Le modèle du triple code a été proposé par Dehaene (1992 ; Dehaene & Cohen, 2000)sur la base d’arguments neuro-anatomiques et neuropsychologiques pour rendre compte du traitement des nombres et des quantités. Le modèle postule l’existence de trois types de représentations correspondant chacune à un format de l’information numérique : une représentation analogique approximative préverbale, et deux représentations symboliques,l’une verbale, l’autre arabe. Si des études ont pu être mettre en évidence les caractéristiques de la dimension analogique tant chez le nouveau-né que chez l’adulte, la question de la« greffe » chez l’enfant des représentations symboliques sur la représentation analogique reste posée. L’objectif de cette thèse est de rechercher en suivant le développement comment s’effectue cette mise en relation. Nous avons élaboré un ensemble d’épreuves de comparaisons testant chacune une des représentations du modèle du triple code afin de déterminer chez des enfants dès 4 ans des indices de cette mise en relation. Si le lien entre dimensions analogique et symbolique est présent, un effet de rapport, « signature » de ce lien est attendu tant avec les comparaisons analogiques que symboliques. Cinq expérimentations ont été menées : avec des adultes, des enfants de 4 et 5 ans tout-venant, des enfants prématurés et des enfants atteints du syndrome de Down. Les résultats montrent que, dans toutes les populations, l’effet de rapport est présent avec la dimension analogique. Ensuite,entre 4 et 5 ans, avec l’acquisition du code verbal et indo-arabe la représentation symbolique change de nature. Enfin, les populations qui présentent des troubles du traitement du nombre sont affectées essentiellement sur la dimension verbale. Ces résultats sont discutés en regard de deux conceptions alternatives. / The triple code model was proposed by Dehaene (1992 ; Dehaene & Cohen, 2000) onthe basis of neuro anatomical and neuropsychological arguments in order to account for number and quantity processing. This model postulates the existence of three types of representations, a preverbal and approximate analogical representation, and an Arabic and verbal symbolic representations. If researchers have extendedly studied the characteristics of the analogic dimension in the new born as well as the grown up, the issue of the « graft » ofsymbolic representations for the child on analogical representation remains an open debate inthe current literature. The aim of this thesis is to explore how this connection operates with regard to development. We set out a series of comparing tests to try each representation of the triple code model in order to find signs of this connection in children as young as four years old. If a relation ship between the analogical and symbolical dimensions is found then, asignature of this connection is expected to be found in the analogical comparisons as well as in the symbolical. Five different experiments were carried out on adults and four-five year-oldchildren from all walks of life, including prematured and Down Syndrom children. The results show that in all the samples, a ratio effect is found in the analogical dimension. Then between four and five years old, the acquisition of the Indo Arabic and verbal code, the nature of the symbolic representation changes. Finally, populations showing troubles with numbers are mainly affected on the verbal dimension. These results are assessed with regard to two alternative conceptions.

An Euler tour of a hypergraph is a closed walk that traverses every edge exactly once; if a hypergraph admits such a walk, then it is called eulerian. Although this notion is one of the progenitors of graph theory --- dating back to the eighteenth century --- treatment of this subject has only begun on hypergraphs in the last decade. Other authors have produced results about rank-2 universal cycles and 1-overlap cycles, which are equivalent to our definition of Euler tours. In contrast, an Euler family is a collection of nontrivial closed walks that jointly traverse every edge of the hypergraph exactly once and cannot be concatenated simply. Since an Euler tour is an Euler family comprising a single walk, having an Euler family is a weaker attribute than being eulerian; we call a hypergraph quasi-eulerian if it admits an Euler family. Due to a result of Lovász, it can be much easier to determine that some classes of hypergraphs are quasi-eulerian, rather than eulerian; in this thesis, we present some techniques that allow us to make the leap from quasi-eulerian to eulerian. A triple system of order n and index λ (denoted TS(n,λ)) is a 3-uniform hypergraph in which every pair of vertices lies together in exactly λ edges. A Steiner triple system of order n is a TS(n,1). We first give a proof that every TS(n,λ) with λ ⩾ 2 is eulerian. Other authors have already shown that every such triple system is quasi-eulerian, so we modify an Euler family in order to show that an Euler tour must exist. We then give a proof that every Steiner triple system (barring the degenerate TS(3,1)) is eulerian. We achieve this by first constructing a near-Hamilton cycle out of some of the edges, then demonstrating that the hypergraph consisting of the remaining edges has a decomposition into closed walks in which each edge is traversed exactly once. In order to extend these results on triple systems, we define a type of hypergraph called an ℓ-covering k-hypergraph, a k-uniform hypergraph in which every ℓ-subset of the vertices lie together in at least one edge. We generalize the techniques used earlier on TS(n,λ) with λ ⩾ 2 and define interchanging cycles. Such cycles allow us to transform an Euler family into another Euler family, preferably of smaller cardinality. We first prove that all 2-covering 3-hypergraphs are eulerian by starting with an Euler family that has the minimum cardinality possible, then demonstrating that if there are two or more walks in the Euler family, then we can rework two or more of them into a single walk. We then use this result to prove by induction that, for k ⩾ 3, all (k-1)-covering k-hypergraphs are eulerian. We attempt to extend these results further to all ℓ-covering k-hypergraphs for ℓ ⩾ 2 and k ⩾ 3. Using the same induction technique as before, we only need to give a result for 2-covering k-hypergraphs. We are able to use Lovász's condition and some counting techniques to show that these are all quasi-eulerian. Finally, we give some constructive results on hypergraphs with small edge cuts. There has been analogous work by other authors on hypergraphs with small vertex cuts. We reduce the problem of finding an Euler tour in a hypergraph to finding an Euler tour in each of the connected components of the edge-deleted subhypergraph, then show how these individual Euler tours can be concatenated.

O objetivo deste trabalho é analisar o impacto dos Sistemas de Gestão Integrados (SGI) no desempenho organizacional sob a óptica do Triple Bottom Line (TBL), verificando se esta implementação auxilia a empresa a se tornar mais sustentável. A abordagem multi-método utilizada está dividida em três partes. A primeira compreende uma revisão sistemática da literatura, tendo como base a abordagem bibliométrica. A base de dados escolhida para a seleção dos artigos que compõem a amostra foi a ISI Web of Knowledge (Web of Science). As análises conduzidas sugerem lacunas na literatura a serem pesquisadas de modo a relacionar a integração dos sistemas de gestão como meio para as organizações tornarem-se mais sustentáveis, auxiliando assim na elaboração de um modelo teórico e das hipóteses de pesquisa. Os resultados parciais obtidos ressaltam a lacuna na literatura de estudos nessa área, principalmente que contemplem a dimensão social do Triple Bottom Line. Lacunas na literatura foram identificadas também no que se refere à análise do impacto da adoção dessas abordagens normativas no desempenho organizacional. A segunda etapa da metodologia é composta por estudos de casos múltiplos em empresas de diferentes setores e que tenham implantado sistemas de gestão de maneira integrada. Os resultados obtidos mostram que a certificação auxilia no desenvolvimento de ações sustentáveis, resultando em impactos econômicos, ambientais e sociais positivos. Nesta etapa, testou-se o modelo e as hipóteses levantadas na abordagem bibliométrica. A terceira etapa da metodologia é composta por análises estatísticas de dados secundários extraídos da revista Exame ?Maiores e Melhores\'. Os dados do ano de 2014 das empresas foram tratados por meio do software MINITAB 17 ®. Por meio do teste de mediana de mood, as amostras foram testadas e apresentaram diferenças estatisticamente significativas para o desempenho das empresas em diferentes setores. De maneira geral, as empresas com SGI apresentam melhor desempenho econômico do que as demais. Com a mesma base de dados, utilizando o modelo de equações estruturais e o software Smart PLS 2.0, criou-se um diagrama de caminhos analisando os constructos (SGI) com variáveis de desempenho (Endividamento, Lucratividade, Patrimônio, Crescimento e Retorno). O modelo de equações estruturais testado apresentou força para a relação entre SGI com Endividamento, Lucratividade, Patrimônio e Crescimento. As diferentes metodologias apresentadas contribuíram para responder a hipótese e afirmar com base na amostra deste trabalho que o SGI leva as empresas a terem melhor desempenho econômico, ambiental e social (baseado no TBL). / The objective of this study is to analyze the impact of the integration of management systems (SGI) into organizational performance based on a Triple Bottom Line perspective in order to ascertain if this implementation contributes for the company to become more sustainable. The multi-method approach utilized was divided into three phases. Firstly, a systematic literature review was elaborated using a bibliometric approach as ISI Web of Knowledge (Web of Science) was the database selected. These analyzes suggest gaps to be researched in order to connect the management systems as a way to become more sustainable, thereby assisting in the development of a theoretical model and research hypotheses. Partial results highlight the gap in the research literature in this area, especially those related to the social dimension of the Triple Bottom Line. Literature gaps were also identified in regards to the impact of adopting these normative approaches to organizational performance. The second step of the methodology consists of multiple case studies in companies from different sectors which have implemented integrated standards. Findings show that certification helps developing sustainable actions, resulting in economic, environmental and social positive impacts. In this phase, a model and assumptions extracted from the bibliometric approach were tested. Lastly, the third phase of the methodology consists of secondary statistical data analysis. The database was extracted from Exame \'Maiores e Melhores\' magazine. Company data for the year of 2014 were processed using MINITAB 17® software. Using Mood\'s median test, the samples were tested and showed statistically significant differences in the performance of companies in different sectors. In general, companies with integrated management systems have had better economic performance compared to other companies. In addition, using the same database, a diagram path analyzing the constructs (SGI) with performance variables (Debt, Profitability, Equity, Growth and Return) was created using the structural equation model and software Smart PLS 2.0. The tested structural equation model showed strong links to the relationship between SGI with Debt, Profitability, Growth and Equity. The different methodologies hereby presented contributed to answer the hypothesis and to affirm that, based on the samples utilized in this work, SGI lead companies to have better economic, environmental and social performance (based on TBL).

En raison de leur haute spécificité d’interaction, les protéines thérapeutiques sont de plus en plus utilisées et représentent une part majoritaire du marché pharmaceutique. Néanmoins, ces molécules sont fragiles et leur stabilité est une problématique majeure pour l'industrie pharmaceutique. La dégradation des protéines thérapeutiques peut survenir à chaque étape de leur cycle de vie : production, stockage, transport et administration au patient. Les modifications chimiques, l'exposition à des forces de cisaillement (fort débit fluidique), la température, le pH et les interactions avec les matériaux et/ou les interfaces gazeuses sont autant de facteurs qui peuvent nuire à la stabilité de ces protéines. De plus, l'utilisation croissante de dispositifs médicaux automatisés pour la manipulation et l'injection de protéines thérapeutiques augmente drastiquement le risque de dégradation. Dans cette thèse, nous étudions l’effet et le rôle de la triple interface solide/liquide/air sur l'agrégation des protéines. Ce phénomène se produit fréquemment dans les procédés de manipulation d’une solution de protéines thérapeutiques (cavitation, agitation…). Lors d’un mouillage intermittent, les interfaces air/liquide et liquide/solide se confondent en une seule et même interface appelée triple interface ou ligne triple. La ligne triple est une zone favorisant fortement l'agrégation des protéines. Notre étude, basée sur l’insuline, montre que la ligne triple cause une accumulation progressive de protéines qui déclenche, après une période de nucléation, leur agrégation, précisément à l’endroit de cette ligne triple. Nos résultats démontrent aussi que les forces de cisaillement, seules, n’entrainent pas l’agrégation de l’insuline. De plus, nous observons que la diminution de la tension superficielle (induite par l’ajout de polysorbates) d'une solution de protéines réduit le risque de formation d’agrégats. En conclusion de ce travail, nous proposons des recommandations pour la conception des dispositifs médicaux de préparation et d’administration de protéines thérapeutiques. / Due to the high specificity of their interactions, proteins are increasingly used in therapy and represent a vast majority of the global pharmaceutical market. Nevertheless, these molecules are fragile and therapeutic protein stability is a major concern in pharmaceutical industry. Protein degradation and aggregation can occur at every step during production, storage, transport and delivery. In this thesis, we interrogate the possible role of intermittent wetting in protein aggregation. Intermittent wetting frequently occurs in protocols involving pumping (cavitation), agitation, and liquid handling. During intermittent wetting, the air/liquid and liquid/solid interfaces meet at a triple line or triple interface, which is a local trigger for protein aggregation because it concentrates the mechanical action of the recessing fluid on the surface adsorbed proteins. We study the effect of surface intermittent wetting on insulin aggregation. Our results demonstrate that the triple interface line, where an air/water interface meets a hydrophobic surface, allows progressive protein accumulation, and finally triggers local insulin aggregation. We also show that shear stress, alone, is not detrimental for protein stability. Additionally, Additives such as polysorbates were tested, showing that the modification of the surface tension of a protein solution impacts its ability to form aggregates. Based on this work, we propose recommendations for the design of drug delivery and preparation devices in order to limit the risk of protein aggregation at the triple interface.

Consider distinct latin squares, L and M, of order n. Then the pair (T1, T2) where T1 = L \M and T2 = M \ L is called a latin bitrade. Furthermore T1 and T2 are referred to as latin trades, in which T2 is said to be a disjoint mate of T1 (and vice versa). Drápal (1991) showed that, under certain conditions, a partition of an equilateral triangle of side length n, where n is some integer, into smaller, integer length sided equilateral triangles gives rise to a latin trade within the latin square based on the addition table for the integers modulo n. A partial latin square P of order n is said to be completable if there exists a latin square L of order n such that P ⊆ L. If there is only one such possible latin square, L, of order n then P is said to be uniquely completable and P is called a defining set of L. Furthermore, if C is a uniquely completable partial latin square such that no proper subset of C is uniquely completable, C is said to be a critical set or a minimal defining set. These concepts, namely latin trades and defining sets in latin squares, are intimately connected by the following observation. If L is a latin square and D ⊆ L is a defining set, then D intersects all latin bitrades for which one mate is contained in L. In Part I of this thesis Dr´apal’s result is applied to investigate the structure of certain defining sets in latin squares. The results that are obtained are interesting in themselves; furthermore, the geometric approach to the problem yields additional appealing results. These geometric results are discussed in Chapters 3, 4, 5 and 6. They pertain to partitioning regions (polygons in R2 that satisfy certain obvious conditions) into equilateral, integer length sided, triangles, such that no point, in the region, is a corner of more than three distinct triangles. In Chapter 2 one of the main two theorems on defining sets is established, as is a method for using the above geometric results to prove the nonexistence of certain types of defining sets. In Part II of this thesis, intersection problems, for latin squares and Steiner triple systems, are considered. The seminal works, for problems of these types, are due to Lindner and Rosa (1975) and Fu (1980). A natural progression, from the established literature, for intersection problems between elements in a pair of latin squares or Steiner triple systems is to problems in which the intersection is composed of a number of disjoint configurations (isomorphic copies of some specified partial triple system). In this thesis solutions to two intersection problems for disjoint configurations are detailed. An m-flower, (F,F), is a partial triple system/configuration, such that: F = {{x, yi, zi} | {yi, zi} ∩ {yj , zj} = ∅, for 0 ≤ i, j ≤ m − 1, i 6= j}; and F = UX∈FX. The first such problem considered in this thesis asks for necessary and sufficient conditions for integers k and m ≥ 2 such that a pair of latin squares of order n exists that intersect precisely in k disjoint m-flowers. The necessary terminology, constructions, lemmas and proof for this result are contained in Chapters 7, 8 and 9. The second such problem considered in this thesis asks for necessary and sufficient conditions for integers k such that a pair of Steiner triple systems of order u exists that intersect precisely in k disjoint 2-flowers. This result relies on the solution to the latin square problem and an additional result from Chapter 9. The further constructions and lemmas used to prove this result are detailed in Chapter 10.

Die Metastasierung in den Knochen ist beim fortgeschrittenen Mammakarzinom ein häufiges Problem. Insbesondere die Mammakarzinome, welche keinen Östrogenrezeptor α (ERα), keinen Östrogenrezeptor ß (ERß) und keine Überexpression des human epidermal growth factor receptor 2 (Her2/neu) aufweisen, die so genannten triple-negativen Mammakarzinome (TNBCs), werden als sehr aggressiv angesehen und haben eine schlechte Prognose. Kürzlich konnten wir zeigen, dass die Invasion von Mammakarzinomzellen in Kokultur mit der Osteoblastenähnlichen Zelllinie MG63 stark anstieg. Unter Verwendung dieses Modells haben wir nun untersucht, inwieweit der ERß eine Rolle bei der Zellinvasion von TNBC-Zellen in vitro spielt. Die ERα-und ERß-Proteinexpression wurde mithilfe des Western Blot-Verfahrens untersucht. Die Zellinvasion wurde mithilfe der Migrationsrate von TNBC-Zellen durch eine künstliche Basalmembran in einer modifizierten Boyden-Kammer während Kokultur mit der Osteoblastenähnlichen Zelllinie MG63 quantifiziert. Die Migration wurde mithilfe eines Scratch-Assays untersucht. Die Wirkung der ERß-Agonisten auf die CXC motif chemokine receptor 4 (CXCR4)-Proteinexpression während der Kokultur mit der Osteoblastenähnlichen Zelllinie MG63 wurde mithilfe des Western Blot-Verfahrens analysiert. Die Proliferation ist mit dem almarBlue®assay untersucht worden. Die TNBC-Zellen HCC1806 und HCC1937 zeigten keine ERα-Proteinexpression, jedoch eine hohe ERß-Proteinexpression. Die Zellinvasion der TNBC-Zelllinien HCC1806 und HCC 1937 zeigte in Kokultur mit Osteoblastenähnlichen Zelllinie MG63 einen signifikanten Anstieg. Die Behandlung mit den selektiven ERß-Agonisten Liquiritigenin und ERB-41 reduzierte die Invasion der TNBC-Zellen durch eine künstliche Basalmembran als Antwort auf eine zelluläre Stimulation. Während der Kokultur stieg die CXCR4-Proteinexpression der TNBC- Zelllinien HCC1806 und HCC1937 signifikant an. Die Behandlung mit Liquiritigenin resultierte in einem signifikanten Abfall der CXCR4-Proteinexpression. Beide ERß-Agonisten zeigten keinen Effekt auf die Proliferation der TNBC-Zelllinien. Unsere Ergebnisse weisen darauf hin, dass der ERß eine wesentliche Rolle bei der Invasion von TNBC-Zellen spielt. Die knochengerichtete Invasion kann durch ERß-Agonisten inhibiert werden.

Die Verhältnisse der stabilen Isotope des Sauerstoffs (16O, 17O, 18O) und des Kohlenstoffs (12C, 13C) im biogenen Apatit des Zahn- und Knochenmaterials von Säugetieren lassen Rückschlüsse auf die Isotopie der entsprechenden Sauerstoff- und Kohlenstoffquellen zu. Die Isotopenverhältnisse dieser Quellen (z.B. Trinkwasser, Luftsauerstoff, Nahrung) sind an bestimmte Umwelt- und Klimabedingungen wie Temperatur, Luftfeuchtigkeit, CO2-Konzentration, Bioproduktivität, Art der Vegetation, Grad der Vegetationsdichte etc. geknüpft. Bestimmt man die Sauerstoff- und Kohlensoffisotopenverhältnisse in diagenetisch unalteriertem fossilem Säugetiermaterial können Aussagen über solche Klima- und Umweltparameter weit in die Erdgeschichte zurück getroffen werden. Darüber hinaus ist es möglich Informationen über Lebensweise und Verhalten der untersuchten Taxa, wie z.B. Wanderverhalten, Geburtensaisonalität, Trinkverhalten, Nahrungspräferenzen, Ressourcenteilung und Habitatnutzung zu erlangen. Seit dem Beginn der Forschungen auf diesem Gebiet in der 70er und 80er Jahren des 20. Jahrhunderts ist eine große Zahl von Studien erschienen, welche sich der Untersuchung der Sauerstoff- und Kohlenstoffisotopie (18O/16O, 13C/12C) des Zahn- und Knochenmaterials rezenter und fossiler (vorwiegend großer) Säugetiere zu diesen Zwecken widmen. Noch keine zwei Jahrzehnte ist es her, dass erkannt wurde, das troposphärischer Sauerstoff eine anomale 3-O-Isotopenzusammensetzung (17O/16O, 18O/16O) besitzt, die signifikant von fast allen anderen terrestrischen Materialien abweicht. Diese wird in Folge von nicht massenabhängiger Fraktionierung durch photochemische Prozesse in der Stratosphäre hervorgerufen und durch Gasaustausch in die Troposphäre übertragen. Die Magnitude dieser Sauerstoffisotopenanomalie ist eine Funktion der atmosphärischen CO2-Konzentration, sowie der globalen Bioproduktivität. Kann die 3-O-Isotopie des Luftsauerstoffs zu vergangenen Zeitpunkten in der Erdgeschichte rekonstruiert werden, lässt dies somit auch Rückschlüsse auf die entsprechende CO2-Konzentration bzw. die globale Bioproduktivität zu. Geologische Archive die dies ermöglichen sind jedoch kaum vorhanden. Da für Säugetiere der eingeatmete Luftsauerstoff neben Trinkwasser und freiem Wasser in der Nahrung zu den wichtigsten Sauerstoffquellen zählt, ist biogener Apatit rezenter und fossiler Säugetiere eines der wenigen möglichen Materialien die das Potential haben, ein solches Archiv darzustellen. Die vorliegende Arbeit untersucht die Variation der 3-O-Isotopenzusammensetzung im Bioapatit rezenter Säugetiere, sowie deren Bedeutung als neuen Proxy zur paläo-CO2-Rekonstruktion und als Indikator für diagenetisch alteriertes Skelettmaterial. Desweiteren werden zwischenartliche, innerartliche und intraindividuelle Variationen der Sauerstoff- und Kohlenstoffisotopie im Bioapatit rezenter Nagetiere untersucht um eine bessere Interpretationsgrundlage für entsprechende Analysedaten fossiler Vertreter dieser größten Ordnung der Säugetiere herzustellen. Kapitel 2 beschäftigt sich mit der Frage, ob die anomale Isotopensignatur troposphärischen Sauerstoffs als Indikator für diagenetische Alteration des Zahn- und Knochenmaterial von fossilen Säugern genutzt werden kann. Hierzu wurde die 3-O-Isotopie von Zahnschmelz, Dentin und in geringem Umfang auch Knochenmaterial von einzelnen Individuen känozoischer Nagetiere separat analysiert. Während alle Zahnschmelzproben eine deutliche Sauerstoffisotopenanomalie aufweisen, welche in einer Größenordnung liegt die für diagenetisch unalterierten Bioapatit kleiner Säugetiere zu erwarten wäre, zeigen alle Dentinproben eine deutlich niedrigere bis gar keine Anomalie, was auf Isotopenaustausch mit diagenetischen Fluiden hindeutet. In Kapitel 3 werden die Variationen der anomalen Isotopensignatur troposphärischen Sauerstoffs im Skelettmaterial von rezenten Säugetieren evaluiert. Dies geschieht anhand zweier voneinander unabhängiger Ansätze: 1. durch 3-O-Isotopenanalyse von rezentem Bioapatit und 2. durch ein detailliertes Massenbilanzmodell. Da der Anteil des veratmeten Luftsauerstoffs im Verhältnis zu den weiteren Sauerstoffquellen in erster Linie von der spezifischen metabolischen Rate abhängt, die weitgehend mit dem Körpergewicht skalierbar ist, wurden Arten aus einem möglichst großen Körpergewichtsbereich von wenigen g bis zu einigen tausend kg untersucht. Es zeigte sich, dass das anomale Isotopensignal mit sinkender Körpermasse zunimmt. Auf Basis der daraus gewonnenen Erkenntnisse wurde versucht die Magnitude der anomalen Sauerstoffisotopensignatur in der Troposphäre zu verschiedenen Zeitpunkten im Känozoikum durch 3-O-Isotopenanalyse von eozänem, oligozänem und miozänem Zahnschmelzmaterial von Nagetieren zu bestimmen um daraus Erkenntnisse über die entsprechenden CO2-Konzentrationen zu erhalten. Das theoretische Massenbilanzmodell stimmt gut mit den analytisch gewonnenen Daten überein, beide zeigen eine Vergrößerung der 3-O-Isotopenanomalie im Bioapatit mit sinkender Körpermasse. Die rekonstruierten CO2-Konzentrationen stimmen generell mit vorhandenen Daten diverser Proxies überein, jedoch erlaubt der assoziierte Fehler es nicht, CO2-Schwankungen im Bereich von wenigen 100 ppm aufzulösen. An der Grenze von Paläozän zu Eozän fand eine der einschneidendsten Umwelt- und Klimaveränderungen des Känozoikums statt, welche ihren Höhepunkt im sogenannten “Palaeocene Eocene Thermal Maximum” (PETM) hatte. Dieses war verbunden mit einer globalen negativen Kohlenstoffisotopenexkursion (CIE), deren Quelle bis heute kontrovers diskutiert wird. Kapitel 4 beschäftigt sich mit den Temperaturschwankungen und Veränderungen der CO2-Konzentration im Übergangsbereich dieser beiden Zeitalter. Dies geschieht anhand einer diesen Zeitabschnitt umspannenden Probenserie von Zahnschmelz der Säugetiergattung Ectocion aus dem Clarks Fork Basin (Wyoming, USA). Die rekonstruierten Temperaturschwankungen stimmen gut mit bereits vorhandenen Studien des 18O/16O Verhältnisses an biogenem Apatit aus diesem Zeitintervall überein. Die aus der 3-O-Isotopenzusammensetzung rekonstruierten CO2-Konzentration deuten darauf hin, dass auch während des Temperaturmaximums an der Paläozän-Eozän Grenze ein Wert von 1550 ppm nicht überschritten wurde, was auf die Dissoziierung von marinem Methanhydrat als Hauptquelle der CIE hinweist. Kapitel 5 untersucht die zwischenartlichen, innerartlichen und intraindividuellen Variationen der Karbonatsauerstoff-, Phosphatsauerstoff- und Kohlenstoffisotopie sieben verschiedener Nagetierarten anhand von Proben aus Eulengewöllen eines einzelnen Fundortes. Die Ergebnisse werden mit ähnlichen Studien an Großsäugern verglichen, und es werden Schlüsse zum Umgang mit Probenmaterial kleiner Säugetiere bei der Verwendung zur Paläoklimarekonstruktion mittels stabiler Isotope gezogen. Die Variabilität der Sauerstoff- und Kohlenstoffisotopie der untersuchten Zähne und Knochen ist nicht höher als die vieler Großsäuger, was die Relevanz der im Fossilbericht viel häufigeren Nagetiere für derartige Studien unterstützt. Jedoch sollte strikt darauf geachtet werden, dass auf Rezentmaterial basierende Bioapatit-Temperatur-Kalibrationen exakt auf dem gleichen Skelettelement beruhen welches auch als Fossilmaterial untersucht wird, da durch die unterschiedliche Mineralisierungsintervalle verschiedener Zähne und Knochen deutliche Unterschiede in den entsprechenden Isotopenzusammensetzungen, insbesondere in der des Sauerstoffs beobachtet werden konnten.

Triple negative breast cancer (TNBC) represents an aggressive subtype for which only chemotherapy is available. The RB1 tumour suppressor is frequently lost in human breast cancer, primarily in TNBC. Loss of RB1 deregulates the cell cycle and is thought to affect BC response to endocrine, radiation, and chemotherapy. However, the global chemosensitivity of Rb null BC is not known. Here I demonstrate that RB1-deficient TNBC cells are highly sensitive to radiation, and moderately sensitive to doxorubicin and methotrexate. However, loss of RB1 does not increase sensitivity to multiple other drugs. Moreover, a non-biased screen of 2 RB-deficient versus 2 RB-proficient lines with ~3500 drugs did not reveal any difference in sensitivity, but identified disulfiram as a potent drug, which compared favourably with current chemotherapeutics against TNBC. Disulfiram’s efficacy was validated against 13 human TNBC lines with an average IC50 of 300nM. IQGAP1 was identified as a potential target of disulfiram.

Triple negative breast cancer (TNBC) represents an aggressive subtype for which only chemotherapy is available. The RB1 tumour suppressor is frequently lost in human breast cancer, primarily in TNBC. Loss of RB1 deregulates the cell cycle and is thought to affect BC response to endocrine, radiation, and chemotherapy. However, the global chemosensitivity of Rb null BC is not known. Here I demonstrate that RB1-deficient TNBC cells are highly sensitive to radiation, and moderately sensitive to doxorubicin and methotrexate. However, loss of RB1 does not increase sensitivity to multiple other drugs. Moreover, a non-biased screen of 2 RB-deficient versus 2 RB-proficient lines with ~3500 drugs did not reveal any difference in sensitivity, but identified disulfiram as a potent drug, which compared favourably with current chemotherapeutics against TNBC. Disulfiram’s efficacy was validated against 13 human TNBC lines with an average IC50 of 300nM. IQGAP1 was identified as a potential target of disulfiram.

Behavioural and emotional problems in children have been linked with a number of deleterious effects for the child, their family and the community at large. Research has demonstrated that targeting parents through behavioural family interventions is an effective way of ameliorating the negative long term effects of early behaviour problems. A number of evidence-based interventions have been shown to be effective in reducing dysfunctional parenting practices and reducing the severity and intensity of behaviour problems however less than 10% of parents’ access parenting services and even fewer access evidence-based interventions. Some researchers now advocate that a population approach that emphasizes prevention rather than treatment and considers parenting in its broader ecological context is required to increase parental access to evidence-based parenting interventions and reduce population levels of disruptive behaviour problems. One important context that affects parenting is the workplace. Changing economic and demographic climates mean the majority of parents are now employed and must balance the competing demands of work and family commitments leading to increased levels of work and family conflict as functioning in one domain invariably effects functioning in the other. High levels of work and family conflict have been shown to increase psychological distress and dysfunctional parenting and are associated with a range of negative organisational outcomes such as increased turnover and absenteeism. Additionally, levels of work and family conflict are highest in parents of young children indicating that balancing work and parenting is particularly difficult at a point in a child’s life where there is greatest development plasticity. This thesis argues that one way to improve parents’ access to services and to reduce work and family conflict is to provide support to working parents in the form of a workplace parenting intervention. Such an intervention has the potential to ease the burden on working parents, increase parental access to evidence-based parenting support and reduce population levels of disruptive behaviour problems. This research comprises of a randomised controlled trial of Workplace Triple P, a variant of Triple P- Positive Parenting Program that is tailored to the specific needs of working parents. Two studies are presented. Study 1 examined the utility of a model that posits that the relationship between parental exposure to disruptive behaviour problems and occupational stress is mediated by family-work conflict. Data analyses supported the hypothesised model. The relationship between parental exposure to disruptive behaviour problems and occupational stress was fully mediated by family-work conflict. The results of this study provide a rationale for examining parenting in a workplace context by demonstrating that disruptive behaviour problems in the children of employees are related to higher levels of occupational stress and that reducing disruptive behaviour and family-work conflict should result in reductions in occupational stress. Study 2 built on the findings of Study 1 by evaluating the effectiveness of Workplace Triple P, a workplace parenting intervention that aims to assist parents to more effectively manage work and family demands. Using a sample of teachers balancing work and parenting commitments, a randomised controlled trial was conducted comparing Workplace Triple P to a waitlist control condition. Results indicated that participants who completed the Workplace Triple P intervention reported improvements in five key outcome areas: disruptive behaviour problems, parenting style and satisfaction, personal adjustment, work and family conflict and occupational wellbeing. Specifically, compared with participants in the waitlist control condition participants in the intervention condition reported that their child displayed lower numbers of disruptive behaviours and engaged in problem behaviour less frequently, that they themselves engaged less in verbose, over-reactive and lax parenting styles, that they felt more confident in dealing with a range of behaviour problems across a range of home and community settings and enjoyed parenting more. Participants in the intervention condition also reported lower levels of personal anxiety and depression. The intervention was also effective at improving work-related variables. Participants who completed the Workplace Triple P intervention reported lower levels of work-family conflict, family-work conflict and occupational stress, as well as reporting increased levels of occupational efficacy. No changes were reported for participants in the waitlist control condition. Participants in the intervention condition were reassessed at 4-months post intervention. Results indicated that all intervention gains were maintained. Together these studies contribute significantly to our understanding of work-family interface by providing insight into the mechanisms by which family life exerts an influence on occupational stress and by demonstrating that a workplace parenting intervention has the potential to improve functioning both family and occupational domains. The findings have significant implications for assisting parents more effectively manage work and family demands, for increasing parental access to services, and informing family-friendly policies and practices. Research, clinical and policy implications are discussed.