Maintaining replication fork integrity is vital to preserve genomic stability and avoid cancer. Physical DNA damage and altered nucleotide or protein pools represent replication obstacles, generating replicative stress. Numerous cellular responses have evolved to ensure faithful DNA replication despite such challenges. Understanding those responses is essential to understand and prevent or treat replication-associated diseases, such as cancer. Re-priming is a mechanism to allow resumption of DNA synthesis past a fork-stalling lesion. This was recently suggested in yeast and explains the formation of gaps during DNA replication on damaged DNA. Using a combination of assays, we indicate the existence of re-priming also in human cells following UV irradiation. The gap left behind a re-primed fork must be stabilised to avoid replication-associated collapse. Our results show that the checkpoint signalling protein CHK1 is dispensable for stabilisation of replication forks after UV irradiation, despite its role in replication fork progression on UV-damaged DNA. It is not known what proteins are necessary for collapse of an unsealed gap or a stalled fork. We exclude one, previously suggested, endonuclease from this mechanism in UV-irradiated human fibroblasts. We also show that focus formation of repair protein RAD51 is not necessarily associated with cellular sensitivity to agents inducing replicative stress, in rad51d CHO mutant cells. Multiple factors are required for replication fork stability, also under unperturbed conditions. We identify the histone methyltransferase SET8 as an important player in the maintenance of replication fork stability. SET8 is required for replication fork progression, and depletion of SET8 led to the formation of replication-associated DNA damage. In summary, our results increase the knowledge about mechanisms and signalling at replication forks in unperturbed cells and after induction of replicative stress. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Submitted.

Nous avons étudié, le statut de la voie p53/p14arf dans l'adénocarcinome bronchique muté pour EGFR ou KRAS ainsi que l'impact du complexe NTS/NTSR1 sur la progression tumorale et la survie du cancer bronchique non à petites cellules. Dans une série de 96 patients, les mutations de TP53, KRAS et EGFR ont été détectées dans respectivement 45.2%, 15.8% et 34.4% des cas. La diminution de l'expression de p14arf a été observée dans 57.1% des cas. Le déficit de la voie p53/p14arf a été observé dans 83,3% et 76.9% des tumeurs mutées pour EGFR et KRAS respectivement, ce qui suggère que les altérations de la voie p53/p14arf sont des événements communs dans ces tumeurs mais pas systématiques. L'expression du NTSR1 a été mise en évidence par immunohistochimie dans 60.4% des adénocarcinomes de stades I (n= 139); 47% de stade II (n = 74) et 50% de stade III (n = 133). A l'analyse univariée et multivariée, l'expression du NTSR1, était associée significativement à un mauvais pronostic en termes de survie globale (p = 0,0081 pour les stade I, p = 0.0087 pour les stade II-III). Par contre, l'expression de NTSR1 n'était pas associée avec une différence significative en terme de survie globale pour le carcinome épidermoïde ou le carcinome à grandes cellules. Les études, in vivo et in vitro, ont montré que le complexe NTS/NTSR1 favorise la progression tumorale en augmentant l'expression HER2 et HER3 et la transactivation d' EGFR, HER2 et HER3 par l'activation de MMP1 et la libération de HB-EGF et de NRG1. Ces résultats suggèrent que le complexe NTS/NTSR1 contribue activement à l'agressivité et à la progression tumorale bronchique

This study seeks to answer the question of what significant barriers are present for women managers in the organisational structure of hotels in Australia and New Zealand that impedes their progress to top management positions. Women seem to be under-represented at senior management levels in hotel companies and this exploratory research endeavoured to find out why this is the case.The research was carried out in conjunction with a major international group represented by more than 30 hotels in both countries. It consisted of an online survey sent to the hotel group's female supervisors and managers and a series of 18 follow up interviews. There was a high response rate to the survey and from respondents wishing to be interviewed. Issues arising from the research included organisational culture, the Old Boy Network, geographical mobility, role models, and the pathway to General Manager.The research concluded that for female managers aspiring to proceed up the career ladder in Australian or New Zealand hotels, it would be difficult for them to combine family life and career in the same manner as their male colleagues. There were also negative aspects of hotel culture and organisational practices that disadvantaged women at various stages of their career life cycle. If hotels companies wish to retain more women, they need to review whether their organisations consist of 'opportunity 'structures' (Scully 2003) or 'inequality regimes' (Acker 2006) for women.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Feb 19, 2009). Includes bibliographical references (p. 114-124).

Thesis (Ph. D.)--University of Virginia, 2009. / Includes bibliographical references. Also available online through Digital Dissertations.

Source: Masters Abstracts International, Volume: 46-05, page: 2668. Adviser: Wenyaw Chan. Includes bibliographical references.

Thesis--University of Oklahoma. / Bibliography: leaves 57-60.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The aim of the present study was to examine the role of oxytocin (OT) on the control of oocyte meiotic resumption in the events that involves progesterone (P4) and prostaglandins (PGs). Oocytes were co-cultured with follicular hemisections for 15 h to determine the effect of different doses of OT or atosiban (ATO; oxytocin receptor antagonist) on the oocyte meiotic resumption. In another experiment, we examine the effect of P4, OT and PGs interaction on the regulatory cascade of the induction of oocyte meiotic resumption. Oxytocin in the concentration of 1 μM was effective in inducing the resumption of meiosis of oocytes co-cultured with follicular cells (84.0%), not differing statistically from the positive control group (74.4%). Similarly, atosiban inhibited the positive effect of OT on meiotic resumption in a dose-dependent manner, in which the metaphase I (MI) rate was only 27.6% in the presence of 10 μM ATO, not differing from the negative control group (25.5%). The possible toxic effect of ATO was tested in a 15 or 24 h-cumulus-oocyte complex culture system. In the third experiment, we demonstrated that P4 was able to induce the oocyte meiotic resumption, which was inhibited by ATO. However, the positive effect of OT was not blocked by mifepristone (P4 antagonist) but was inhibited by indometacine (a non-selective PTGS2 inhibitor). Collectively, these results evidenced that P4 is upstream to OT and PGs are required for the positive effect of OT to induce oocyte meiotic resumption. In conclusion, our results evince that together with Ang II, already proved by our group as involved in oocyte meiotic resumption, P4, OT and PGs are sequential steps in the hormonal cascade that culminates with resumption of meiosis in cattle. / O objetivo do presente estudo foi examinar o papel da ocitocina (OT) no controle da retomada meiótica de oócitos bovinos, além da interação desse peptídeo com a progesterona (P4) e prostaglandinas (PGs) neste evento fisiológico. Nesse estudo, verificamos a interação da P4, OT e PGs na cascata de indução de retomada meiótica do oócito. Oócitos foram co-cultivados com metades foliculares por 15 h para determinar o efeito de diferentes doses de OT ou atosiban (ATO; antagonista do receptor de ocitocina) no reinício da maturação meiótica A OT na concentração de 1 μM foi eficaz em induzir a retomada da meiose de oócitos co-cultivados com células foliculares (84,0%), não diferindo estatisticamente do grupo controle positivo (74,4%). O ATO inibiu o efeito positivo da OT sobre o reinício da meiose de uma forma dose-dependente onde a porcentagem de oócitos que atingiu o estádio de metáfase I (MI), foi apenas 27,6% na presença de 10 μM de ATO, não diferindo do grupo controle negativo (25,5%). Para confirmar que este efeito não era resultante de toxicidade ocasionada pelo ATO, foi realizado um experimento onde o efeito tóxico do ATO foi testado em um cultivo durante 15 e 24 horas, e foi possível observar que ele não apresenta efeitos tóxicos aos oócitos em cultivo, permitindo a retomada da meiose. Foi demonstrado também que a P4 foi capaz de induzir a retomada da meiose do oócito bovino ao qual foi inibida pelo ATO. No entanto, o efeito positivo da OT não foi bloqueado pela mifepristona (antagonista P4), mas foi inibida por indometacina (inibidor não-seletivo de PTGS2). Coletivamente, estes resultados evidenciam que P4 requer OT e esta requer PGs para que oócitos bovinos reiniciem a meiose. Em conclusão, nossos resultados demonstram que, P4, OT e PGs são passos seqüenciais da cascata hormonal que culmina com a retomada da meiose em bovinos.

Ämnesområdet för den här studien är matematik, specificerat geometri.Studien undersöker hur van Hiele's teori kan användas för att utveckla eleversförståelse inom geometri, eftersom elever tenderar att ha problem med attbenämna geometriska figurer. Studiens syfte är därför att undersöka eleverskunskapsutveckling gällande geometriska figurer utifrån van Hiele´s teori. Detsker genom den kvalitativa metoden deltagande observation. Insamlat datamaterialanalyseras genom användning av ett analysschema. Den vetenskapliga teorin somligger till grund för studien är det sociokulturella perspektiv, eftersom bådedet sociokulturella perspektivet och van Hiele’s teori belyser språketsbetydelse för inlärning. Resultatet påvisar att observationsgruppen somundervisades utifrån van Hiele gick från en ospecifik och konkret uppfattningtill att vara förtrogna med ingående geometriska figurer och deras explicitaegenskaper. Eleverna gick från att sortera informellt till abstrakt, till attbörja förstå grunden till figurers definitioner. Den andra observationsgruppenbefann sig på en abstrakt nivå under hela progressionen, behandlade fleraegenskaper samtidigt och sortering skedde fragmentariskt utifrån olika axiom.Utifrån studiens resultat blir min slutsats att, den visuella början och en stegvisprogression inte bör exkluderas i geometriundervisning. / The subject   area for this study is mathematics, specified geometry. The study examine how   van Hiele's theory can be used to develop students' geometric understanding.   Therefore, the purpose of this study was to investigate pupils' knowledge   development regarding geometric figures based on Van Hiele's theory. The   qualitative method participation observation was conducted. Collected data   was analyzed using an analysis chart. The scientific theory underlying the   study is the socio-cultural perspective since both the socio-cultural   perspective and van Hiele’s theory highlight the importance of language for   learning. The result shows that the observation group taught by Van Hiele   went from an inaccurate and concrete understanding to being familiar with   in-depth geometric figures and their explicit characteristics. They went from   sorting informally to abstract, to beginning to understand the reason for   figures definitions. Compared to the second observation group, which was at   an abstract level throughout the progression, several characteristics were   treated at the same time and sorting occurred fragmentarily based on   different axioms. Based on the results of the study, I conclude that the   visual beginning and a gradual progression should not be excluded while   teaching geometry.