, evidenciando que os preços na região mato-grossense se tornaram menos voláteis. O trabalho concluiu que, dado o processo transitório em termos logísticos observados no Brasil, principalmente no que diz respeito à finalização das obras na BR-163 e expansão da capacidade de escoamento por Santarém (PA), os preços de Sorriso (MT) ainda se mantém integrados ao porto de Paranaguá (PR). Existem, porém, várias evidências que apontam mudanças na formação de preço de Sorriso (MT) após a intensificação das exportações por Santarém (PA). / The objective was to analyze the effects of soybean exports through the Port of Santarem (PA) in the price formation process at the domestic market. It was evaluating the integration prices of two traditional markets: the port of Paranagua (PR) and Sorriso (MT). The study period was from 2004 to 2013, with daily values, divided into two sub-periods according to the potential structural break point at the level of relative prices differences (percentage) between Sorriso (MT) and Paranagua (PR). The first sub-period considered prices from January/04 to March/07, characterized by the absence or adaptation to new market opportunities from the effective beginning port of Santarem (PA) operation. The second was from March/07 to December/13, considering most significant and consolidated volumes exports by port of Santarem. The cointegration tests showed that the price series remained cointegrated in both periods analyzed, but an interesting result was the estimates regression coefficients of long-run equilibrium relationship showed transmission price elasticity statistically different. Considering the VEC model, was observed by analysis of variance decomposition that there was a relative reduction of the influence of Paranagua (PR) in price changes in Sorriso (MT) in the second sub-period, however, this importance remained high. By Pulse analysis, it was found that price changes in Paranaguá (PR) are transmitted in full (unit elasticity) to Sorriso (MT) in the first period and around 80% in the second, showing that prices at Mato Grosso region became less volatile. The work concluded that, given the transitional process in terms of logistics observed in Brazil, especially with regard to the completion of works on the BR-163 and expansion of the flow capacity by Santarem (PA), Sorriso (MT) prices still maintains integrated into the port of Paranagua (PR) . However, there are several evidences those changes in the formation of Sorriso (MT) price after the intensification of exports by Santarem (PA).

[pt] A legislação brasileira obriga trabalhadores a pouparem parte de seus rendimentos em contas do Fundo de Garantia por Tempo de Serviço (FGTS). Essas contas rendem juros abaixo dos de mercado e têm liquidez limitada. Essa dissertação propõe um modelo para a análise dos efeitos que o FGTS causa nos rendimentos do trabalhador. Para isso, dividimos os rendimentos do trabalhador em duas porções, o salário líquido e as verbas rescisórias, sobre as quais a introdução do FGTS pode exercer efeitos distintos. Do modelo, extraímos que o FGTS diminui o salário dos trabalhadores formais e que, proporcionalmente, maior será essa diminuição quanto maior for a probabilidade de demissão do empregado. Tal resultado advém do fato de que o empregador, ao provisionar para o pagamento das verbas rescisórias no futuro, se beneficia do diferencial entre a remuneração das contas-vinculadas e os juros vigentes. Já o efeito do FGTS sobre o rendimento do trabalhador, quando se leva em conta também a expectativa das verbas rescisórias, é ambíguo. Se, por um lado, há um prejuízo para o trabalhador proveniente da baixa remuneração do saldo de sua conta, por outro, sobre todas as verbas do FGTS - depósitos mensais, resgate e multa - não incidem quaisquer tributos, para débito do empregado ou empregador. Dessa maneira, o FGTS poderia aumentar o rendimento do trabalhador. Finalmente, utilizando as modificaçõees introduzidas pela Lei Complementar 110 de 2001, que celebrou o Acordo do FGTS, encontramos alguma evidência empírica que, de fato, o FGTS diminui salários dos trabalhadores formais. / [en] According to the Brazilian labor legislation, it is mandatory for workers to save part of their rent into Fundo de Garantia por Tempo de Serviço (FGTS) accounts. These accounts yield below-market interest rates and have a limited liquidity. This paper proposes a model to analyze the effects the FGTS legislation causes on the worker´s income. We divide the worker´s income in two portions, the liquid wages and severance payments, on which FGTS might produce different effects. From the model, we extract that the FGTS decreases formal worker´s wages and that, proportionally, the larger the probability of being fired, the larger the decrease. That result comes from the fact that, when provisioning for the severance payments in the future, the employer benefits from the difference between FGTS account returns and market interest rates. The effect of the FGTS on the worker´s total income, on the other hand, is ambiguous. The fact that all the FGTS savings and fines are exempt from taxes - for both the employer and the employee - might compensate the worker from the low returns of this mandatory savings, increasing the total worker´s income. Finally, using the 2001 FGTS Agreement changes in the legislation, we found some empirical evidence that the FGTS decreases wages of formal workers.

Por meio de ensaios em reatores estáticos (em equipamento de jarteste) foram estudados os efeitos da ruptura e da refloculação na sedimentação dos flocos, para diferentes velocidades de sedimentação. A água de estudo foi preparada com substâncias húmicas aquáticas (SHA) extraídas de água coletada do rio Itapanhaú - Bertioga/SP, resultando cor verdadeira de 100 uH, e coagulada com sulfato de alumínio e cloreto férrico. Para os dois coagulantes, foram realizadas as etapas de coagulação, mistura rápida, floculação, ruptura (G=50, 100 e 150/s) e refloculação (G=10 e 20/s). Na sedimentação sem a ocorrência de ruptura o cloreto férrico teve um desempenho superior ao sulfato de alumínio, principalmente nas velocidades de sedimentação mais altas. Isso se deve ao fato da floculação da água coagulada com o cloreto férrico ter gerado flocos de tamanho muito superior aos flocos gerados com o sulfato de alumínio. A ruptura, em poucos segundos, prejudicou a remoção dos flocos por sedimentação. Quanto maior o gradiente de velocidade na ruptura, maiores foram os valores da cor aparente remanescente, mesmo após a refloculação. A refloculação, mesmo nos primeiros minutos, diminuiu a cor aparente remanescente se comparada a logo após a ruptura. O menor gradiente de velocidade durante a refloculação testado (10/s) apresentou menores valores da cor aparente remanescente. Tanto na água coagulada com o sulfato de alumínio quanto na coagulada com o cloreto férrico a refloculação se comportou de modo semelhante, havendo recuperação na eficiência de remoção de cor sem, porém, atingir os resultados obtidos antes da ruptura. / By using the jar test equipment, the effects of breakage and reflocullation on the efficiency of floc sedimentation were studied, using different settling velocities. Water of study was prepared with aquatic humic substances (AHS) extracted from the Itapanhaú river (Bertioga, SP, Brazil), resulting a true color of 100 uH. Coagulation was performed by using aluminum sulfate and ferric chloride. For both coagulants, coagulation, flocculation, breakage (G=50, 100 and 150/s) and reflocculation (G=10 and 20/s) tests were carried out. In the sedimentation without the floc breakage occurrence the ferric chloride had a superior performance to aluminum sulphate, mainly in higher settling velocities. This occurred because of flocculation of the ferric chloride coagulated water have generated higher size flocs than that generated with aluminum sulphate. The breakage of flocs, in few seconds, hindered the settling removal. The higher the average shear rate in the break-up, the higher result the residual turbidity even after the reflocculation. The reflocculation, even in the first minutes, decreased the apparent color if compared to the results just after the break-up and sedimentation. The lower average share rate used during the reflocculation (10/s) resulted lower values of the remaining apparent color. During the flocculation, the aluminum sulphate coagulated water as well as in the ferric chloride coagulated water held in similar way, recovering the efficiency of removal of color without, however, reach the results gotten before the breakage.

Este trabalho apresenta um estudo prático da aplicação do conceito Leak Before Break (LBB), usualmente aplicado em usinas nucleares, em uma tubulação fabricada a partir de aço AISI 316LN soldada com a utilização de eletrodo revestido AISI 316L. O LBB é um critério fundamentado em análises de mecânica da fratura, que considera que um vazamento proveniente de uma trinca, presente em uma tubulação, possa ser detectado por sistemas de detecção de vazamento, antes que esta trinca alcance um tamanho crítico que implique na falha da tubulação. Na tubulação estudada, foram realizados ensaios mecânicos de tração e análises de Ramberg-Osgood, bem como ensaios de tenacidade à fratura para a obtenção da curva de resistência J-R do material. Os ensaios foram realizados considerando o metal base, a solda e a zona termicamente afetada (ZTA), nas temperaturas de operação de uma planta nuclear. Para as propriedades mecânicas encontradas nos ensaios foram realizadas análises de carga limite para se determinar o tamanho da trinca que cause um vazamento detectável e, também, o seu tamanho crítico que cause a falha por colapso plástico. Para o tamanho crítico de trinca encontrado na solda, região que apresentou a menor tenacidade, foram realizadas análises de Integral J e de módulo de rasgamento T, considerando falha por rasgamento dúctil. Os resultados demonstram um comportamento bem definido entre o metal base, a ZTA e a solda, onde o metal base apresenta um comportamento altamente tenaz, a solda um comportamento pouco tenaz e a ZTA apresentou propriedades mecânicas intermediárias entre o metal base e a solda. Utilizando o software PICEP, foram determinadas as curvas de taxa de vazamento versus tamanho de trinca e também o tamanho crítico da trinca, considerando análise por carga limite. Observou-se que, após certo tamanho de trinca, a taxa de vazamento do metal base é muito maior do que para a ZTA e solda, para um mesmo comprimento de trinca. Isso ocorre porque é esperado que a trinca cresça de forma mais arredondada no metal base, devido à sua maior tenacidade. O menor tamanho crítico de trinca foi encontrado para o metal base para trincas circunferenciais. Para as análises de Integral J realizadas na solda, foi demonstrado que a falha por rasgamento dúctil não ocorrerá nas condições consideradas e essa hipótese foi sedimentada pela análise de mecânica da fratura elasto-plástica (MFEL) com o uso do diagrama J/T. Dessa forma, pode-se concluir que a tubulação estudada estaria apta a ser empregada em um circuito primário de um reator que utilizasse o critério de LBB, nas condições de carregamento e geometria consideradas. Adicionalmente, concluiu-se que nessas condições apenas o modo de falha por colapso plástico é esperado. / This work presents a study of application of the Leak Before Break (LBB) concept, usually applied in nuclear power plants, in a pipe made from steel AISI type 316LN welded a coated electrode AISI type 316L. LBB concept is a criterion based on fracture mechanics analysis to show that a crack leak, present in a pipe, can be detected by leak detection systems, before this crack reaches a critical size that results in pipe fail. In the studied pipe, tensile tests and Ramberg-Osgood analyses were performed, as well as fracture toughness tests for obtaining the material resistance curve J-R. The tests were performed considering the base metal, weld and heat affected zone (HAZ), at the same operating temperatures of a nuclear power plant. For the mechanical properties found in these tests, load limit analyses were performed in order to determine the size of a crack which could cause a detectable leakage and the critical crack size, considering failure by plastic collapse. For the critical crack size found in the weld, which is the region that presented the lowest toughness, Integral J and tearing modulus T analyses were performed, considering failure by tearing instability. Results show a well-defined behavior between the base metal, HAZ and weld zones, where the base metal has a high toughness behavior, the weld has a low toughness behavior and the HAZ showed intermediate mechanical properties between the base metal and the weld. Using the PICEP software, the leak rate curves versus crack size and also the critical crack size were determined by considering load limit analysis. It was observed that after a certain crack size, the leak rate in base metal is much higher than for the HAZ and the weld, considering the same crack length. This occurs because in the base metal crack, it is expected that the crack grows in a more rounded form due to its higher toughness. The lowest critical crack size was found for the base metal presenting circumferential cracks. For the Integral J analyses performed in the weld, it was demonstrated that the failure by tearing instability will not occur under the considered conditions and this hypothesis was confirmed by elastic-plastic fracture mechanic (EPFM) analysis using the J/T diagram. Thereby, it can be concluded that it would be possible to apply the investigated pipe in a primary circuit of a reactor that utilizes the criterion LBB under the considered geometry and load conditions. Additionally, it was found that under these conditions, only the failure mode by plastic collapse is expected.