Les parasites Theileria (Theileria. annulata and T. parva) sont des protozoaires intracellulaires qui font partie du phylum des Apicomplexa. Theileria infecte les leucocytes bovins et les transforment en cellules cancéreuses, induisant un genre de leucémie chez le bovin et conduisant à la mort de l’animal. Les cellules infectées par Theileria démontrent certaines caractéristiques de cellules cancéreuses telles qu’une importante capacité d’invasion et de migration cellulaire. Cependant, le traitement de cellules infectées avec une drogue Theiléricide spécifique (buparvaquone) permet l'élimination du parasite et la réversion du phénotype transformé. De plus, la virulence peut être atténuée par passages répétés sur culture cellulaire. La similitude entre les cellules transformées par Theileria et la leucémie humaine fait de Theileria un modèle très important permettant l’étude des mécanismes cellulaires induits par le parasite au cours de la transformation de la cellule hôte. Mon laboratoire d’accueil a publié une augmentation significative de TGF-β2 dans les cellules virulentes et a constaté que parmi les 1158 cibles de TGF-β, 68 gènes ont été reconnus d'avoir modifié leurs niveaux de transcription concomitante avec l'atténuation. Dans ce travail de thèse, nous avons étudié les voies de signalisations impliquées dans la régulation de l’adhésion et l’invasion des cellules infectées par Theileria. Nous nous sommes particulièrement intéressés à l’étude de la voie de signalisation TGF-β2 et ses effecteurs. Nos résultats montrent que l’activation de la voie de signalisation de TGF-β2 par Theileria entraîne une augmentation de l’invasion et de l’adhérence des cellules transformées par deux mécanismes différents, soit en activant la voie de signalisation PGE2/EP4/cAMP/PKA/EPAC/CREB, soit en stimulant la voie GRB2/PI3-K/AP-1. Les macrophages atténués infectés par Theileria sont plus stressés oxydativement ce qui diminue leur adhérence et leur invasion cellulaire. Ceci nous a amené à étudier en collaboration avec un autre doctorant (Mehdi Metheni) le rôle de TGF-β2 dans la régulation du stress oxydatif dans les macrophages infectés par Theileria. Nos données montrent que les niveaux élevés de TGF-β2 stimule l’expression de la catalase, une enzyme anti-oxydante qui convertit le H2O2 en H2O et la baisse de H2O2 favorise la virulence en augmentant l’invasion et l’adhésion des cellules infectées par Theileria (résultats supplémentaires). De plus, nous avons examiné le statut de stress oxydatif et le type de glycolyse utilisé par les cellules infectées par Theileria. Les cellules transformées par Theileria agissent comme des cellules cancéreuses, elles consomment énormément de glucose. La protéine BAD joue un rôle important dans l’apoptose ainsi que dans la voie de glycolyse. Son activité est régulée par phosphorylation en réponse à des facteurs de croissance et de survie. BAD peut être phosphorylée par la PKA sur le résidu sérine 155. Durant ma thèse, nous avons examiné le rôle de la phosphorylation de BAD par la PKA dans la régulation du métabolisme cellulaire des macrophages infectés par Theileria. Nos résultats montrent que l’abolition de la phosphorylation de BAD par la PKA dissocie le complexe mitochondrial formé entre BAD et HK2, ce qui induit l’ubiquitynation et la dégradation de HK2 par le protéasome. La baisse de HK2 stimule la voie de phosphorylation oxydative en faveur de l’effet Warburg dans les cellules infectées par Theileria. / Theileria parasites (Theileria. annulata and T. parva) are intracellular protozoa and members of the phylum Apicomplexa. Theileria parasites are the only eukaryotes that possess the property of being able to transform another eukaryote, their leukocyte host cells. Transformed leukocytes show many characteristics of tumour cells such as heightened invasive capacity; however the tumour-like phenotype can be totally reversed upon drug induced parasite death and attenuated by multiple in vitro passages. Such multiple-passaged attenuated lines are used as live vaccines against tropical theileriosis. The similarities in tumour hyper-invasiveness between Theileria-transformed leukcocytes and human lymphomas imply that observations on Theileria-induced leukocyte transformation have the potential to give generally applicable insights into the mechanisms underpinning tumour virulence. My host laboratory described higher TGF-β2 levels in virulent infected macrophages and following microarray analysis of virulent compared to attenuated macrophages found that among the 1158 TGF-β-targets, 68 genes had altered transcript levels concomitant with attenuation. In this study, we investigate the signalling pathways involved in the regulation of cellular adhesion and invasiveness of Theileria-infected cells. We were especially interested in the study of TGF-β2 signalling in Theileria-transformed virulent versus attenuated macrophages. My results indicate that following Theileria infection of macrophages, the TGF-β2 signalling pathway is activated and induces an increase in adhesion of virulent transformed macrophages through two different mechanisms: either by activating a PGE2 / EP4 / cAMP / PKA / EPAC / CREB signaling pathway, or by stimulating a GRB2 / PI3-K / AP-1 pathway. As attenuated macrophages display heightened oxidative stress, which underpins their loss of adhesion and invasiveness, in collaboration with another PhD student (Mehdi Metheni) we investigated the role of TGF-β2 in the regulation of the oxidative stress status of Theileria-infected macrophages. Our data show that high levels of TGF-β2 increase the expression of catalase, an anti-oxidant enzyme that converts H2O2 into H2O and the drop in H2O2 output results in regain of the virulence trait heightened adhesion of Theileria-transformed macrophages to fibronectin. Theileria-transformed macrophages display many features of cancer cells such as their consumption of larger quantities of glucose. The BCL-2 family protein BAD has an alternative function in glucose metabolism separate from its role in apoptosis. The activity of BAD is regulated by phosphorylation in response to growth/survival factors. BAD can be phosphorylated on Ser155 by PKA. So during my thesis studies I examined the role of PKA mediated phosphorylation of BAD in the regulation of the cellular metabolism of Theileria-transformed macrophages. My results showed that ablation of BAD S155 phosphorylation dissociates the mitochondrial complex of BAD and HK2 and cytosolic HK2 becomes ubiquitinated and degraded by the proteasome. Loss of HK2 switches the metabolism of Theileria-transformed leukocytes from Warburg-like to OXPHOS-like glycolysis.

Submitted by Fabiano Vassallo (fabianovassallo2127@gmail.com) on 2017-04-20T19:09:12Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTACAO-LuizaMonteiro.pdf: 3560286 bytes, checksum: ad8c0fa7a9b1fc3a2a2d5137f21a3174 (MD5) / Approved for entry into archive by Josimara Dias Brumatti (bcgdigital@ndc.uff.br) on 2017-04-25T14:52:26Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTACAO-LuizaMonteiro.pdf: 3560286 bytes, checksum: ad8c0fa7a9b1fc3a2a2d5137f21a3174 (MD5) / Made available in DSpace on 2017-04-25T14:52:26Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) DISSERTACAO-LuizaMonteiro.pdf: 3560286 bytes, checksum: ad8c0fa7a9b1fc3a2a2d5137f21a3174 (MD5) / A presente dissertação de mestrado propõe-se a analisar, por meio do aparato da semiótica francesa, a série de televisão Breaking bad, transmitida entre 2008 e 2013 pelo canal norte-americano AMC. Parte da chamada nova “era de ouro” da televisão americana, a série criada por Vince Gilligan apresenta uma narrativa inventiva que conquistou tanto público quanto crítica, sobretudo pelo apelo de seu protagonista, Walter White. A partir do percurso gerativo de sentido de Algirdas Greimas, a análise concentrase nos níveis narrativos e discursivos para acompanhar quais estratégias são empregadas nesta obra audiovisual. Em especial, propomos um estudo sobre as paixões do protagonista e os valores que são postos em jogo por meio da articulação entre recursos verbais e visuais / This work uses french semiotics to analyse the TV series Breaking bad, transmited between 2008 and 2013 on AMC channel in the United States. Identified as part of the so called new american TV “Golden age”, the series created by Vince Gilligan features an inventive narrative that was equally accepted by the audience and TV critics, with its protagonist, Walter White, as the greatest cause of its success. In this work, the narrative and discoursive levels of Algirdas Greimas’ generative meaning trajectory are used to follow which strategies are used in this audiovisual work. In special, we propose a study about the protagonist’s passions and the values that are displayed through the articulation between verbal and visual recourses

Syftet med denna uppsats var att undersöka hur musikbolagen skapar ett varumärke kring deras artister. Frågeställningarna kretsar kring varumärkesskapande, hur samarbetet mellan kvinnliga artister och musikbolagen de tillhör ser ut i de olika stadierna av artisternas karriärer. Jag ställde mig också frågan hur mycket artisternas karriärer påverkas av att de är kvinnor och hur relationen mellan sociala medier, artister och musikbolagen ser ut.    Uppsatens fokus ligger till största del på den svenska musikindustrin men eftersom båda musikbolagen rör sig utanför Sverige, fanns den internationella marknaden i bakgrunden under studiens gång.    Den metod som valts för denna uppsats var den kvalitativa forsknings intervjun. Det skedde tre stycken intervjuer med fyra kvinnor inom musikbranschen och som jobbar på den musikbolag som är fokuset för denna studie. De musikbolag som besöktes var Playground Music, Universal Music Group och MTA Production. Intervjuerna var uppbyggda kring varumärkesskapandet kring en artist, hur man skapar en långsiktig karriär, sociala mediers betydelse för artister idag och hur kvinnliga artisters karriärer ser ut.    Resultatet blev en tydligare bild kring hur musikbolagen jobbar med artister i stort samt vad de tyckte var viktigt att tänka på som musikbolag och artist. Playground Music och Universal Music skiljer sig i storlek men i grunden vill de båda samma sak: att ge en röst och en plattform för kreativa artister.

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Membrane depolarization is an effective neurotrophic stimulus, with its trophic effect on spiral ganglion neurons (SGNs) even surpassing that of neurotrophins. Thus, SGN cultures are a favorable system to investigate pro-survival signal transduction downstream of depolarization. Depolarization promotes SGN survival by recruiting three distinct kinase pathways: cyclic AMP-dependent protein kinase (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV. CaMKIV mediates the pro-survival effect of depolarization by activating CREB in nucleus. However, the mechanisms by which PKA and CaMKII promote survival are still not clear. By targeting constitutively active PKA or a PKA inhibitor (PKI) to the outer mitochondrial membrane (OMM), we showed that PKA activity at the OMM is sufficient to support SGN survival in the absence of other trophic factors and necessary for cAMP-dependent SGN survival. It has been suggested that PKA can promote survival by inactivating pro-apoptotic protein Bad. By cotransfection of SGNs with OMM-PKA and wild-type Bad, we showed that this was the case. We further showed that Ser112 and Ser136 in Bad, but not Ser155, a hypothetical PKA target, were necessary for functional inactivation of Bad by PKA. CaMKII mediates the third depolarization-dependent pro-survival pathway. A specific pro-survival target for CaMKII was identified through a separate investigation of the pro-apoptotic JNK-Jun signaling pathway, which we had identified as active in apoptotic SGNs in vivo. By measuring anti-phosphoJun immunofluorescence, we could quantify JNK-Jun activation in SGNs under different conditions. We showed that JNK inhibition or genetic deletion of JNK3 reduces SGN death after neurotrophic factor withdrawal. Neurotrophins have been shown to suppress JNK activation via their receptor protein tyrosine kinases (PTKs). By expressing constitutively active and dominant negative forms of candidate protein kinases, we identified a novel signaling pathway linking depolarization to JNK: Ca2+ entry - CaMKII - FAK/Pyk2 - PI-3-OH Kinase - Protein Kinase B - inhibition of MLKs (upstream activators of JNK). Thus, depolarization also recruits PTKs - the nonreceptor PTKs FAK and Pyk2 - to suppress JNK activation, implying a conserved PTK-PI3K-PKB pathway for suppression of pro-apoptotic JNK activation by neurotrophic stimuli.

The best interest test is the legal mechanism which governs decision making on behalf of adults who lack the capacity to make their own health care treatment decisions. The test has attracted considerable criticism from health professionals, academics, judges and lawyers for being ill-defined and non-specific. The question of what is meant by 'best interests' remains largely unanswered. As a consequence, the test gives medical and legal decision makers considerable discretion to apply their personal value judgements within supposedly value-free philosophical frameworks - unreasoned and opaque decision making processes are the inevitable result. Because of the dominance of supposedly value-free philosophical frameworks, the place of values in decision making is not always fully understood. Reasoning is not possible without values, which stem from our emotions and passions, our upbringing, our religion, our cultures, our processes of socialisation and from our life experiences. Values help us make sense of our daily lives. I argue that law - like any other social institution - is essentially a human, values based construct. I put forward a theory of values-based law which argues for the recognition that laws, rules and conventions are based on, and contain, individual values. Currently, medical and legal decision makers justify grave decisions on behalf of society's most vulnerable citizens without revealing, or even acknowledging the values which drive and inform their decisions. Any opportunities to scrutinise or debate the values driving decisions are lost. Ultimately, values-based law argues that values underlying best interest determinations must be exposed to facilitate honest, transparent and fulsome decision making on behalf of adults who lack capacity. By applying the theory of values-based law, supposedly value-free decision making processes are exposed as insufficient to facilitate fulsome, honest and transparent legal reasoning.

<p>Vårt sätt att kommunicera med varandra är i hög grad situationsberoende. Ett tillfälle när samtalets form kan ha stor betydelse är i kontakten mellan läkare och patient och då speciellt när läkaren behöver förmedla tråkiga nyheter till patienten. I denna studie undersöktes faktorer som påverkar hur läkaren upplever sin förmåga att genomföra samtal med ”bad news” för patienten. Nio läkare på två sjukhus i Mellansverige intervjuades. När materialet analyserades induktivt genom meningskoncentrering framkom det att patientens ålder och personlighet tycks ha större inverkan än kön, och att anhöriga ansågs kunna vara både ett värdefullt stöd och en belastning för informationsgivningen i svåra samtal. Eftersom de flesta studier om svåra samtal inom vården bygger på uppgifter ur vårdpersonalens synvinkel diskuterades vikten av att i framtida studier fokusera patientens egna upplevelser.</p>

Vårt sätt att kommunicera med varandra är i hög grad situationsberoende. Ett tillfälle när samtalets form kan ha stor betydelse är i kontakten mellan läkare och patient och då speciellt när läkaren behöver förmedla tråkiga nyheter till patienten. I denna studie undersöktes faktorer som påverkar hur läkaren upplever sin förmåga att genomföra samtal med ”bad news” för patienten. Nio läkare på två sjukhus i Mellansverige intervjuades. När materialet analyserades induktivt genom meningskoncentrering framkom det att patientens ålder och personlighet tycks ha större inverkan än kön, och att anhöriga ansågs kunna vara både ett värdefullt stöd och en belastning för informationsgivningen i svåra samtal. Eftersom de flesta studier om svåra samtal inom vården bygger på uppgifter ur vårdpersonalens synvinkel diskuterades vikten av att i framtida studier fokusera patientens egna upplevelser.

Texte révisé de: Diss.--Universität Salzburg, 2002. / Bibliogr. p. 255-269.

Diss.--Philosophische Fakultät--Bonn--Rheinische Friedrich-Wilhelms Universität, 2001. / Bibliogr. p. 756-778. Index.