La présente étude est une analyse et une reconstruction interprétative de la centurie de Calliste Cataphygiotès, intitulée De l'union avec Dieu et de la vie contemplative, chapitres syllogistiques et hauts. Notre approche à ce texte pluridisciplinaire est prioritairement philosophique. Dans le but de mettre en valeur l'intérêt philosophique qu'il représente, nous avons concentré notre analyse sur les problèmes liés au rapport de l'intellect avec l'Un, sur l'étude du concept de l'infini, sur son rôle dans la contemplation et sur la méthode dialectique dont Calliste Cataphygiotès s'en sert. Nous avons reconstruit la doctrine de la contemplation, implicite au texte de Calliste et nous avons tenté une reconstruction globale de la centurie qui permettra au lecteur d'apprécier les qualités spéculatives et l'esprit synthétique de ce mystique byzantin presque inconnu. / The present study is an analysis and an interpretative reconstruction of Callistus Cataphygiotes's syllogistic chapters, entitled The union with God and the contemplative life. Our approach to this multidisciplinary text is primarily philosophical. In order to emphasize the philosophical aspect of the text we focused our analysis on issues related to the concept of infinity, its role in contemplation, the relation of the intellect with the One, as well as the dialectical method used by Callistus Cataphygiotes. We rebuilt the doctrine of contemplation, implied in the text of Callistus and we tried to do a complete reconstruction of the text that will allow the reader to appreciate the speculative and the synthetic spirit of this almost unknown Byzantine mystic.

Among multiple interconnected pathways for L-Lysine catabolism in pseudomonads, it has been reported that Pseudomonas aeruginosa PAO1 employs the decarboxylase and the transaminase pathways. However, knowledge of several genes involved in operation and regulation of these pathways was still missing. Transcriptome analyses coupled with promoter activity measurements and growth phenotype analyses led us to identify new members in L-Lys and D-Lys catabolism and regulation, including gcdR-gcdHG for glutarate utilization, dpkA, amaR-amaAB and PA2035 for D-Lys catabolism, lysR-lysXE for putative L-Lys efflux and lysP for putative L-Lys uptake. The amaAB operon is induced by L-Lys, D-Lys and pipecolate supporting the convergence of Lys catabolic pathways to pipecolate. Growth on pipecolate was retarded in the gcdG and gcdH mutants, suggesting the importance of glutarate in pipecolate and 2-aminoadipate utilization. Furthermore, this study indicated links in control of interconnected networks of lysine and arginine catabolism in P. aeruginosa. Effect of D-amino acids and the genes involved in their metabolism are of great interest in both bacteria and mammals. D-Arg utilization in PAO1 requires the coupled dehydrogenases DauB and DauA. In this study, DauB was found to use only L-Arg as its substrate unlike its partner dehydrogenase DauA with wide substrate specificity. However, evidence from this study and previous studies suggest that the coupled enzymes DauB and DauA are unique for D-Arg catabolism. The three D-amino acid dehydrogenases DguA, DadA and DauA were found to have somewhat limited in vivo substrate specificity compared to that found in vitro tested using purified enzymes. Many studies showed that D-amino acids are toxic to bacteria. The ΔdguA, ΔdadA and ΔdauA triple mutant had two-fold lower minimum inhibition concentration of carbenicillin and tetracycline compared to wild-type PAO1. Both in the wild-type PAO1 and the triple mutant, synergy was observed between gentamicin or tetracycline (at concentrations below the MIC) and D-amino acids resulting in growth inhibition or reduction, respectively. However, no special synergistic or antagonistic effects were observed specifically in the ΔdguA, ΔdadA and ΔdauA triple mutant as compared to the wild-type PAO1 when D-amino acids were given in combination with antibiotics.

Businesses globally are challenged to innovate their operations strategies and practices towards tighter delivery times, better quality and cheaper prices to remain profitable in addition to managing unpredictable circumstances well in today’s turbulent business environment. They often have to deal with the apparent paradox of advancing efficiency-fostering approaches such as lean production, and enhancing operational resilience against unanticipated disruptions. The purpose of this study is to investigate whether and how practices in seemingly contradicting paradigms in operations management can be utilised to attain a better competitive position in the face of uncertainties. This thesis is comprised of ‘modules’ of studies designed to systematically address the three research questions. This was necessary due to the different maturity level of the concepts brought together. Predominantly qualitative mixed-method approach was used for the overall research with some quantitative analysis included. The critical incident technique, case study and Bayesian inference were used in the different studies (papers). Operational resilience is characterised in terms of five core functions: sense, build, reconfigure, re-enhance, and sustain (RQ1). Resilience is also operationalised using routine practices that are bundled into internal/external, proactive/reactive dimensions of capabilities that positively influence performance upon recovery from disruption. An analysis showing that lean practice bundles lead to better operational performance under high uncertainty context is also done in this thesis (RQ2). Finally, operational resilience (based on routine practices that form the core functions) was found to have stronger synergies than trade-off with lean (based on practice bundles) in times of turbulence (RQ3). This thesis extends the resource-based view to high uncertainty contexts through empirical evidence and shows that resilience (dynamic) capabilities can be built from practices that firms normally employ; the capabilities are sources of better performance and competitive advantages in turbulent business environments. The thesis contributes to the discussion on the paradox of lean and operational resilience based approaches in the same context; lean practices bundles lend themselves to synergy with resilience capabilities, and leverage competitive gains in turbulent times. Practically, findings of this thesis suggest that companies need not abandon their lean implementation to become more resilient. In fact, it shows that lean implementation should be extended to address value chain processes beyond the shop floor for integrative removal of wastes, while being able to flexibly mitigate disruptions. / La sfida della competitività nei mercati globali dipende in larga parte dalla capacità delle imprese di innovare le loro operations per ottenere termini di consegna sempre più stretti, maggior qualità  a prezzi sempre più competitivi; tutto questo in un contesto industriale e socio-economico sempre più incerto e turbolento. Oggi le imprese sono chiamate a prendere decisioni e ad adottare dei modelli di business dagli effetti contrastanti, come ad esempio l’adozione di pratiche che enfatizzano risultati di efficienza produttiva (i.e. lean production) a fianco di strategie e soluzioni che mirano ad accrescere la capacità del sistema di adattarsi dinamicamente ad eventi perturbanti (resilienza), esterni o interni all’organizzazione. Lo scopo di questa ricerca è quello di investigare se e come l'adozione di pratiche potenzialmente contrastanti nell'ambito della gestione delle operations, possono essere utilizzate per mantenere e migliorare la propria posizione competitiva in contesti di forte incertezza e turbolenza dei mercati. La ricerca si compone di una serie di "moduli", ovvero di singoli studi progettati per affrontare sistematicamente e organicamente le tre domande di ricerca fondamentali, la cui risposta conduce alla proposta di tesi. Questa impostazione si è rivelata necessaria a causa del diverso livello di maturità dei concetti studiati e sviluppati nella tesi. Anche la metodologia di ricerca rispecchia le diverse esigenze e peculiarità dei vari aspetti studiati e per questo è stata definita seguendo un approccio misto, in cui metodi di tipo qualitativo sono affiancati da analisi quantitative che implementano tecniche statistiche. In particolare, nei diversi “moduli” (paper) si utilizzano: la critical incident technique, diverse metodiche di studi di caso, e inferenza Bayesiana. La resilienza operativa è stata caratterizzata secondo cinque funzioni principali (core functions): sense, build, reconfigure, re-enhance, e sustain (RQ1). Ciascuna di queste è tradotta a livello operativo attraverso procedure e pratiche stabili (routine) - interne/esterne, proattive/reattive - che sono in grado di influenzare positivamente le prestazioni a seguito di un evento perturbante. Attraverso la ricerca, viene analizzato l’effetto positivo che differenti pratiche lean (lean practice bundles) inducono sulle prestazioni operative in condizioni di incertezza (RQ2). Infine, un’analisi bayesiana sui parametri tipici di un campione selezionato di eventi incidentali a carico di organizzazioni e supply chain globali ha rivelato che tra resilienza operativa (implementata attraverso specifiche  routine) e lean production (implementata attraverso specifiche lean practice bundles) esistono fenomeni sinergici più forti dei meccanismi di trade-off, quando valutati in contesti turbolenti (RQ3). I risultati della tesi contribuiscono ad ampliare e rafforzare un approccio teorico contingent resource-based view all’analisi delle organizzazioni che operano in regimi di forte incertezza (complessità e dinamicità); il contributo originale si concentra in particolar modo nel fornire evidenza empirica che le capacità di resilienza di una organizzazione (dynamic capabilities) possono essere costruite su processi e routine normalmente eseguite dalle imprese. Ove disponibili, queste capacità sono usate come fonte di miglioramento prestazionale e per l’ottenimento di un vantaggio competitivo in contesti turbolenti. Ulteriori evidenze supportano la tesi che un’ampia gamma di lean practices possono essere usate in maniera sinergica per un ulteriore rafforzamento della resilienza operativa. Dal punto di vista pratico e in contrasto con parte della letteratura esistente, la tesi offre ai manager industriali solidi argomenti per non abbandonare la propria strategia lean o limitare i propri obiettivi di efficienza allo scopo di conseguire una maggiore resilienza operativa. Si dimostra infatti che quando l’adozione di partiche lean viene estesa ad una porzione sempre più ampia della value chain, alla conseguente riduzione degli sprechi si associa anche una maggior flessibilità nella gestione di eventi perturbanti o distruttivi. / I dagens turbulenta affärsklimat står företag världen över inför utmaningen att på ett effektivt sätt hantera oförutsägbara händelser och samtidigt förnya sina verksamheter med syfte att uppnå kortare leveranstider, bättre kvalitet och ökad lönsamhet. I dessa ansträngningar möter företagen ofta det skenbara dilemmat av att vissa arbetssätt såsom lean produktion ställs i kontrast mot aktiviteter syftande till att skapa återhämtningsförmåga, dvs angreppssätt och rutiner för att hantera oväntade störningar (operational resilience). Syftet med denna avhandling är att undersöka om och hur dessa två olika arbetssätt, med till synes motstridiga paradigm, kan användas för att uppnå ökad konkurrenskraft för företag verksamma under osäkra marknadsförhållanden. Avhandlingen består av fem artiklar och syftar till att, på ett systematiskt sätt, avhandla tre övergripande forskningsfrågor. Uppdelningen i artiklar motiveras av olikheter i mognadsgrad hos de båda grundbegreppen. En kombination av forskningsmetoder har använts. Den övergripande forskningsstrategin har varit kvalitativ och fallstudiebaserad. Även kritiska händelse metoden, (Critical Incident Technique, CIT) och kvantitativa metoder såsom statistisk analys och Bayesiansk inferens har använts som komplement i några av artiklarna. Resultaten visar att operativ återhämtningsförmåga kan beskrivas i termer av fem kärnfunktioner: uppfatta, formera, konfigurera, återförbättra och bibehålla (RQ1). Resultaten visar även att återhämtningsförmågan kan operationaliseras såsom kombinationer av sammansatta organisatoriska rutiner (practice bundles) vilka kan karaktäriseras i termer av interna/externa och proaktiva/reaktiva dimensioner. Kombinationer av dessa sammansatta organisatoriska rutiner har identifierats vilka både samverkar och förstärker varandra i situationer av störning och efterföljande återhämtning. Vidare visas att implementering av lean rutiner leder till ökad effektivitet i situationer karakteriserade av hög osäkerhet (RQ2). Avslutningsvis visar resultaten att återhämtningsförmåga och lean, operationaliserade som kärnfunktioner respektive sammansatta organisatoriska rutiner, har stark samverkan då det gäller att hantera störningar. Några sammansatta organisatoriska rutiner har dock en trade-off relation till vissa kärnfunktioner (RQ3) Ur ett teoretiskt perspektiv utökar avhandlingen det resursbaserade synsättet till att även inkludera företag som verkar under osäkra marknadsförhållanden. Resultaten visar att (dynamisk) återhämtningsförmåga kan byggas med hjälp av metoder som företagen normalt använder idag (sammansatta organisatoriska rutiner). Genom att omkonfigurera existerande förmågor och rutiner skapas en källa till ökad produktivitet och ökad konkurrenskraft. Således bidrar avhandlingen till diskussionen om det skenbara dilemmat av att en samtidig användning av strategier baserade på lean production och strategier fokuserande på återhämtningsförmåga (operational resilience) samverkar och förstärker varandra snarare än motverkar varandra. Avhandlingens praktiska implikation är att företag inte behöver överge sitt lean arbetssätt för att öka sin återhämtningsförmåga (operational resilience). I själva verket, bör företag utgå ifrån existerande lean arbetssätt och utvidga dessa till att även omfatta processer utanför den direkta tillverkningen. / <p>This thesis is produced as part of the EMJD Programme <em>European Doctorate in Industrial Management (EDIM) </em>funded by the European Commission, Erasmus Mundus Action 1.</p><p>EDIM is run by a consortium consisting of the industrial management departments of three institutions.</p><p>•KTH Royal Institute of Technology, Stockholm, Sweden</p><p>•Politecnico de Milano, POLIMI, Milan, Italy</p><p>•Universidad Politécnica de Madrid, UPM, Madrid, Spain</p><p>QC 20151105</p><p></p>

Les cellules épithéliales pulmonaires constituent la première ligne de défense face aux virus respiratoires via la sécrétion de mucus, de peptides, de cytokines et chimiokines qui déterminent l'élimination ou la progression de l’infection. Les principales cytokines antivirales produites par les cellules épithéliales alvéolaires (AEC) sont les interférons (IFN) type I (α/β) et III (λ). La liaison d’IFNβ à son récepteur induit une voie antivirale bien caractérisée qui aboutit à l’activation du complexe ISGF3 (STAT1, STAT2 et IRF9) qui permet la transcription de multiples gènes codant pour des protéines à activité antivirale et immunorégulatrice. Il a récemment été démontré que la costimulation des cellules épithéliales pulmonaires par l’IFNβ et le Tumor Necrosis Factor α (TNFα), également produit lors d’une infection, synergisent pour induire un état antiviral tardif distinct. D’autre part, il a été montré que la synergie entre le TNFα et l'IFNβ induit une voie de signalisation impliquant STAT2 et IRF9, mais indépendante de STAT1 permettant l’expression du gène DUOX2. Notre but est de déterminer l’importance de cette nouvelle voie de signalisation induite par la costimulation du TNFα+IFNβ, impliquant STAT2 et IRF9 indépendamment de STAT1 dans la régulation d’un programme transcriptionnel antiviral et immunorégulateur tardif. Notre premier objectif est de déterminer si des gènes antiviraux et immunorégulateurs qui sont induits par la costimulation par TNFα+IFNβ sont dépendants de la voie STAT2/IRF9, indépendamment de STAT1. En utilisant la technique de qRT-PCR, nous avons identifié 3 gènes immunorégulateurs, CXCL10, IDO et APOBEC3G, induits de manière synergique en réponse à TNFα+IFNβ dans les cellules A549, un modèle de cellules épithéliales pulmonaires. Afin de confirmer que ces gènes sont induits indépendamment de STAT1, nous avons validé leur expression dans la lignée cellulaire U3A déficiente en STAT1. Par l'utilisation d'ARN interférants (ARNi) dirigés contre STAT2 et IRF9, nous avons confirmé que l’induction de ces gènes est dépendante de STAT2 et IRF9. Finalement, l’analyse de l’activité du promoteur de CXCL10 en réponse à TNFα+IFNβ par des essais rapporteurs luciférases a permis de montrer que la régulation se fait au niveau transcriptionnel. Notre deuxième objectif, est de déterminer si STAT6 pourrait remplacer STAT1 dans la voie de signalisation induite par TNFα+IFNβ. En effet, STAT6 est un inducteur connu de l’expression de DUOX2 en réponse à IL4+IL13. Contrairement à notre hypothèse, l’inhibition de STAT6 par ARNi augmente l’expression de DUOX2 en réponse à TNFα+IFNβ suggérant que STAT6 est un régulateur négatif. Nos résultats ont permis de comprendre de manière plus détaillée les mécanismes mis en place dans le développement d’une réponse antivirale. D’autre part, l’étude de l’effet de l’IFNβ et du TNFα est également pertinente pour les maladies chroniques inflammatoires et autoimmunes. De plus, nos résultats illustrent un nouveau paradigme concernant les mécanismes de signalisation cellulaire impliqués dans la synergie entre deux cytokines qui pourrait être applicable à des combinaisons de cytokines autres que TNFα+IFNβ. / Lung epithelial cells are the first line of defense against respiratory viruses via mucus secretion, peptides, cytokines and chemokines that determine the progression of the infection. The main antiviral cytokines produced by alveolar epithelial cells (AEC) are the interferons (IFN) type I (α / β) and III (λ). IFNβ binding to its receptor induces an antiviral pathway that is well characterized and leads to activation of the ISGF3 complex (STAT1, STAT2 and IRF9) which allows the transcription of multiple genes encoding proteins with antiviral and immunoregulatory activity. It has recently been shown that the costimulation of lung epithelial cells by IFNβ and Tumor Necrosis Factor α (TNFα), also produced during infection, induces a separate and late antiviral state, through synergy. On the other hand, it has been shown that the synergy between IFNβ+TNFα induces a signaling pathway involving STAT2 and IRF9 independently of STAT1 permitting the expression of the DUOX2 gene. Our goal is to determine the importance of this new signaling pathway induced by costimulation of TNFα+IFNβ involving STAT2 and IRF9 regardless of STAT1 in regulating the antiviral immunoregulatory and late transcriptional program. Our first objective is to determine whether antiviral and immunomodulatory genes that are induced by costimulation TNFα+IFNβ are dependent on the STAT2/IRF9 way, indenpant of STAT1. Using the technique of qRT-PCR, we identified 3 immunoregulatory genes, CXCL10, IDO and APOBEC3G, synergistically induced in response to TNFα+IFNβ in A549 cells, a model of pulmonary epithelial cells. To confirm that these genes are induced independantly of STAT1, we validated their expression in the STAT1 deficient cell line, U3A. By the use of interfering RNA (siRNA) directed against STAT2 and IRF9, we confirmed that the induction of these genes is dependent STAT2 and IRF9. Finally, the analysis of the activity of CXCL10 promoter in response to TNFα+IFNβ by luciferase reporter assays has shown that the regulation is at the transcriptional level. Our second objective is to determine whether STAT6 could replace the STAT1 in the signaling pathway induced by TNFα+IFNβ. Indeed, STAT6 is a known inducer of the expression of DUOX2 in response to IL4+IL13. Contrarily to our hypothesis, inhibition of STAT6 by RNAi increases the expression of DUOX2 in response to TNFα+IFNβ suggesting that STAT6 is a negative regulator. Our results allow the understanding of the mechanisms in the development of an antiviral response in more detail. On the other hand, the study of the effect of IFNβ and TNFα is also relevant for chronic inflammatory and autoimmune diseases. In addition, our results illustrate a new paradigm for cell signaling mechanisms involved in the synergy between two cytokines that may be applicable to combinations of cytokines other than TNFα+IFNβ.

Qu'est-ce qu'un réseau de distribution ? L'interrogation peut surprendre tant cette notion semble aujourd'hui incontournable. Pourtant force est de constater que la notion de réseau de distribution n'est pas encore parvenue à faire consensus. La première partie de la recherche a pour objectif d'éprouver chacun des fondements proposés. Fondé sur un groupe de contrats, il dévoile son aspect institutionnel à travers l'existence de normes privées, de relations de pouvoir et du partage d'une identité. Ces éléments invitent à y voir une communauté organisée autour d'un intérêt commun ayant une existence distincte de celle des membres. Pourtant, l'analyse du réseau de distribution empêche de considérer qu'il constitue une telle communauté. Dès lors, la recherche de la nature juridique du réseau de distribution permet d'avancer que cette notion est irréductible aux catégories juridiques existantes. La deuxième partie de la recherche affirme les particularismes de la notion. Le réseau de distribution est caractérisé par une synergie originale. Son régime juridique se construit sur un arbitrage entre les divers intérêts concernés par l'existence de cette structure. Ces constats permettent d'avancer qu'il constitue une notion propice à l'élaboration d'une catégorie juridique regroupant les organisations multipartites qui, fondées sur un groupe de contrats et une relation de pouvoir sans subordination, sont caractérisées par une synergie consistant en une affectation de moyens matériels et humains au développement simultané d'une activité économique globale et des activités de chacun des membres, créant une complémentarité, entre leurs intérêts personnels convergents mais différents, source d'un intérêt collectif. / What is a distribution network ? The question may surprise a few given the acceptance of the notion. However, we have to notice that this notion has not reached its quest of identity. The first part of the research aims at verifying the founding principles of each theory. Actually, it appears that the distribution network finds its place beyond the group of contracts qualification and below the qualification of Institution. Based on a group of contracts, it reveals its institutional aspects through the existence of private standards, relations of power and the sharing of an identity. These elements invite to see a community there organized around a public interest having an existence different from that of the members. Nevertheless, the analysis of the distribution network prevents from considering that it constitutes such a community. From then on, the research for the legal nature of the distribution network allows to move forward that this notion is inflexible in the existing legal categories.The second part of the research aims at asserting the particularisms of the notion of distribution network. The distribution network is characterized by an original synergy. Its legal regime builds itself on an arbitration between the diverse interests concerned by the existence of this structure. These reports allow to move forward that it constitutes a notion convenient to the elaboration of a legal category gathering multipartite organization, based on a group of contracts and a relationship without subordination, that are symbolized by a synergy that involves the allocation of material and human resources to the simultaneous development of both the global economic activity and the activity of each member of the group, creating a synergy between their different but convergent own personal interests, source of mutual interest.

L'objectif de notre étude est de mettre en évidence les synergies existantes entre les différents facteurs de vieillissement lors de la dégradation d’un revêtement polymère modèle, représentatif d’une peinture anticorrosion.Notre travail a consisté à suivre le vieillissement hygrothermique du système DGEBA/TETA sous forme de film libre et de revêtement déposé sur substrat acier dans différentes solutions (eau pure et NaCl 3%) pour différentes températures et contraintes mécaniques visco-élastique appliquées. Nos résultats ont montré que le programme de cuisson affectait les propriétés physico-chimiques et mécaniques du système initial et que l’absorption d’eau, non homogène, suivait une loi non-Fickienne, suite à un phénomène de gonflement.La prise en eau et la diffusion ont été caractérisées par gravimétrie et spectroscopie d’impédance électrochimique. Nos résultats montrent que les propriétés barrière du revêtement diminuent avec la quantité d’eau absorbée et avec la température de vieillissement. Cependant, la contrainte plane appliquée sur le système tend à contrarier cet effet. La formalisation de nos observations expérimentales dans le cadre d’une approche thermodynamique a montré l’effet prépondérant de la partie entropique par rapport à la partie enthalpique de l’énergie d’activation des processus de transport de l’eau, en raison de l’orientation des chaînes sous l’action de la contrainte. De plus, une diminution de la permittivité relative du revêtement sec a été observée en fonction de la température et de la contrainte appliquée, indépendamment de son signe (tension ou compression). Dans ce cas, la contribution enthalpique semble être prépondérante. / The objective of this study is to highlight synergies existing between different ageing factors during the degradation of a polymer model coating system, representing an anti-corrosion coating.We first monitored the hygrothermal ageing of DGEBA/TETA system as free films and as attached films onto a steel substrate in different solutions (water and NaCl 3wt% solution) for different temperatures and applied mechanical visco-elastic stresses. Our results showed that the curing programs affected the physic-chemical and mechanical properties of the cured systems and that the non-homogeneous water uptake process followed a non-Fickian law, due to a swelling phenomenon.The water uptake and diffusion were characterized by gravimetry and electrochemical impedance spectroscopy. The results indicate that the barrier properties of the coating decrease with the quantity of absorbed water in system and with the increasing of the ageing temperature. However, the planar stress applied onto the system tends to counteract this effect. The formalization of our experimental observations within a thermodynamic approach showed the predominant effect of the entropic part in comparison with enthalpic part of the activation energy of the water uptake process, due to the reorientation of polymer chains under the applied stress. In addition, a decrease in the relative permittivity of the initial dry coating was observed as a function of the temperature and the applied stress, regardless of its sign (tension and compression). In this case, the enthalpic contribution seems to be predominant.

Orientador: Leandro de Castro Mantovani / Resumo: Acidificação oceânica, processo resultante das emissões de gás carbônico (CO2) na atmosfera pelas atividades de natureza antrópica, vem causando nas últimas décadas uma modificação no equilíbrio químico do sistema bicarbonato/carbonato e consequentemente uma diminuição do pH dos oceanos. Estimativas apontam que esta diminuição pode ser de 0,7 unidades até ano de 2300, o que pode afetar o crescimento, reprodução e até mesmo a sobrevivência das espécies. Nesse sentido, são necessários estudos que avaliem o impacto da acidificação oceânica ao nível fisiológico e molecular nas diferentes espécies marinhas. O siri Callinectes danae é um importante recurso ecológico e econômico da Região da Baixada Santista e habitante de diferentes faixas de salinidade. O presente estudo avaliou os efeitos da acidificação oceânica no siri C. danae sobre um conjunto de parâmetros fisiológicos (consumo de oxigênio, excreção de amônia, razão O:N, índice hepatossomático e capacidade osmo-e ionorregulatória da hemolinfa), e a expressão gênica da Na+/K+- ATPase, enzima importante no processo de osmorregulação e equilíbrio ácido base. Os animais foram mantidos em diferentes salinidades (20, 25, 30, 35 e 40) e nos pHs 8,0 (controle) e 7,3 (acidificado) por um período de três e trinta dias. Foi observado aumento no consumo de oxigênio nas salinidades 25 (3 dias), 20 e 40 (30 dias) provavelmente devido a uma maior necessidade energética para a manutenção de sistemas relacionado a regulação ácido-base. També... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Oceanic acidification, a process resulting from the emission of carbon dioxide (CO2) in the atmosphere by activities of anthropic nature, has been causing in recent decades a change in the chemical balance of the bicarbonate / carbonate system and consequently a decrease in the pH of the oceans. Estimates indicate that this decrease can be 0.7 units per year of 2300, which can affect the growth, reproduction and even survival of the species. In this sense, studies are needed to evaluate the impact of oceanic acidification on physiological and molecular levels in different marine species. The Callinectes danae crab is an important ecological and economic resource of the Region of the Baixada Santista and inhabitant of different ranges of salinity. The present study evaluated the effects of ocean acidification on C. danae crab on a set of physiological parameters (oxygen consumption, ammonia excretion, O: N ratio, hepatosomatic index and osmo-and ionoregulatory capacity of hemolymph), and gene expression of Na + / K + - ATPase, an important enzyme in the process of osmoregulation and acid base balance. The animals were kept at different salinities (20, 25, 30, 35 and 40) and at pHs 8.0 (control) and 7.3 (acidified) for a period of three and thirty days. It was observed an increase in the oxygen consumption in salinities 25 (3 days), 20 and 40 (30 days) probably due to a greater energy requirement for the maintenance of systems related to acid-base regulation. Metabolic depressi... (Complete abstract click electronic access below) / Mestre

Background Glioblastoma Multiforme (GBM) is the most commonly occurring tumour of the central nervous system (CNS). Currently GBM is considered an incurable malignancy with patients experiencing abysmal life expectancies. Lack of progress in the discovery of novel treatments has led to the repurposing of existing licenced medication as a possible alternative option. Metformin is from the biguanide family of drugs and is the most common medication used in the treatment of type 2 diabetes. Clinical studies have reported that, in type 2 diabetic patients, metformin might reduce cancer incidence and severity. Currently, metformin is being assessed in clinical trials as a treatment for a range of cancer types including GBM. The antineoplastic mechanisms utilized by metformin and other biguanides have not been fully elucidated. Methods The effects of metformin were evaluated, alone and in combination with other agents, on a panel of GBM cell cultures. Functional analysis of metformin mechanism of action was assessed through measurement of apoptosis, depolarisation of the mitochondria membrane, caspase pathway activation, cell cycle progression and the expression levels of micoRNAs. Results Analysis of fourteen GBM cell cultures showed a cytotoxic response to metformin that was significantly linked to the P53 status (p=0.0024). In combination drug testing, one of the four drugs showed a synergistic pairing with metformin. The kinase inhibitor sorafenib, showed synergism (CI ≤ 1) in eight GBM cell cultures. Flow cytometry of metformin treated GBM cells showed no significant increase (p > 0.005) in apoptotic cell populations. Caspase 3/7 levels showed no significant increase post metformin treatment (p > 0.005). Metformin caused depolarisation of the mitochondrial membrane in six GBM cell cultures. Four microRNAs were shown to have expression levels changes post-metformin treatment. Upregulation of expression was identified in miR-140, miR-192, let-7c. Downregulation was identified in miR-222. Conclusions Metformin was shown to have cytotoxic effect on a GBM cell cultures and has potential as GBM therapeutic agent and possible treatment synergy with sorafenib. The significance of P53 status to metformin sensitivity may suggest that its use should be directed to a sub-set of GBM patients. Mechanism for cell death by metformin was shown not to rely on apoptotic pathways but caspase 3/7 independent depolarization of mitochondrial cell membranes and cell cycle arrest. Investigations into autophagy may help to further define the pathways metformin is utilising to promote cell death. The impact of metformin on the expression profile of miR-222, miR-192 and let-7c is in line with clinical studies of other cancer types. This shows possible insight into the cancer independent actions of metformin. The interplay recorded between glucose availability and cell death indicates a possible key factor in the utilisation of metformin as a therapeutic agent. This finding may warrant the addition of dietary control regimes in clinical trials to maximise metformin efficacy. This work highlights the strong potential for biguanides in the development of new drug treatments and in expanding our knowledge of cancer metabolism.

Apis mellifera est un insecte pollinisateur jouant un rôle économique et écologique majeur. Depuis plus d’une vingtaine d’années, d’importantes pertes de colonies d’abeilles ont été recensées à l’échelle mondiale. L’origine de ce phénomène impliquerait de nombreux facteurs de stress qui pourraient en outre interagir entre eux. Ce travail de thèse a eu pour but d’évaluer l’impact sur la santé de l’abeille de l’association entre un facteur biotique, le parasite microsporidien Nosema ceranae, et un facteur abiotique, des insecticides neurotoxiques à faibles doses. Des études en laboratoire ont montré que l’association N. ceranae-insecticide entraine une surmortalité significative, et plus précisément un effet synergique sur la mortalité des abeilles. Cet effet synergique semble indépendant de l’ordre d’exposition des abeilles aux deux facteurs de stress. De plus, lorsqu’ils ont été appliqués dès l’émergence des abeilles, ces facteurs ont eu un impact plus fort sur la mortalité. La réponse de l’abeille à N. ceranae et aux insecticides a ensuite été analysée à l’échelle transcriptomique. L’analyse du transcriptome de l’intestin a été réalisée en combinant une approche globale de séquençage à haut débit (RNA-Seq) et un suivi de l’expression d’une sélection de gènes par qRT-PCR. L’exposition à N. ceranae et aux insecticides a entraîné des modifications de l’expression de gènes impliqués dans les défenses de l’abeille (immunité, détoxication) et dans les métabolismes du tréhalose et de la chitine. De nombreuses perspectives à ce travail sont envisageables dans le but de mieux appréhender la réponse de l’abeille à différents facteurs de stress, notamment en combinant des expérimentations en laboratoire avec des études de terrain. / Apis mellifera is a pollinator insect playing of major economical and ecological importance. For more than two decades, severe honeybee colony losses have been reported worldwide. The origin of this phenomenon is thought to involve numerous stressors that could interact with each other. The objective of this work was to evaluate the impact on honeybee health of the association between a biotic stressor, namely the microsporidian parasite Nosema ceranae, and an abiotic stressor, here low doses of neurotoxic insecticides. Laboratory studies showed that the N. ceranae-insecticide association leads to a higher mortality in honeybees, and more precisely to a synergistic effect. This effect seemed to be independent of the exposure sequence to stressors. Moreover, when applied at the emergence of honeybees, these stressors had a higher impact on individuals’ mortality. The honeybee response to N. ceranae and to insecticides has also been analysed at a transcriptional level. A midgut transcriptome analysis has been performed combining a global approach, using high-throughput sequencing (RNA-Seq), and a quantitative RT-PCR monitoring of the expression of selected genes. The exposure to N. ceranae and to insecticides led to modifications in the expression of genes involved in honeybee defenses (immunity, detoxification) and in trehalose and chitin metabolisms. Following this work, several prospects can be initiated in order to improve our understanding regarding the honeybee response to various stressors, combining laboratory experiments with field studies.

Foi estudado o processo de fotopolimerização iniciado através de misturas dos fotoiniciadores, acilfosfínicos (MAPO e BAPO), com canforquinona (CQ). Também foi investigada a existência de um possível efeito sinérgico durante a fotoiniciação. A eficiência de polimerização das duas misturas, MAPO/CQ e BAPO/CQ, foi determinada por actinometria. A fotodilatometria foi a técnica utilizada para o acompanhamento das cinéticas de polimerização. A adição do co-iniciador EDB não apresentou efeito nas velocidades de polimerização iniciadas pelos fotoiniciadores acilfosfínicos. Do ponto de vista do rendimento quântico de polimerização, um efeito antagonístico foi observado devido a transferência de energia a partir dos fotoiniciadores mais eficientes (MAPO ou BAPO) para o menos eficiente, canforquinona (CQ). / The photopolymerization processes involving two different photoinitiators: acylphosphine oxides (MAPO and BAPO) and camphorquinone (CQ) were studied in order to determine possible synergistic effects. The polymerization efficiency of the two mixtures, MAPO/CQ and BAPO/CQ, was studied using actinometry. The polymerization kinetics was followed by photodilatometry. The presence of the coinitiator EDB had no effect in the polymerization rate initiated by the acylphosphine oxides. From the point of view of photopolymerization quantum yields, an antagonistic effect is observed due to the energy transfer from the more efficient initiator (MAPO or BAPO) to the less efficient (CQ).