Meiotic recombination is both a fundamental biological process required for proper chromosomal segregation during meiosis and a fundamental genomic parameter that shapes major features of the genomic landscape. While there is strong evidence of fitness costs of low rates of recombination, the possible fitness costs of high rates of recombination are less defined. To determine whether a single lower fitness bound can explain the variation in recombination rate observed in human populations, we simulated the evolution of recombination rate as a quantitative trait using empirically-derived parameters. For our fitness function, we implemented a hyperbolic tangent curve with flexible parameters to capture a wide range of existing hypotheses. We found that both a lower and upper bound are necessary to explain the observed variation in recombination rate, and we describe a parameter space for an upper bound on recombination rate that produces results consistent with empirical observations.

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La recombinaison homologue est essentielle à la réparation des lésions de l’ADN ainsi qu’à la ségrégation correcte des chromosomes en méiose. Une étape importante de la recombinaison méiotique est la formation des crossovers (CO). Au cours de ma thèse, j’ai mis en évidence un nouveau mécanisme de régulation de la recombinaison méiotique. J'ai montré que les cycles d'activation et de désactivation des cullin-RING ligases (CRL) sont absolument nécessaires à la recombinaison méiotique. Les CRL sont activées par neddylation et désactivées par la deneddylation. De plus, elles peuvent aussi être inhibées par la séquestration via la protéine CAND1. Mon travail a démontré que ces trois niveaux de régulation des CRL jouent des rôles cruciaux dans la recombinaison homologue méiotique chez A. thaliana. J’ai montré qu'AXR1, un composant clé de la machinerie de neddylation, est nécessaire à la localisation correcte des CO méiotiques et à la recombinaison homologue somatique. J’ai aussi prouvé que le processus de deneddylation médié par CSN5A est nécessaire à la formation des CO. J'ai obtenu des données montrant que cette régulation de la localisation des CO agit à travers la régulation d’un complexe CRL4. Enfin, j’ai pu montrer que l'inhibiteur des CRL, CAND1, est requis pour la formation de plus de 90 % des CO. En utilisant des outils génétiques et cytologiques, j'ai montré que CAND1 agit probablement sur la régulation du biais inter-homologue. L’ensemble de ces données, met l’accent sur un nouveau mécanisme de la régulation de la recombinaison homologue, connectant pour la première fois la méiose et l’ubiquitination via les cullin-RING Ligases. / Homologous recombination is essential to all living organisms in order to repair DNA damages. In addition, a large majority of organisms use homologous recombination in meiosis to ensure proper chromosome segregation. A main step of meiotic recombination is crossover (CO) formation. During my PhD, I was able to highlight a new pathway controlling meiotic recombination. I showed that cycles of activation and deactivation of cullin-RING ligases (CRLs) are absolutely required for correct meiosis. CRLs are activated by neddylation, and deactivated by deneddylation. In addition, they can also be inhibited by sequestration by the CAND1 protein. My work demonstrated that these three levels of CRL regulation play crucial roles in meiotic homologous recombination in A. thaliana. First, I showed that AXR1, a key component of the neddylation machinery, is required for the correct localisation of meiotic COs and for somatic homologous recombination. Second, I showed that the deneddylation process mediated by CSN5A is also necessary for normal CO formation. I obtained evidence that this regulation of CO position is likely to be mediated by a CRL4 complex. Last, I could show that the CRL inhibitor, CAND1, is required for the formation of up to 90% of the COs. Using genetic and cytological tools, I showed that CAND1 probably acts on the regulation of the inter-homolog bias. Considering all these data, my work draws the attention to a new mechanism regulating meiotic homologous recombination, connecting for the first time meiosis to CRL-mediated ubiquitylation.

Made available in DSpace on 2015-04-22T22:02:06Z (GMT). No. of bitstreams: 1 DISSERTACAO VERA LUCIA.pdf: 1075794 bytes, checksum: 33b5d3d47e6787d71b4d7ed96ae837be (MD5) Previous issue date: 2010-04-23 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The direct methanol fuel cells are powers alternatives of energy to do support mainly the batteries. The scientific society come in last decades realizing experiments to overcome the technical barriers that block her commercialization. The effect of methanol crossover, from the anode to the cathode through the membrane, is a very serious problem that that severely reduces the cell voltage, current density, fuel utilization and hence the cell performance. The aim this work is better understand the effect of methanol crossover in this type of technology e try to minimize his negative effects improving the efficiency of fuel cell. To this were prepared electrocatalyts of Pt with an second metal so much in anode as us in cathode using three differents methods: alcohol reduction (MRA), ethylene glycol (MRE) and formic acid (MAF) as reducing agents. The electrodes were prepared following technical of the literature, membrane and electrode assemblies were prepared by pressing an anode and a cathode (Pt onto each side of a Nafion 117 membrane at a pressure of 500 kg cm−2 at 125 ◦C for 180 s. The physical characterization of the electrocatalysts was gone by energy dispersive analysis by X-rays and powder X-ray diffractometer pattern. The effect of methanol crossover was investigate through of electrochemical tests realized in unit cell with PtMo/C and PtRu/C, anode, PtCo/C and PtNi/C, cathode, electrocatalysts. The results showed that alcohol reduction method is better to prepared PtMo/C electrocatalyst, however, its catalytic activity is very lower for methanol oxidation that PtRu/C providing high rate of methanol crossover and reduces cell performance. The results found to the PtCo/C e PtNi/C electrocalysts prepared in this laboratory are approximate the commercials and showed efficient to oxygen reduction reaction and tolerant for methanol oxidation. Thus, we can to affirm that the minimize of effect of methanol crossover lead the increase in cell. / As células a combustível de metanol direto são fontes alternativas de energia para dar suporte principalmente às baterias. A sociedade científica vem nas últimas décadas realizando experimentos para superação das barreiras técnicas que impedem sua comercialização. O efeito crossover de metanol, do anodo para o cátodo através da membrana, é um problema muito sério que reduz severamente o potencial da célula, a densidade de corrente, a utilização de combustível e, portanto o desempenho da célula. O objetivo deste trabalho é compreender melhor o efeito crossover de metanol neste tipo de tecnologia e tentar minimizar os efeitos negativos melhorando a eficiência da célula a combustível. Para isso foram preparados eletrocatalisadores de Pt com a impregnação de um segundo metal tanto para o ânodo como para o cátodo usando três diferentes métodos: redução por álcool (MRA), etilenoglicol (MRE) e ácido fórmico (MAF) como agentes redutores. A fabricação dos eletrodos seguiu a técnica de pintura e o eletrólito empregado foi a membrana de Nafion 117. Para a caracterização física dos eletrocatalisadores modificados, amostras foram submetidos às técnicas de energia dispersiva de raio-x e difração de raios-X. O grau de crossover de metanol através da membrana foi investigado durante os testes eletroquímicos dos eletrodos modificados de PtMo/C, ânodo, e PtCo/C e PtNi/C, cátodo, por meio de curvas de polarização realizados na célula unitária. Os resultados mostraram que o método de redução por álcool é o melhor para impregnação da platina, porém a liga formada por este metal possui atividade catalítica ineficiente para oxidação do metanol o que conduz a elevado efeito crossover de metanol e consequentemente desempenho eletroquímico reduzido. Os eletrodos de PtCo/C e PtNi/C modificados tiveram resultados aproximados aos comerciais e mostram-se eficientes para redução do oxigênio e tolerantes a oxidação de metanol. Assim, podemos afirmar que minimizando os efeitos do crossover de metanol sob o desempenho eletroquímico podemos obter células de metanol direto eficientes e capazes de dar suporte às baterias .

Les études de pharmacoépidémiologie consistent à étudier l’effet de médicaments en vie réelle, et sont menées de plus en plus souvent sur bases de données médico-administratives. Ce sont principalement des études observationnelles, et sont donc soumises à des biais liés à des facteurs de confusion. Ces facteurs ne sont pas toujours recueillis dans les bases de données médico-administratives qui sont implémentées à d’autres fins que la recherche. Des plans expérimentaux self-controlled designs (où le patient est son propre témoin, et dont les principaux sont le case-crossover et le self-controlled case-series) permettent d’étudier l’effet transitoire d'expositions brèves sur des évènements à début brutal. Ils sont soumis à certaines conditions d’application. Ils ont la particularité de réaliser des comparaisons sur différentes périodes plutôt que sur différents groupes de patients, permettant ainsi de prendre en compte des facteurs de confusion, y compris non mesurés, et qui ne varient pas entre les périodes observées. Ces méthodes ont montré leur utilité pour pallier l’absence de randomisation, et leur utilisation est recommandée quand leurs conditions d’application sont remplies. Nous avons étudié la fréquence d’utilisation des self-controlled designs en pharmacoépidémiologie sur bases de données, les opportunités manquées d’utilisation et leur usage approprié au regard de leurs conditions d’application, ainsi que la qualité de l’information rapportée dans les articles. Nous avons montré que leur utilisation est rare, que 15% des articles correspondent à des situations d’opportunité où ces méthodes auraient pu être implémentées, que 34% des case-crossover et 13% des self-controlled case-series étaient appliqué de façon inapproprié, et que pour 16% des articles la méthode aurait pu être adaptée pour être valide. Un usage plus approprié permettrait de contribuer à l’investigation en pharmacoépidémiologie tout en bénéficiant des avantages de ces méthodes en particulier sur bases de données de santé. / Pharmacoepidemiology consists in the study of efficacy or safety of drugs in real life, with the use more and more frequently of medico-administrative databases. Study designs are generally observational, thus they are prone to confounding bias. Confounders are not systematically collected in databases, which are implemented for other purposes than research. Self-controlled designs (mainly represented by case-crossover and self-controlled case-series, and in which the patient acts as his own control), have been developed for the study of intermittent exposure with short-term effect on abrupt onset event. They require that validity assumptions being fulfilled. They consist in the comparison over different periods, rather than different groups of patients, thus allowing for confounding factors, also if not measured, which are invariant over observed periods. Such designs have been proved useful in observational studies in the absence of randomization, and their implementation is recommended in case of validity assumptions are fulfilled. We studied their frequency of use in pharmacoepidemiology in healthcare databases, missed opportunities for use, inappropriate use with respect to validity assumptions, as well as quality of reporting. We showed that self-controlled designs are rarely used, that opportunity for use was founds in 15% of articles where such methods could have been implemented, that 34% of case-crossover and 13% of self-controlled case series were inappropriately used, and that the method could have been adapted to be valid in 16% of articles. A more appropriate use of self-controlled designs could contribute to improve investigation in pharmacoepidemiology, while beneficiating from their advantages, especially in healthcare databases.

Meiosis is a specialized division of germ cells in sexually reproducing organisms, which is a fundamental process with key implications for evolution and biodiversity. In two consecutive rounds of cell division, meiosis I and meiosis II, a normal, diploid set of chromosome is halved. From diploid mother cells haploid gametes are generated to create genetic individual cells. This genetic uniqueness is obtained during prophase of meiosis I by essential meiotic processes in meiotic recombination, as double strand break (DSB) formation and repair, formation of crossovers (CO) and holiday junctions (HJs). Checkpoint mechanisms ensure a smooth progress of these events. Despite extensive research key mechanisms are still not understood. Based on an analysis of Massive Parallel Sequencing (MPS) data I could identify 2 genes, Mcmdc2 and Prr19, with high implication in meiotic recombination. In the absence of Mcmdc2 both sexes are infertile and meiocytes arrest at a stage equivalent to mid-­‐pachytene in wt. Investigations of the synaptonemal complex (SC) formation revealed severe defects suggesting a role for MCMDC2 in homology search. Moreover, MCMDC2 does not seem to be essential for DSB repair, as DSB markers of early and mid recombination nodules, like DMC1 and RPA, are decreased in oocytes. Nevertheless, late recombination nodules, which are positive for MutL homolog 1 (MLH1), do not form in both sexes. The absence of the asynapsis surveillance checkpoint mechanism in Hormad2 deficient ovaries with Mcmdc2 mutant background allowed survival of oocytes. This points into the direction that Mcmdc2 knock­out oocytes get eliminated after prophase I due to failed homologous synapsis. Interestingly, MCMDC2 contains a conserved helicase domain, like the MCM protein family members MCM8 and MCM9. I therefore hyphothesize that Mcmdc2 promotes homolgy search.

The overall aim of this master project was to create an audio record consisting of seven tracks that are both cohesive and very individual at the same time. The pieces are thought to showcase the diversity of my creative identity as a composer and music producer and will represent my individual way of composing and producing music freed from all external influences in the best way possible. This written part of the thesis is a documentation and critical reflection as well as investigation of the creation process: from sorting out the original material, writing, producing and arranging over to mixing and mastering. The observations I make are the essential part of investigating my own creative identity as a music producer and composer. In addition to the audio record and its critical reflection, this thesis will also state remarks on three time management methods I apply onto my creation process in order to observe their effects on my working routine. / Det övergripande målet för detta examensarbete var att skapa en ljudinspelning bestående av sju låtar som är både sammanhängande och mycket individuella samtidigt. Låtarna ska presentera mångfalden av min kreativa identitet som kompositör och musikproducent och ska representera mitt individuella sätt att komponera och producera musik befriad från alla yttre influenser på bästa möjliga sätt. Denna masteruppsats är en dokumentation och kritisk reflektion samt en undersökning av skapandeprocessen: från att sortera ur originalmaterialet, skriva, producera och arrangera till mixning och mastering. Observationerna jag gör är den väsentliga delen av att undersöka min egen kreativa identitet som musikproducent och kompositör. Förutom ljudinspelningen och dess kritiska reflektion kommer denna masteruppsats också att ge kommentarer om tre metoder för time management som jag använder under min skapandeprocess för att observera effekterna på min arbetsrutin.

Syftet med denna kvalitativa studie var att undersöka om och i så fall hur människor påverkas av sina privata liv på arbetsplatsen och hur de hanterar situationen. Vikten låg på anställdas upplevelser genom att tydliggöra deras känslor och uppfattningar. Urvalet delades in i två grupper, yrken som jobbar med barn i åldern 4-8 år och yrken som jobbar inom produktion och det genomfördes 8 semistrukturerade intervjuer. Datan analyserades med hjälp av en tematisk analys. Resultatet synliggjorde tre teman utifrån deltagarnas upplevelser. För det första, en upplevd förändring av humör, tankar och beteenden, för det andra följder som crossover och förändrad prestation, och för det tredje olika tillvägagångssätt med olika bakomliggande anledningar. Slutsatsen är att majoriteten upplevde FW-spillover och att alla intervjuade påverkades av vissa följder på arbetsplatsen samt hanterade situationen på olika sätt. Det fanns inga stora skillnader mellan grupperna eller kön. / The aim of this qualitative study was to investigate whether, and if so how, people are affected by their private lives in the workplace and how they cope with such situations. The emphasis was on employees' experiences by clarifying their feelings and perceptions. The sample was divided into two groups, professions that work with children aged 4-8 years and professions that work in production and 8 semi-structured interviews were conducted. The data was analyzed using thematic analysis. The results showed three themes based on participants' experiences. First, a perceived change in mood, thoughts and behaviors; second, consequences as crossover and changed performance; and third, various approaches with different underlying reasons. The conclusion was that the majority experienced FW spillover and that all interviewees were affected by certain consequences at the workplace and used special coping strategies. There were no significant differences between the groups or gender.

The present dissertation focuses on the synthesis of iron(II) complexes and the study of their SCO behavior. The equilibrium between the HS and the LS states gives to the SCO systems large potential applications for molecular electronics. However, today there is not a single molecular device from SCO compounds in the market. This is due to the fact that the SCO systems discovered up to now were unable (e.g. TLIESST « 300 K) for these applications. The aim of this thesis is to synthesize new SCO compounds with sustainable properties for applications. In the beginning of the thesis, [Fe(rac-22a))]2+∙2[BF4]- and [Fe(rac-22b)]2+∙2[BF4]- employing rigid hexadentate ligands were described. In contrast to the expectation, the N-methylation of the amines shifts the equilibrium towards the LS state. [Fe(rac-22b)2+∙2[BF4]- shows a T1/2 higher at 74 K and 52 K than the non methylated [Fe(rac-22a)2+∙2[BF4]- respectively in nitrobenzene and acetonitrile. The T1/2 are solvent-dependent for these complexes. After that, ligand series 9-R2-2-(6-R1-pyridin-2-yl)-1,10-phenanthroline 25b (R2 = Me), 25f (R2 = Ph), 25d (R2 = C(O)H), 25c (R1 = Ph), 25l (R1 = oxylphenyl-4-oxymethylene), 25m (R1 = oxymesitylene) and 25j (R1 = pyrol-1-yl) were synthesized. It was observed that the size of the substituent influences the SCO properties (T1/2). In addition, the influence of the counterion was shown with [Fe(25c)2]2+∙2[BF4]- and [Fe(25c)2]2+∙2[B(Ph)4]-. The B(Ph)4- conterions bring π∙∙∙π interactions in the molecular cell which shift the T1/2 parameter to a high temperature (200 K) compared to the complex with BF4- ions (175 K). Moreover the substituents R1 on the terminal position of the pyridine effect on T1/2 more than the substituents R2 on the terminal position of the phenanthroline. For example, [Fe(25f)]2+∙2[BF4]- (R1 = Ph) is a pure HS complex while the complex [Fe(25c)]2+∙2[BF4]- (R2 = Ph) is a SCO system (T1/2 = 175 K). The expansion of the coordination mode from N6 to N8 was investigated by the synthesis of the tetradentate ligands. This expansion shows an unexpected coordination mode, [Fe(25i)2]2+∙2[BF4]- (R2 = pyrazol-1-yl) forms a distorted square antiprism coordination geometry (HS iron(II)-complex) and does not show any Fe-N bond breaking over the application of the temperature as expected. / Die vorliegende Dissertation behandelt die Synthese von Eisen(II)-Komplexen und ihr spin crossover (SCO)-Verhalten. Das Gleichgewicht zwischen high-spin (HS)- und low-spin (LS)-Zustand verleiht den SCO-Systemen eine großes Anwendungspotential im Bereich der molekularen Elektronik. Dennoch existiert bis heute kein SCO-basiertes molekulares Bauteil auf dem Markt. Hauptgrund hierfür ist, dass die bislang bekannten SCO-Systeme keine hinreichenden Eigenschaften (z.B. TLIESST « 300 K) aufweisen. Das Ziel der vorliegenden Arbeit ist die Synthese neuer SCO-Verbindungen mit geeigneten Eigenschaften für die Anwendung. Zu Beginn der Arbeit werden die Komplexe [Fe(rac-22a)]2+∙2[BF4]– und [Fe(rac-22b)]2+ ∙2[BF4]– mit starren hexadentaten Liganden beschrieben. Entgegen der Erwartung verschiebt die N-Methylierung der Amine das Gleichgewicht in Richtung des LS-Zustandes. Verglichen mit dem nicht-methylierten Komplex Fe(rac-22b)]2+∙2[BF4]– zeigt Fe(rac-22a)]2+∙2[BF4]– eine höhere Übergangstemperatur T1/2, welche in Nitrobenzen 74 K und in Acetonitril 52 K beträgt. Für die Komplexe ist T1/2 lösungsmittelabhängig. Im Folgenden wurde die Ligandenserie 9-R2-2-(6-R1-pyridin-2-yl)-1,10-phenanthrolin mit den Vertretern 25b (R2= Me), 25f (R2 = Ph), 25d (R2 = C(O)H, 25c (R1 = Ph), 25l (R1 = oxyphenyl-4-oxymethylen), 25m (R1 = oxymesitylen) und 25j (R1 = pyrol-1-yl) hergestellt. Es wurde beobachtet, dass die Größe des Substituenten das SCO-Verhalten (T1/2) beeinflusst. Ergänzend wurde der Einfluss des Gegenions anhand der Komplexe [Fe(25c)]2+∙2[BF4]– und [Fe(25c)]2+∙2[B(Ph)4]– untersucht. Das Gegenion B(Ph)4– ermöglicht intra- und intermolekulare π···π-Wechselwirkungen in der Zelle, welche die Übergangstemperature T1/2 (200 K) gegenüber dem BF4–-Komplex (175 K) erhöhen. Des Weiteren beeinflussen die Substituenten R1 an der Pyridin-Einheit die ubergangskomplexes T1/2 stärker als die Substituenten R2 an der Phenanthrolin-Einheit. So ist [Fe(25f)]2+∙2[BF4]– (R1 = Ph) ein reiner HS-Komplex, während der Komplex [Fe(25c)]2+∙2[BF4]– (R2 = Ph) ein SCO-System ist (T1/2 = 175 K). Die Erhöhung der Koordinationszahl von N6 auf N8 wurde über die Synthese von tetradentaten Liganden untersucht. Diese Erhöhung führt zu einem unerwarteten Koordinationsmodus. So bildet [Fe(25i)]2+∙2[BF4]– (R2 = pyrazol-1-yl) eine quadratisch-antiprismatische Koordinationssphäre (HS Eisen(II)-Komplex) und zeigt, wie erwartet, über den untersuchten Temperaturbereich keine Fe–N-Bindungsspaltung.