<p>The purpose of this thesis is to develop a model to enhance the effectiveness of machining centers with multi-pallet automatic pallet changers (APCs). From critical literature review no existing theories within this field were found. The multi-pallet APC allows multi-setups and a more flexible sequencing of jobs. The model together with the developed heuristic scheduling algorithm with the objective to minimize the total weighted tardiness can be used to plan in n jobs on m pallets in a shop-floor. The right maintenance policy ensures a high availability, which together with the program guarantees a high level of utilization of the machinery. Consequently the effectiveness will be enhanced. A case study approach was used to test the model at Växjöfabriken in Sweden, which treats cast material. The results of this case study are a more effective utilization of the machines with decreased tardiness costs, increased customers’ satisfaction and goodwill of the company. The contribution of this thesis is a model with a flexible, adjustable and expandable heuristic scheduling algorithm, which can be applied in all manufacturing companies using machining centers with multi-pallet APCs.</p> / <p>Syftet med denna uppsats är att utveckla en modell för att förbättra effektiviteten av maskincentra med automatiska palletväxlare (APCs) för multi-palleter. När en kritisk litteratursökning genomfördes hittades inga relevanta teorier inom det aktuella området. Multi-pallet APC tillåter att många jobb kan förberedas samtidigt och gör planeringen av jobben mer flexibel. Modellen, tillsammans med den utvecklade heuristiska planeringsalgoritmen med målet att minimera den totala viktade förseningen, kan användas för att planera in n jobb med m palleter på ett verkstadsgolv. Rätt underhålls policy försäkrar en hög tillgänglighet vilket tillsammans med programmet garanterar en hög utnyttjandenivå av maskinerna. Som följd kommer effektiviteten att höjas. En fallstudie utfördes på Växjöfabriken i Sverige för att utvärdera modellen, på företaget efterbehandlas gjutgods. Resultatet från denna fallstudie blev ett effektivare utnyttjande av maskinerna, med minskade förseningskostnader, ökad kundtillfredställelse och goodwill för företaget. Denna uppsats bidrar med en modell och en flexibel, anpassningsbar och utvecklingsbar heuristisk planeringsalgoritm, vilken kan användas i alla industriföretag som använder maskincentra med multi-pallet APCs.</p>

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La régulation post-transcriptionnelle joue un rôle de premier plan dans le contrôle fin de l’expression génique en permettant une modulation de la synthèse de protéines dans le temps et l’espace, en fonction des besoins de la cellule. Ainsi, des protéines reconnaissant des éléments d’ARN présents sur des transcrits peuvent influencer toutes les étapes de leur existence, soit leur épissage, leur export nucléaire, leur localisation subcellulaire, leur traduction et leur dégradation. Staufen1 (Stau1) est un membre de la famille des protéines liant l’ARN double-brin qui contribue à la régulation post-transcriptionnelle par son implication dans des mécanismes qui vont promouvoir l’épissage alternatif, le transport, la dé-répression de la traduction et l’induction de la dégradation d’ARN messagers (ARNm) spécifiques. L’identité des cibles potentielles de Stau1 est maintenant connue puisqu’une étude à l’échelle du génome a montré que la protéine s’associe à près de 7% du transcriptome des cellules HEK293T. Ces ARNm se classent dans un large éventail de catégories fonctionnelles, mais il est tout de même intéressant de noter qu’une grande proportion d’entre eux code pour des protéines reliées au métabolisme cellulaire et à la régulation de processus cellulaires. En considérant toutes ces informations, nous avons émis l’hypothèse que les différentes activités de Stau1 puissent être modulées afin de contrôler adéquatement l’expression des transcrits liés par la protéine. Dans la mesure où certains ARNm faisant partie des complexes définis par la présence de Stau1 codent pour des régulateurs clés de la prolifération cellulaire, nous avons voulu examiner si l’expression de la protéine varie au cours du cycle de division cellulaire. Nous avons montré que l’abondance de Stau1 est maximale en début de mitose et qu’elle diminue ensuite lorsque les cellules complètent la division cellulaire. Nous avons ensuite découvert que cette baisse d’expression de Stau1 en sortie de mitose dépend du complexe promoteur d’anaphase/cyclosome (APC/C). En soutien à l’idée que Stau1 soit une cible de cette ubiquitine ligase de type E3, nous avons de plus démontré que Stau1 est ubiquitiné et dégradé par le protéasome. Ce contrôle des niveaux de Stau1 semble important puisque la surexpression de la protéine retarde la sortie de mitose et entraîne une diminution importante de la prolifération cellulaire. Par ailleurs, nous avons supposé que les différentes fonctions de Stau1 puissent également être sujettes à une régulation. Compte tenu que les activités de nombreuses protéines liant l’ARN peuvent être contrôlées par des modifications post-traductionnelles telles que la phosphorylation, nous avons voulu tester la possibilité que Stau1 soit phosphorylé. L’immunopurification de Stau1 et son analyse par spectrométrie de masse nous a permis d’identifier trois phosphosites dans la protéine. L’évaluation du rôle de ces événements de phosphorylation à l’aide de mutants phoshomimétiques ou non-phoshorylables a révélé que la modification de Stau1 pourrait compromettre son association à la protéine UPF1. Comme cette interaction est nécessaire pour déstabiliser les transcrits liés par Stau1, nos résultats suggèrent fortement que la fonction de Stau1 dans la dégradation d’ARNm est régulée négativement par sa phosphorylation. Toutes ces données mettent en lumière l’importance des modifications post-traductionnelles telles que l’ubiquitination et la phosphorylation dans la modulation de l’expression et des fonctions de Stau 1. Somme toute, il est vraisemblable que ces mécanismes de contrôle puissent avoir un impact significatif sur le destin des ARNm liés par Stau1, particulièrement dans un contexte de progression dans le cycle cellulaire. / Post-transcriptional regulation plays a major role in the fine tuning of gene expression by allowing a modulation of protein synthesis in space and time, according to cellular requirements. For instance, proteins recognizing RNA elements on transcripts can influence all the steps of their existence, such as their splicing, nuclear export, subcellular localization, translation and degradation. Staufen1 (Stau1) is a member of the double-stranded RNA-binding protein family that contributes to the post-transcriptional regulation of gene expression by its involvement in mechanisms that promote alternative splicing, transport, de-repression of translation and decay of specific messenger RNAs (mRNAs). The identity of potential Stau1 targets is now known as genome-wide analyses have shown that the protein is associated with about 7% of the HEK293T cell transcriptome. Although these mRNAs are classified in a broad range of functional categories, a large proportion of them code for proteins related to cellular metabolism and regulation of cellular processes. Considering all this information, we hypothesized that the different activities of Stau1 may be modulated in order to control appropriately the expression of Stau1-bound mRNAs. Since some of the mRNAs that are part of Stau1-containing complexes encode key regulators of cell proliferation, we wanted to examine whether Stau1 expression fluctuates during the cell division cycle. We showed that Stau1 abundance peaks at the onset of mitosis and then decreases as cells complete division. We then found that Stau1 down-regulation in mitosis exit is mediated by the anaphase promoting complex/cyclosome (APC/C). To support the idea that Stau1 is a target of this E3-ubiquitin ligase, we further demonstrated that Stau1 is ubiquitinated and degraded by the proteasome. The importance of controlling Stau1 levels during the cell cycle is underscored by the observation that its overexpression delays mitotic exit and impairs cell proliferation. Furthermore, we speculated that Stau1 different functions may also be regulated. In the view that the activities of numerous RNA-binding proteins can be controlled by post-translational modifications such as phosphorylation, we tested the possibility that Stau1 is phosphorylated. Mass spectrometry analysis of immunopurified Stau1 allowed the identification of three phosphosites in this protein. Assessment of the role of these phosphorylation events using phosphomimetic or non-phosphorylatable mutants revealed that Stau1 phosphorylation may compromise its association with Upf1. Because this interaction is necessary to elicit the destabilisation of Stau1-bound RNAs, our results strongly suggest that Stau1 function in mRNA decay is negatively regulated by its phosphorylation. Collectively, these data highlight the importance of post-translational modifications such as ubiquitination and phosphorylation in the modulation of Stau1 expression and functions. Overall, the mechanisms that control Stau1 are likely to have a significant impact on the fate of Stau1-bound mRNAs, especially in the context of cell cycle progression.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-21T17:31:58Z No. of bitstreams: 1 marcilenegomesevangelista.pdf: 1574607 bytes, checksum: acb74a623ce9dd5bb6068182a1172534 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-07T19:11:59Z (GMT) No. of bitstreams: 1 marcilenegomesevangelista.pdf: 1574607 bytes, checksum: acb74a623ce9dd5bb6068182a1172534 (MD5) / Made available in DSpace on 2017-08-07T19:11:59Z (GMT). No. of bitstreams: 1 marcilenegomesevangelista.pdf: 1574607 bytes, checksum: acb74a623ce9dd5bb6068182a1172534 (MD5) Previous issue date: 2013-03-06 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A esclerose múltipla (EM) é uma doença inflamatória, crônica e desmielinizante do sistema nervoso central (SNC). É na maioria dos casos grave e incapacitante, afetando cerca de 2,5 milhões de pessoas em todo mundo. Encefalomielite autoimune experimental (EAE) é um modelo murino de doença autoimune, mediada por linfócitos Th1 e Th17, desenvolvido para o estudo da EM. O protocolo de indução do modelo utiliza o adjuvante completo de Freund (CFA) que contem padrões moleculares associados ao patógeno (PAMPs) que se ligam aos receptores Toll-like (TLRs), expressos em células apresentadoras de antígeno (APC), cruciais para ativação dos linfócitos T. Estes receptores são necessários à indução da EAE, ativando vias de sinalização nas células da imunidade inata e adaptativa, que podem induzir a produção de mediadores pró-inflamatórios, responsáveis pela lesão no SNC, ou mediadores anti-inflamatórios, que podem participar da regulação da doença. O presente estudo avaliou a resposta imune inata na fase inicial de desenvolvimento da EAE em camundongos C57BL/6 imunizados com o peptídeo MOG35-55 (glicoproteína mielínica de oligodendrócitos) e CFA (grupo EAE) ou somente CFA (grupo MOG negativo). Os animais foram sacrificados nos dias 2, 4 e 7 após a indução do modelo. Os linfonodos inguinais e a medula espinhal foram removidos e submetidos à análise histológica, dosagens de citocinas e quimiocinas, assim como avaliação da expressão dos TLRs. Os resultados obtidos indicaram que somente os animais do grupo EAE desenvolveram sinais clínicos da doença. Este grupo também apresentou intenso infiltrado celular na medula espinal no 7º dia após a indução, níveis elevados de quimiocinas CCL5 e CCL20 e citocinas IL-6, IL-12, IL-1β, TNF-α, IFN-γ, IL-17, IL-10 e TGF- β no SNC, além de maior número de APCs expressando TLR3, TLR4 e TLR9. Desta forma, estes dados sugerem que a expressão dos TLRs e a produção das citocinas pró-inflamatórias mostram-se como sendo fatores críticos para a indução da EAE e, o aumento de padrões anti-inflamatórios, ainda nos pontos iniciais do desenvolvimento da doença, sugere o uso destes padrões, como mecanismos de regulação do modelo experimental e, possivelmente da EM. / Multiple sclerosis (MS) is an inflammatory, chronic demyelinating disease of the central nervous system (CNS). It is in most cases severe and disabling, affecting about 2.5 million people worldwide. Experimental autoimmune encephalomyelitis (EAE) is a murine model of autoimmune disease mediated by Th1 and Th17 lymphocytes developed for studying MS. The induction protocol model uses the complete Freund's adjuvant (CFA) containing the pathogen associated molecular patterns (PAMPs) that bind to Toll-like receptors (TLRs) expressed on antigen presenting cells (APC), crucial for activation T lymphocytes. These receptors are necessary for the induction of EAE by activating signal pathways in cells of the innate and adaptive immunity, which can induce the production of pro-inflammatory mediators responsible for the CNS lesions or anti-inflammatory mediators that can participate in the regulation of disease. The present study evaluated the innate immune response in the initial phase of development of EAE in C57BL/6 mice immunized with MOG35-55 peptide (myelin oligodendrocyte glycoprotein) and CFA (group EAE) or CFA alone (group MOG negative). The animals were sacrificed on days 2, 4 and 7 after induction model. The inguinal lymph nodes and spinal cord were removed and subjected to histological, serum cytokines and chemokines, as well as evaluating the expression of TLRs. The results showed that only animals of group EAE developed clinical signs of disease. This group also showed an intense cellular infiltrate in the spinal cord on day 7 after induction, high levels of chemokines CCL5 and CCL20 and cytokines IL-6, IL-12, IL-1β, TNF-α, IFN-γ, IL-17, IL-10 and TGF-β in the CNS, and increased number of APCs expressing TLR3, TLR4 and TLR9. Thus, these data suggest that expression of TLRs and production of pro-inflammatory cytokines are shown as being critical for the induction of EAE, and increased anti-inflammatory patterns, still in the initial points of development of the disease, suggests the use of these patterns as regulation mechanisms of the experimental model and possibly the MS.

Background: Surgical procedures are invariably accompanied by the use of inhalational and intravenous anesthetics. Both groups have strong influence on cardiovascular system by the interaction with myocardial oxygen supply/demand ratio and cardiomyocyte functions at the level of cell membranes, ion channels and regulatory enzymes. Aims: 1. To examine the effects of different isoflurane concentrations on the left ventricular (LV) dimensions and systolic function in the rat. 2. To examine the effects of isoflurane-induced myocardial preconditioning (APC) on the cardiac tolerance to ischemia- reperfusion (I-R) injury. 3. To compare the influence of anesthesia, based on ketamine- dexmedetomidine (KET-DEX), on the release of biochemical markers of myocardial injury and the early postoperative course with the anesthesia, based on sevoflurane-sufentanil (SEVO), in the patients undergoing coronary artery bypass grafting (CABG). Methods: 1. We carried out transthoracic echocardiographic examination in the rats immobilized by 1.5-3% concentration of isoflurane. 2. After inducing APC by isoflurane (0.5 and 1 MAC), we evaluated ventricular arrhythmias during regional ischemia (45 min), induced by the occlusion of the left anterior descending artery, and subsequent reperfusion (60 min), using the model of...

Meiosis is a specialized cell cycle, which generates haploid gametes from diploid parental cells. During meiosis one round of cohesion establishment during premeiotic DNA replication mediates two rounds of chromosome segregation. During meiosis I homologous chromosomes separate, whereas sister chromatids segregate during the second meiotic division without an intervening round of DNA replication. Both rounds of chromosome segregation are triggered by an ubiquitin ligase called the Anaphase-Promoting Complex or Cyclosome (APC/C). APC/C-dependent destruction of securin/Pds1 is required to activate separase, a thiol protease that mediates chromosome segregation by cleavage of the cohesin complex. The first meiotic division is preceded by an extended prophase I, during which maternal and paternal chromatids undergo recombination. The persistence of cohesion during premeiotic S- and prophase I is essential for recombination and both meiotic nuclear divisions. In order to prevent premature loss of cohesion, the APC/C has to be inactivated during early meiosis. How the APC/C is kept inactive during premeiotic S- and prophase I was unknown. This question has been addressed by studying the APC/C subunit Mnd2 from the budding yeast Saccharomyces cerevisiae. This work demonstrates that Mnd2 is required for the persistence of cohesion during premeiotic S- and prophase I. Mnd2 prevents premature activation of the APC/C by the meiosis-specific substrate recognition factor Ama1. In cells lacking Mnd2, the APC/C-Ama1 enzyme triggers premature ubiquitin-dependent degradation of Pds1, which leads to premature separation of sister chromatids due to an unrestrained activity of separase. Thus, chromosome segregation during meiosis depends on both inhibition of a meiosis-specific APC/C and timely activation of APC/C- dependent proteolysis. / Die Meiose ist ein spezialisierter Zellzyklus, der zum Ziel hat haploide Gameten aus diploiden Vorläuferzellen zu produzieren. Dafür erfolgen nach der prä-meiotischen DNA Replikation zwei aufeinanderfolgende Kernteilungen. In der ersten meiotischen Teilung erfolgt die Trennung der homologen Chromosomen. In einer zweiten meiotischen Teilung werden dann die Schwesterchromatiden getrennt. Die Trennung der Chromosomen wird durch den Anaphase-Promoting Complex oder Cyclosome (APC/C), einer Ubiquitin Ligase, reguliert. Der APC/C initiiert den Abbau von Securin/Pds1, einem Inhibitor der Thiol-Protease Separase, welche für die Trennung der Chromosomen zum Beginn der Anaphase verantwortlich ist. In einer im Vergleich zur Mitose extrem langen meiotischen Prophase I findet Rekombination zwischen maternalen und paternalen Chromosomen statt. Für diesen Vorgang, sowie für die beiden folgenden meiotischen Teilungen, wird Kohäsion zwischen den Schwesterchromatiden benötigt. Ein frühzeitiger Verlust der Kohäsion führt zur frühzeitigen Trennnung der Schwesterchromatiden, wodurch aneuploide Gameten produziert werden können. Daher muss die Aktivität des APC/C während der meiotischen Prophase I inhibiert werden. Wie der APC/C während der Prophase I inaktiviert wird, war bisher unbekannt. Einsicht in dieses Problem ergab sich aus der Untersuchung der APC/C Untereinheit Mnd2 aus der Bäckerhefe Saccharomyces cerevisiae. Es wird gezeigt, dass Mnd2 für den Verbleib der Kohäsion zwischen den Schwesterchromatiden während der meiotischen S- und Prophase I benötigt wird. Während dieser Phase verhindert Mnd2 die frühzeitige Aktivierung der Meiose-spezifischen Form des APC/C-Ama1. In meiotischen Zellen, die kein Mnd2 besitzen, löst das APC/C-Ama1 Enzym die Ubiquitin-abhängige Zerstörung von Pds1 aus. Dies führt zu einer frühzeitigen Aktivierung von Separase, welches die Trennung der Schwesterchromatiden schon während der meiotischen S- und Prophase I zur Folge hat. Die korrekte Verteilung der Chromosomen hängt daher sowohl von der Inhibierung als auch der Aktivierung des APC/C ab.

Background: Surgical procedures are invariably accompanied by the use of inhalational and intravenous anesthetics. Both groups have strong influence on cardiovascular system by the interaction with myocardial oxygen supply/demand ratio and cardiomyocyte functions at the level of cell membranes, ion channels and regulatory enzymes. Aims: 1. To examine the effects of different isoflurane concentrations on the left ventricular (LV) dimensions and systolic function in the rat. 2. To examine the effects of isoflurane-induced myocardial preconditioning (APC) on the cardiac tolerance to ischemia- reperfusion (I-R) injury. 3. To compare the influence of anesthesia, based on ketamine- dexmedetomidine (KET-DEX), on the release of biochemical markers of myocardial injury and the early postoperative course with the anesthesia, based on sevoflurane-sufentanil (SEVO), in the patients undergoing coronary artery bypass grafting (CABG). Methods: 1. We carried out transthoracic echocardiographic examination in the rats immobilized by 1.5-3% concentration of isoflurane. 2. After inducing APC by isoflurane (0.5 and 1 MAC), we evaluated ventricular arrhythmias during regional ischemia (45 min), induced by the occlusion of the left anterior descending artery, and subsequent reperfusion (60 min), using the model of...

I samarbete med Norconsult och kund ska denna rapport undersöka inomhusklimatet i ett museum och resultera i ett förslag på ett kontrollsystem för Heating, Vetilation and Air conditioning (HVAC) som genererar stabil temperatur och relativ luftfuktighet (RF) inom rekommenderade gränsvärden för konstbevaring. Genom litteraturstudier, fältstudier, dataanalys och skapandet av en simulerad modell av utrymmet, ska ett förslag om lämplig kontrollmetod av HVAC framläggas. Vid test av olika kontrollmetoder, tog sig MPC-kontrollen sig bäst ut. Litteraturstudien innefattar flera studier och rapporter som använt sig av MPC-kontroll för liknande projekt med fördelaktiga resultat. Resultaten av dataanalysen visar att under stor del av loggnings-perioden avvek temperatur och/eller RF från gränsvärdena. I vissa utrymmen var uppemot 99% av de loggade värdena utanför gränsvärdet för antingen temperatur eller RF. Av samtliga sensorsamplingar på museet låg 48,53% av dessa utanför de satta rekommendationerna. Generellt var luften i museet för varm och torr till syftet konstförvaltning. Vid jämförelse av de tre utvecklade MPC-kontrollerna, visar alla varianterna till att generera stabila resultat. Det framarbetade förslaget indikerar på ett energieffektivare kontrollsystem gentemot befintligt. Om simuleringsmodellen av utrymmet visar skilja sig från verkliga förhållanden, förändras dynamiken i systemet, och inställningarna för MPC-kontrollen gäller ej längre utan behövs konfigureras om. Projektets primära mål om att generera ett optimerat systemförslag som kontrollerar parametrarna temperatur RF, anses ha uppnåtts - om än endast i simulerade resultat. Vidare arbete innefattar att verifiera modellen mot befintligt system, och därefter inkludera kostnadsfunktioner till MPC-kontrollen. Efter systemimplementering bör faktiska utfall jämföras med simulerade utfall för att utvärdera modellens precision. / In collaboration with Norconsult and the customer, this report will examine the indoor climate in the museum and result in a proposal for a control system for HVAC that generates stable temperature and RH within recommended values ​​for the preservation of art. A proposal for an appropriate control method of the HVAC shall be presented through literature studies, field studies, data analysis, and the creation of a simulated model of the environment. The MPC control performed best during the testing of different control methods. The literature study includes several studies and papers that use MPC control for similar projects with beneficial results. The results of the data analysis show that during a large part of the logging period, the temperature and/or RH deviated from the limit values. In some areas, up to 99% of the logged values ​​were outside recommendations. Of all sensor samplings at the museum, 48.53% of these were registered outside limit values. In general, the air in the museum was too hot and dry for art preservation. When comparing the three developed MPC controllers, all variants show to generate stable results. The elaborated proposal indicates a more energy-efficient control system compared to the existing one. If the simulation model of the environment turns out to differ from real conditions, the dynamics of the system change , and the settings for the MPC control no longer apply and need to be reconfigured. The project's primary goal of generating an optimized system proposal that controls the temperature and relative humidity is considered to have been achieved - albeit only in simulated results. Further work includes verifying the model against the existing system and including cost functions to the MPC control. After system implementation, actual outcomes should be compared with simulated outcomes to evaluate model precision.

歷年來台灣地區女性整體勞動力參與率持續上升，今時今日，在所有適合工作的女性中，有將近一半以上的女性有意願、有能力投入勞動力市場，但是在整體女性勞動力參與率「量」的提升之外，其中歷年趨勢所呈現的形態也有所不同，本研究將要探討的主題即為此趨勢改變的原因，分析研究在年齡（Age）、時期（Period）與世代（Cohort）相互作用下，台灣地區女性勞動力參與率模式改變的背後，這三者所扮演的角色。 經由採用APC模型，控制1978年與1979年的迴歸係數相等，以此來分解出當Age、Period與Cohort同時對於女性的勞動力參與產生影響之下，它們分別對於女性勞動力參與率的淨效果。在分析的最後，本研究亦加入女性的婚姻狀態和教育程度作為控制，並以出生世代作為分類，除了試圖分析個人條件的不同會造就不一樣參與勞動的機率之外，也可以觀察到不同出生世代的女性之間有什麼差異。 研究結果：（一）女性的勞動力參與率的整體提升是受年代效應所影響；（二）女性參與勞動的生命歷程深受年齡效應影響，每一個年齡階段具有不同的年齡效應，當女性走到某一年齡時，便會有遵循同樣模式，也就是年齡規範（Age Norm）；（三）女性勞動力參與率形態的「變形」是受出生世代效應差異所影響，2006年的女性較1978年受到出生世代效應影響減弱，從高同質性轉變為高異質性的勞動參與行為；（四）女性的婚姻狀態與教育程度對於其勞參率的影響會隨著世代改變：當女性教育程度提高時，其世代間參與勞動的機率變異則縮小；不同出生世代的未婚女性其參與勞動的機率變異最大；未婚女性隨著教育程度提高，以及出生世代越年輕，其參與勞動的機率越高。