This thesis is concerned with the description of Yulu, a language which has not previously been subjected to modern linguistic analysis. Thus this thesis has two important aspects. Firstly, however remote a Language, its description adds a valuable contribution to linguistic knowledge. Secondly, its description tests the validity of linguistic theories in general and the theory used in this work in particular; as a linguist should not only be able to describe one universal but any number of parallel universes of speech-phenomena, namely different languages or dialects or even idiolects. Since the theory has been instrumental in describing the phonological system of Yulu in a consistent and adequate manner, it has once again proved its usefulness as a 'general' linguistic theory. The theory applied is that of Professor J. W. F. Mulder and is a sub-component of his 'Axiomatic Functionalist Linguistics'. This thesis is divided into three parts. Part I, dealing with the theoretical background, comprises twelve chapters, of which the first four provide an introduction to the basic principles of axiomatic functionalism. The remaining eight chapters introduce the theoretical notions of phonological theory and analysis as practised by axiomatic functionalists. Chapter I deals with the axiomatic functionalist principle of maintaining a strict distinction between the linguistic theory, linguistic descriptions, and the speech-phenomena and also with the basic criteria for evaluating both the linguistic theory and linguistic descriptions. Chapter II, dealing with the 'hypothetico-deductive Method', explains the philosophical principles underlying the axiomatic functionalist approach, Chapter III deals with 'The origin and scope of the theory'. Chapter IV explains the definition of 'language' as "a semiotic system with a 'double articulation'" (Mulder 1968). Chapter V covers 'The domain of phonology'; Chapter VI 'The notion "phoneme" as defined in axiomatic functionalism'; Chapter VIII 'The "abstract" approach to phonology'; Chapter VIII is concerned with 'Identity and distinctive function of a phoneme'; Chapter IX with 'Phonematics'; Chapter X with 'Neutralization' and 'archiphoneme'; Chapter XI with 'phonemes and their realizations (allophony)'; and Chapter XII with 'Phonotactics’. Part II, consists of one basic chapter, and is intended to give general background information about Yulu - the language whose phonological analysis we are concerned with in this thesis. Part III, dealing with the actual phonological analysis consists of five chapters. Chapter I deals with 'The phonemes of Yulu and their realizations'; Chapter II 'Neutralization' and 'Concord'; Chapter III 'Classificatory calculus in Yulu'; Chapter IV 'Phonotactic distribution in Yulu'; and Chapter V 'The tones of Yulu'.

This study investigates the dynamic of hope, specifically the Christian hope as it is expressed in the expectation of Christ's return. This belief has a number of implications, and affects the believer's attitude to God, man and the world, the relationship to past, present and future events, and the understanding of meaning and purpose in life. The examination of the belief in the parousia is primarily concerned with the question "why?" The question "Why the parousia?" is basic to this thesis, and the various sections reflect the different modes of answer. Section One examines the belief as it is portrayed in the New Testament by a brief review of its role and importance (with several examples), followed by a more interpretative analysis of the concept of the "God who comes," and the implications of the parousia parables. Section Two provides a wide-ranging summary of the different manifestations of the parousia hope in Christian history, along with some comment and analysis of its influences and consequences. Section Three illustrates the implications and effects of a strong parousia belief through an account of the nineteenth century Millerite movement. Section Four, enters into greater detail with an examination of the role that the parousia belief plays within a group that strongly affirms its importance: the Seventh-day Adventist Church. This examination is both on a personal and community level, and provides considerable material for understanding the factors influencing the adoption and consequent effects of this belief. Section Five reviews the interpretation of the parousia belief in modern theology and comments on the relative attitudes and outlooks that result both from an acceptance of the belief and from its denial. This leads on to a discussion of the concept of the "delay," a major influence on the parousia belief in contemporary thought. Section Six provides some synthesis of the various elements of the parousia belief, and also indicates other more abstract implications and components. The parousia belief is seen as a part of an ordered belief structure; then as a major belief in terms of hope, consummation, termination, purpose, vindication and so on. Yet finally it is the temporal aspect so frequently noted in other Sections that is of greatest importance, and the interaction of time and the parousia provides the conclusion -- the concept of a dynamic, time-related belief that activates the present out of the future.

No description available.

No description available.

No description available.

Grid computing is a field of research that combines many computers from distant locations to form one large computing resource. In order to be able to make use of the full potential of such a system there is a need to effectively manage resources on the Grid. There are numerous scheduling systems to perform this management for clusters of computers and a few scheduling systems for the Grid. These systems try for optimality (or close to optimality) with the goals of obtaining good throughput and minimizing job completion time. In this research, we examine issues that we believe have not been tackled in schedulers for the Grid. These issues revolve around the problem of coordinating resources belonging to separate administrative domains and scheduling in this context. In order for grid computing's vision of virtual organizations to be realized to its fullest extent, there is a need to implement and test schedulers that find resources and schedule tasks on them in a manner that is transparent to the user. These resources might be on a different administrative domain altogether and obtaining either resource or user account information on those resources might be difficult. Also, each organization might require their own policies and mechanisms to be enforced. Hence having a centralized scheduler is not feasible due to the pragmatics of the Grid. There are two basic aims to this thesis. The first aim is to design and implement a framework that takes administrative concerns into consideration during scheduling. The aim of the framework is to provide a lightweight, extensible, secure and scalable architecture under which multiple scheduling algorithms can be implemented. Second, we evaluate two prototypical of scheduling algorithms in the context of this framework. Scheduling algorithms are diverse and the applications are varied. Thus no single algorithm can obtain a good mapping for every application. We believe that different scheduling algorithms will be necessary to schedule different types of applications. In order to facilitate development of such algorithms, a framework in which it is easy to integrate other scheduling algorithms is necessary. The framework developed in this project is designed for such extensibility. / Master of Science

BMI1 est une protéine appartenant à la famille des polycombs impliquée dans la régulation épigénétique de la transcription. Il a été montré que cette protéine est essentielle à la régulation de la prolifération, de la sénescence et du métabolisme ainsi qu’à l’auto-Renouvellement des cellules souches hématopoïétiques et cancéreuses. Ce répresseur transcriptionnel au fort potentiel oncogénique est retrouvé surexprimé dans de nombreux types de cancer ; dans le cas de la Leucémie Myéloïde Chronique (LMC) le niveau d’expression de BMI1 augmente avec l’aggravation de la pathologie. Cependant, les voies de signalisation impliquées dans sa surexpression et le rôle qu’il joue au sein de cette maladie demeurent méconnus. En réprimant l’expression de BMI1 par ARN interférence nous avons pu mettre en évidence que ce polycomb était essentiel à la prolifération cellulaire ainsi qu’au potentiel clonogénique des cellules de LMC. Nous avons également démontré pour la première fois que BMI1 soutenait la croissance tumorale à travers la répression d’un processus autophagique délétère pour la cellule cancéreuse. Une approche transcriptomique nous a permis d’identifier la cible transcriptionnelle impliquée dans ce processus, la Cycline G2. Nous avons, pour finir, trouvé une molécule, via une approche bioinformatique, capable de réinduire l’expression de la Cycline G2 dans les cellules de LMC, l’alexidine dihydrochloride. Cette molécule induit une forte autophagie dans les cellules cancéreuses ainsi que de l’apoptose. Elle s’est également montrée capable de resensibiliser à l’imatinib (un inhibiteur de BCR-ABL) une lignée pourtant résistante. / The polycomb protein Bmi1 is a major epigenetic regulator. It has been shown that this protein is essential for the regulation of cell proliferation, senescence and metabolism but also self-Renewal of hematopoïetic and cancer stem cells. This transcriptional repressor, with a strong oncogenic potential, is overexpressed in many types of cancer. In case of Chronic Myeloid Leukemia (CML) the expression level of BMI1 is associated with worsening prognosis. However, the signaling pathways involved in its overexpression and its role in this disease remains unclear. By using RNAi to repress BMI1 expression we highlighted that this polycomb was essential for proliferation and clonogenicity of CML cells. We also demonstrated, for the first time, that BMI1 supported tumor growth through repression of deleterious cancer cell autophagy. A transcriptomic approach allowed us to identify a transcriptional target involved in this process: the Cyclin G2. Through a bioinformatic approach, we finally found a molecule capable of expression re-Induction of Cyclin G2 in CML cells : alexidine dihydrochloride. This molecule induced a high level of autophagy as well as apopotosis in cancer cells. It had also been able to re-Sensitize to imatinib a resistant cell line. In conclusion, our results revealed a new role for the polycomb BMI1 in supporting the CML pathology. Moreover, our work allowed the identification of two new approaches for therapeutically targeting this oncogene functions.

Aquest estudi s’ha realitzat en el marc del projecte titulat: “Ecotoxicidad, micotoxinas y degradación de nonilfenoles en lodos de depuradora y suelos tratados” finançat pel Ministeri d’educació i ciència amb número de referència: CTM2006-14163-C02-02, en col•laboració amb el Centre de Recerca i Aplicacions Forestals. La present Tesi Doctoral aborda els aspectes de determinació analítica de la presència de micotoxines en compost i l’evolució del nonilfenol en sòls. En concret, s’ha estudiat la presència de les aflatoxines G2, G1, B2, B1 i l’ocratoxina A, en tres mostres de compost produït en dues EDAR de Catalunya. Per això s’ha desenvolupat un mètode per a l’anàlisi simultània de les aflatoxines G2, G1, B2, B1 i l’ocratoxina A en compost. En primer lloc s’ha adaptat per aquestes mostres un procediment per HPLC-MS desenvolupat anteriorment en el nostre equip per a la determinació de les aflatoxines G2, G1, B2 i B1 aplicat en matrius de tipus alimentari, que s’ha estès a la determinació conjunta de les quatre aflatoxines i l’ocratoxina A. Aquest procediment ha mostrat problemes pel que fa a la recuperació i precisió dels resultats. Vistes les dificultats, s’ha desenvolupat un nou procediment per UHPLC-Fluorescència que permet una preparació de mostra més ràpida i simple, així com una millor sensibilitat. Aquest nou mètode ha estat validat i permet millorar el temps d’anàlisi i aconseguint eliminar l’etapa de purificació de mostra amb cartutxos de reblert polimèric, utilitzats en el mètode emprat com a punt de partida. Els dos procediment han permès demostrar que, en les mostres de compost estudiades no hi ha quantitats significatives de cap de les cinc micotoxines estudiades. Pel que fa al nonilfenol, s’ha estudiat la seva evolució temporal, durant 32 setmanes, en mostres de sòl, mescles de sòl amb torba i mescles de sòl amb compost, a les que s’ha addicionat nonilfenol a dos nivells de concentració. De la mateixa manera, s’ha estudiat la concentració de nonilfenol en els lixiviats de les mostres de sòl i de les mescles de sòl amb torba. Per això, s’ha posat al punt un procediment analític per HRGC-MS tant per a les mostres de sòls com per a les mostres aquoses dels lixiviats. S’ha posat de manifest la ràpida eliminació del nonilfenol en les tres mostres estudiades i que el nivell de pèrdua per lixiviació és molt baix. En els mateixos lixiviats s’ha determinat la matèria orgànica total i la seva toxicitat a través de l’assaig de Microtox. Les dues determinacions mostren que aquests lixiviats no presenten problemes ja que, complirien les exigències per poder ser abocats a les xarxes públiques de clavegueram. Finalment, es pot afirmar que l’ús del compost en agricultura és una pràctica segura, tant pel que fa a l’absència de les micotoxines, com per la ràpida degradació del nonilfenol en el sòl. / Este estudio se llevó a cabo en el marco del proyecto titulado, "Ecotoxicidad, micotoxinas y degradación de nonilfenoles en lodos de depuradora y suelos tratados" financiado por el Ministerio de educación y ciencia con número de referencia: CTM2006-14163-C02-01, en colaboración con el “Centre de Recerca i Aplicacions Forestals”. La presente Tesis Doctoral aborda los aspectos de determinación analítica de la presencia de micotoxinas en compost y la evolución del nonilfenol en suelos. En concreto, se ha estudiado la presencia de las aflatoxinas B1, B2, G1, G2 y la ocratoxina A en tres muestras de compost producido en dos EDAR de Catalunya. Por lo tanto, se ha desarrollado un método de análisis simultáneos de aflatoxinas B1, B2, G1, G2 y la ocratoxina A en compost. En primer lugar se ha adaptado a estas muestras un procedimiento por HPLC-MS desarrollado previamente en nuestro equipo para la determinación de aflatoxinas B1, B2, G1 y G2 aplicado a matrices alimentarias y se ha extendido a la determinación conjunta de las cuatro aflatoxinas y la ocratoxina A. Este procedimiento ha revelado problemas relativos a la recuperación y la precisión de los resultados. Vistas las dificultades, se ha desarrollado un nuevo procedimiento por UHPLC-fluorescencia que permite una rápida y simple preparación de muestra, así como una mejor sensibilidad. Este nuevo método ha sido validado y puede mejorar el tiempo de análisis y eliminar la etapa con cartuchos de purificación de muestra con cartuchos poliméricos, utilizados en el método de partida. Ambos procedimientos han permitido mostrar que, en las muestras del compost estudiado no hay cantidades significativas de ninguna de las cinco micotoxinas estudiadas. En cuanto a nonilfenol, se ha estudiado su evolución temporal, durante 32 semanas, en muestras de suelo, mezclas de suelo con turba y mezclas de suelo con compost, donde se ha adicionado nonilfenol en dos niveles de concentración. Asimismo, se ha estudiado la concentración del nonilfenol en las muestras de lixiviados de los suelos y mezclas de suelo con turba. Por lo tanto, se ha puesto a punto un procedimiento analítico por HRGC-MS tanto para muestras de suelo como para muestras de lixiviados acuosa. Se ha demostrado la rápida eliminación del nonilfenol en las tres muestras estudiadas y que el nivel de pérdidas por lixiviación es muy baja. Finalmente, en los mismos lixiviados se ha determinado la materia orgánica total y su toxicidad mediante el ensayo de Microtox. Ambas determinaciones muestran que estos lixiviados no presentan problemas ya que cumplen las exigencias para poder ser enviados a las redes de alcantarillado público. Se puede afirmar que el uso de compost en la agricultura es una práctica segura, tanto en cuanto a la ausencia de micotoxinas, como la degradación rápida de nonilfenol en el suelo. / This work was carried out in the framework of the project: “Ecotoxicidad, micotoxinas y degradación de nonilfenoles en lodos de depuradora y suelos tratados". This project was performed in collaboration with "Centre de Recerca i Aplicacions Forestals" and it was supported by “Ministerio de Educación y Ciencia” (contract number CTM2006-14163-C02-01). The present work is referred to the analytical determination of mycotoxins and the degradation of the nonylphenol in soils. Aflatoxins B1, B2, G1, G2 and ochratoxin A in three different samples of compost, produced in two sewage wastewater in Catalonia, has been studied. Also, a method for simultaneous determination of aflatoxins B1, B2, G1, G2 and ochratoxin A in compost has been developed. An analytical method using HPLC-MS has been developed to determinate aflatoxins B1, B2, G1, G2 and ochratoxin A in compost matrices. This method is based on a previous work performed in the Chromatographic Methods Lab at IQS to determinate aflatoxins B1, B2, G1, and G2 in food matrices. It is important to mention that the HPLC-MS method showed low recovery factors and precision problems in the compost samples analyzed. In a second set of experiments a new method using UHPLC-fluorescence has been designed to analyze aflatoxins B1, B2, G1, G2 and ochratoxin A in compost samples. UHPLC-fluorescence allowed quick and simple sample preparation, high sensitivity, short analysis time and the elimination of the purification step using polymeric cartridges. Finally, this method using UHPLC-fluorescence was validated for aflatoxins B1, B2, G1, G2 and ochratoxin A in compost matrices. It is important to mention that HPLC-MS and UHPLC-fluorescence methods verify the absence of mycotoxins in all compost samples analyzed. In a third set of experiments the temporal evolution of nonylphenol has been studied in soil samples, mixtures of soil with peat and soil with compost. The experiments were performed during 32 weeks in which nonylphenol was added at two levels of concentration in the samples at the beginning of the assay. Also, the concentration of nonylphenol in samples of leachates from soil and mixtures of soils with peat has been studied. An analytical method to analyze nonylphenol using HRGC-MS for soil samples and leachates has been designed. Rapid nonylphenol degradation in the three samples analyzed (soil, soil + compost and soil + peat) has been observed and very low nonylphenol levels in samples of leachates from soil and mixtures of soils have been obtained. Finally, Total Organic Carbon (TOC) of the leachates has been measured and also toxicity assays by Microtox test have been performed. Both techniques showed that the leachates analyzed can be dumped in the public sewerage networks because it’s low TOC and toxicity levels. To summarize, it can be assured that the use of compost in agriculture is a safe practice because the absence of mycotoxins and the rapid degradation of nonylphenol in soil.

No description available.

Quelques évidences suggèrent que Bcl-xL, un membre anti-apoptotique de la famille Bcl-2, possède également des fonctions au niveau du cycle cellulaire et de ses points-contrôle. Pour étudier la régulation et fonction de Bcl-xL au cours du cycle cellulaire, nous avons généré et exprimé dans des cellules humaines une série de mutants de phosphorylation incluant Thr41Ala, Ser43Ala, Thr47Ala, Ser49Ala, Ser56Ala, Ser62Ala et Thr115Ala. L'analyse de cette série de mutants révèle que les cellules exprimant Bcl-xL(Ser62Ala) sont moins stables au point-contrôle G2 du cycle cellulaire comparées aux cellules exprimant le type sauvage ou les autres mutants de phosphorylation incluant Thr41Ala, Ser43Ala, Thr47Ala, Ser56Ala et Thr115Ala. Les études de cinétiques de phosphorylation et de localisation de phospho-Bcl-xL(Ser62) dans des cellules synchronisées et suite à l'activation du point-contrôle en G2 médié par l'étoposide (VP16), nous indiquent que phospho-Bcl-xL(Ser62) migre dans les corps nucléolaires durant l'arrêt en G2 dans les cellules exposées au VP16. Une série d'expériences incluant des essais kinase in vitro, l'utilisation d'inhibiteurs pharmacologiques et d'ARN interférant, nous révèlent que Polo kinase 1 (PLK1) et MAPK9/JNK2 sont les protéines kinase impliquées dans la phosphorylation de Bcl-xL(Ser62), et pour son accumulation dans les corps nucléolaires pendant le point-contrôle en G2. Nos résultats indiquent que durant le point-contrôle en G2, phospho-Bcl-xL(Ser62) se lie et se co-localise avec CDK1(CDC2), le complexe cycline-kinase qui contrôle l'entrée en mitose. Nos résultats suggèrent que dans les corps nucléolaires, phospho-Bcl-xL(Ser62) stabilise l'arrêt en G2 en séquestrant CDK1(CDC2) pour retarder l'entrée en mitose. Ces résultats soulignent également que les dommages à l'ADN influencent la composition des corps nucléolaires, structure nucléaire qui émerge maintenant comme une composante importante de la réponse aux dommages à l'ADN. Dans une deuxième étude, nous décrivons que les cellules exprimant le mutant de phosphorylation Bcl-xL(Ser62Ala) sont également plus stables au point-contrôle de l'assemblage du fuseau de la chromatine (SAC) suite à une exposition au taxol, comparées aux cellules exprimant le type sauvage ou d'autres mutants de phosphorylation de Bcl-xL, incluant Thr41Ala, Ser43Ala, Thr47Ala, Ser56Ala. Cet effet est indépendent de la fonction anti-apoptotique de Bcl-xL. Bcl-xL(Ser62) est fortement phosphorylé par PLK1 et MAPK14/SAPKp38α à la prométaphase, la métaphase et à la frontière de l'anaphase, et déphosphorylé à la télophase et la cytokinèse. Phospho-Bcl-xL(Ser62) se trouve dans les centrosomes avec γ-tubuline, le long du fuseau mitotique avec la protéine moteure dynéine et dans le cytosol mitotique avec des composantes du SAC. Dans des cellules exposées au taxol, phospho-Bcl-xL(Ser62) se lie au complexe inhibiteur CDC20/MAD2/BUBR1/BUB3, alors que le mutant Bcl-xL(Ser62Ala) ne se lie pas à ce complexe. Ces résultats indiquent que durant le SAC, la phosphorylation de Bcl-xL(Ser62) accélère la résolution du SAC et l'entrée des cellules en anaphase. Des expériences bloquant l'expression de Bcl-xL révèlent ègalement un taux très élevé de cellules tétraploïdes et binuclées après un traitement au nocodazole, consistant avec une fonction de Bcl-xL durant la mitose et dans la stabilité génomique. Dans la troisième étude, l'analyse fonctionnelle de cette série de mutants de phosphorylation indique également que les cellules exprimant Bcl-xL(Ser49Ala) sont moins stables durant le point-contrôle G2 et entre en cytokinèse plus lentement dans des cellules exposées aux inhibiteurs de la polymérisation/dépolymérisation des tubulines, composantes des microtubules. Ces effets de Bcl-xL(Ser49Ala) sont indépendents de sa fonction anti-apoptotique. La phosphorylation de Bcl-xL(Ser49) est dynamique au cours du cycle cellulaire. Dans des cellules synchronisées, Bcl-xL(Ser49) est phosphorylé en phase S et G2, déphosphorylé à la prométaphase, la métaphase et à la frontière de l'anaphase, et re-phosphorylé durant la télophase et la cytokinèse. Au cours du point-contrôle G2 induit par les dommages à l'ADN, un pool important de phospho-Bcl-xL(Ser49) se trouve aux centrosomes, un site important pour la régulation de l'entrée en mitose. Durant la télophase et la cytokinèse, phospho-Bcl-xL(Ser49) se trouve le long des microtubules avec la protéine moteure dynéine et dans le cytosol mitotique. Finalement, nos résultats suggèrent que PLK3 est responsable de la phosphorylation de Bcl-xL(Ser49), une protéine kinase impliquée pour l'entrée des cellules en mitose et pour la progression de la mitose jusqu'à la division cellulaire. / Accumulating evidence suggest that Bcl-xL, an anti-apoptotic member of the Bcl-2 family, also functions in cell cycle progression and cell cycle checkpoints. To further understand Bcl-xL regulation and function in cell cycle progression, we first expressed a series of single-point Bcl-xL cDNA phospho-mutants, including Thr41Ala, Ser43Ala, Thr47Ala, Ser49Ala, Ser56Ala, Ser62Ala and Thr115Ala in human cancer cell lines and investigated their impact on cell cycle progression. Analysis of this series of phosphorylation mutants reveals that cells expressing Bcl-xL(Ser62Ala) mutant are less stable at the G2 checkpoint and enter mitosis more rapidly than cells expressing wild type Bcl-xL or Bcl-xL phosphorylation mutants, including Thr41Ala, Ser43Ala, Thr47Ala, Ser56Ala and Thr115Ala. Dynamic phosphorylation and location studies on phospho-Bcl-xL(Ser62) in unperturbed, synchronized cells and during DNA damage-induced G2 arrest revealed that phospho-Bcl-xL(Ser62) translocates into nucleolar structures in VP16-exposed cells during G2 arrest. Using in vitro kinase assays, pharmacological inhibitors and specific siRNAs experiments, we found that Polo kinase 1 and MAPK9/JNK2 are major protein kinases involved in Bcl-xL(Ser62) phosphorylation and accumulation into nucleolar structures during the G2 checkpoint. In nucleoli, phospho-Bcl-xL(Ser62) binds to and co-localizes with CDK1(CDC2), the key cyclin-dependent kinase required for entry into mitosis. These data indicate that, during G2 checkpoint, phospho-Bcl-xL(Ser62) stabilizes G2 arrest by timely trapping CDK1(CDC2) in nucleolar structures to slow mitotic entry. It also highlights that DNA damage affects the dynamic composition of the nucleolus, which now emerges as a key event in the DNA damage response. In a second study, we describe that cells expressing Bcl-xL(Ser62Ala) are also more stable at a sustained spindle-assembly checkpoint (SAC) after exposure to taxol than cells expressing wild-type Bcl-xL or other mutants, an effect that appears to be independent of its anti-apoptotic activity. Bcl-xL(Ser62) is strongly phosphorylated by PLK1 and MAPK14/SAPKp38α at prometaphase, metaphase and the anaphase boundary, while it is dephosphorylated at telophase and cytokinesis. Phospho-Bcl-xL(Ser62) localizes in centrosomes with γ-tubulin, along the mitotic spindle with dynein motor protein and in cytosol with SAC signaling components. In taxol-exposed cells, phospho-Bcl-xL(Ser62) binds to the CDC20/MAD2/BUBR1/BUB3 complex, while Bcl-xL(Ser62Ala) does not. The data indicate that during SAC, Bcl-xL(Ser62) phosphorylation accelerates SAC resolution and cell entry into anaphase, even in the presence of unattached or misaligned chromosomes. Silencing Bcl-xL expression also leads nocodazole-exposed cells to tetraploidy and binucleation, consistent with a Bcl-xL function in SAC and genomic stability. In the third study, the functional analysis of a Bcl-xL phosphorylation mutant series has revealed that cells expressing Bcl-xL(Ser49Ala) mutant are less stable at G2 checkpoint after DNA damage and enter cytokinesis much more slowly after microtubule poisoning than cells expressing wild-type Bcl-xL. These effects of Bcl-xL(Ser49Ala) mutant seem to be distinct from Bcl-xL function in apoptosis. Bcl-xL(Ser49) phosphorylation is cell cycle-dependent. In synchronized cells, phospho-Bcl-xL(Ser49) appears during the S phase and G2, whereas it disappears rapidly in early mitosis during prometaphase, metaphase and early anaphase, and re-appears during telophase and cytokinesis. During DNA damage-induced G2 arrest, an important pool of phospho-Bcl-xL(Ser49) accumulates in centrosomes which act as essential decision centers for progression from G2 to mitosis. During telophase/cytokinesis, phospho-Bcl-xL(Ser49) is found along microtubules and at midbody with dynein motor protein. In a series of in vitro kinase assays, specific small interfering RNA and pharmacological inhibition experiments, polo kinase 3 (PLK3) was implicated in Bcl-xL(Ser49) phosphorylation. These data indicate that during G2 checkpoint phospho-Bcl-xL(Ser49) is another downstream target of PLK3, acting to stabilize G2 arrest. Bcl-xL phosphorylation at Ser49 also correlates with essential PLK3 activity and function, enabling cytokinesis and mitotic exit.