Cette thèse s’inscrit dans le cadre de la recherche d’agonistes et d’antagonistes de récepteurs de chimiokines d’intérêt thérapeutique chez des champignons et des levures pathogènes pour l’homme ou l’animal. Un screening préliminaire réalisé sur 88 souches de microorganismes a permis de sélectionner trois extraits de champignons présentant une activité compétitrice. Des champignons Aspergillus ochraceus et Microsporum cookei, nous avons isolé une substance possédant une activité compétitrice sur le récepteur CCR5. Des chromatographies d’exclusion effectuées sur les lyophilisats des milieux conditionnés (CO.4) ont conduit à l’isolement d’une fraction active dont les constituants ont une masse moléculaire comprise entre 30 et 80 kDa. L’étude de ces substances n’a pas été poursuivie plus en détail. Par contre, de l’extrait dichlorométhane (CO.1) du champignon Trichoderma virens, nous avons isolé la gliotoxine [102] qui possède une activité antagoniste sur les récepteurs CCR2b et CCR5. Différents essais de culture de Trichoderma virens et d’Aspergillus fumigatus, connus pour synthétiser cette toxine, ont été entrepris en vue d’améliorer la quantité de gliotoxine produite. Malheureusement, ceux-ci n’ont pas abouti. A partir des faibles quantités de gliotoxine isolées, nous avons synthétisé deux analogues, la déthiogliotoxine [133] et la déhydrogliotoxine [134]. La comparaison des résultats des tests de compétition de ceux-ci sur le récepteur CCR2b démontre l’importance du pont disulfure pour l’observation de cette activité. Nous avons ensuite synthétisé les épidithiopipérazinediones (ETP) reprises ci-dessous, afin d’évaluer l’importance de cet élément structural pour l’activité compétitrice vis-à-vis des récepteurs CCR2b et CCR5. R1 R2 R3 R4 Me Me H H [141] Et Et H H [155a] i-Pr i-Pr H H [155b] Bz Bz H H [155c] Me Ph H H [161] Cyclohexyle Ph H H [164] Ph Ph H H [168] MEM MEM H H [186] Me Me Me H [191] Me Me Me Me [192] A cet effet nous avons utilisé le schéma de synthèse suivant : Pour l’introduction du pont disulfure, la méthode de Trown modifiée par Fukuyama a été utilisée. A l’exception de la pipérazinedione N,N’-diméthylée [137] qui est commercialement disponible, toute les autres pipérazinediones ont dû être synthétisées. Pour cela, plusieurs méthodes ont été mises en œuvre. Pour les composés N,N’-diéthyle, N,N’-diisopropyle et N,N’-dibenzyle [153 a, b, c] et N,N’diméthoxyéthoxyméthyle [184], un traitement de l’anhydride de glycine [152] avec une base et le chlorure d’alkyle correspondant permet d’obtenir la pipérazinedione symétrique avec de bons rendements. Les pipérazinediones non symétriques N-méthyl-N’-phényle [159] et N-cyclohexyl-N’-phényle [162] ont quant à elles été synthétisées par la méthode de Monforte. La synthèse de la pipérazinedione N,N’-diphényle [170] a été réalisée par dimérisation de l’a-chloramide [172]. De plus, deux dérivés substitués au niveau des carbones portant le pont disulfure ([191] et [192]) ont également été synthétisés en utilisant le schéma suivant : Les activités compétitrices de tous les dérivés synthétisés ont été évaluées et comparées.

Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.

New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.

En France, on estime à 150 000 le nombre d’accident vasculaire cérébraux par an. Avec un coût de 8,3 milliards d’euros, c’est devenu une problématique de santé publique. Les dépenses sont, entre autres, lié aux séquelles, car 43,2 % sortent d’hospitalisation en étant dépendant physiquement.Ces séquelles vont séquelle vont être à l’origine de limitations, provoquant un cercle vicieux d’inactivité, et amenant un déconditionnement. Pour lutter contre ce déconditionnement, il semble pertinent de respecter les recommandations des sociétés savantes en termes d’activité physique (AP). Néanmoins en retour à domicile, très peu de patients atteignent le minimum d’AP requis. L’éducation thérapeutique du patient (ETP) semble être une option pertinente pour remédier à ce problème.Ce travail de recherche s’est donc intéressé à l’effet d’un programme ETP à l’AP chez des patients en phase subaigue. Le programme était effectué au domicile des patients, et était composé de visites à domicile et d’appels téléphoniques. L’AP était contrôlée grâce à un actimètre et des livrets de suivi.Après les 6 mois du programme, il ressort une augmentation du périmètre de marche, mais pas d’impact sur la force des membres inférieurs, la composition corporelle, la fatigue et la dépression.Les principales caractéristiques des patients volontaires à un programme ETP à l’AP étaient la persistance de la fatigue, la dépression, peu de séquelles neuro-motrices physiques et un fort soutien de l’entourage. Enfin, au cours des 6 mois de suivi, les patients ont maintenu des durées d’AP qui étaient au-dessus des recommandations en termes d’AP. / In France, we estimate at 150,000 the number of cerebral vascular accident per year. With a cost of 8.3 billion euros, it has become a public health issue. The expenses are, among others, related to legacy, as 43.2% leave hospital being physically dependent.These effects will aftereffect will cause limitations, causing a vicious cycle of inactivity and deconditioning bringing. To fight against this deconditioning, it seems appropriate to follow the recommendations of learned societies in terms of physical activity (PA). Yet back home, very few patients reach the minimum required AP. Therapeutic patient education (TPE) seems to be a relevant option to address this problem.This research is therefore interested in the effect of ETP to the AP in patients with subacute phase. The program was conducted in patients' homes, and consisted of home visits and phone calls. The PA was controlled through a actimeter and monitoring booklets.After 6 months of the program, it appears an increase in the walking distance, but no impact on the strength of lower limbs, body composition, fatigue and depression.The main characteristics of volunteer patients to ETP to the PA were persistent fatigue, depression, few physical neuro-motor sequelae and strong support from the entourage.Finally, during the 6 months follow-up, patients maintained durations of AP which were above recommendations in terms of AP.

T-cell acute lymphocytic leukemia (T-ALL) affects approximately 1,500 people per year in the United States, many of them children. The overall survival rate of children with T-ALL is greater than 80%. However, patients in a newly identified subtype called early T-cell progenitor acute lymphocytic leukemia (ETP-ALL), have a survival rate of only 19%. We have used the Sleeping Beauty (SB) transposon/transposase system in mice to model the T-ALL subtypes and identify cancer-causing mutations in the diseases. We have also developed three strains of NOTCH1 transgenic mice. NOTCH1 is a gene that is mutated in over 60% of cases of T-ALL, and these NOTCH1 transgenic mice could be used to better understand the role NOTCH1 plays in T-cell transformation. In order to model T-ALL subtypes we crossed SB mice to Vav-iCre mice, Lck-Cre mice, and CD4-Cre mice. This causes activation of SB in hematopoietic stem cells (HSCs), double negative (DN) thymocytes, and double positive (DP) T-cells, respectively. The Vav/SB tumors were characterized by mutations in Notch1, Ikzf1, and Rasgrp1. The predominant mutations found in the Lck/SB and CD4/SB models were Stat5b, Myc, Gfi1, Whsc1, and Jak1. Microarray was performed on a subset of samples. It was found that the CD4/SB tumors had expression profiles very similar to human ETP-ALL samples, and the Vav/SB tumors had expression profiles very similar to typical T-ALL samples. This data indicates that the cell-of-origin for ETP-ALL may not be an early T-cell progenitor, but instead may be a double positive or single positive T-cell. It also indicates that the cell-of-origin for typical T-ALL may be a stem/progenitor cell of the T-lineage. In order to better study the oncogenic potential of mutant NOTCH1 in T- ALL, we produced three NOTCH1 transgenic mouse strains that mimic the most common NOTCH1 mutations found in human T-ALL patients. These mutations are found in two distinct regions of the gene, the heterodimerization (HD) domain and the PEST domain and can occur alone or in combination. The strains also contain a lox-stop-lox (LSL) cassette in the first exon of NOTCH1, making expression Cre-dependent. Preliminary results from NOTCH1-HD-PEST (NHDP) transgenic mice indicate that, when crossed to Lck-Cre mice, offspring do not develop T- cell lymphoma. However, when NHDP/Lck-Cre mice are crossed to SB mice, the mutant NOTCH1 transgene accelerates a SB-induced model of T-cell lymphoma.

In the Eastern Tropical Pacific (ETP), the operation mode of purse-seine fishing can be divided into dolphin sets and non-dolphin sets. Dolphin sets can catch more yellowfin tuna, but cause a lot of dolphin deaths. On the contrary, non-dolphin sets can catch more skipjack tuna, but discard a lot of tuna. Therefore, the choice of the operation mode to the ETP purse-seine fishery is very influential. If the fishermen use more dolphin sets, they are able to catch high quantity and more valuable yellowfin tuna. Conversely, if the fishermen use more non-dolphin sets, they will not hurt dolphins. But the tuna fish caught by this operation mode is smaller in size and the discarding rate is extremely high which will affect the overall profits of the fishermen. The research will investigate how the fishermen make the choice of the operation mode in the dilemma between dolphin sets which cause dolphins-bycatch and non-dolphin sets which result in tuna-discarding, In addition, if managers can ban dolphin sets or non-dolphin sets to maximize the profit of the fishermen and maintain the ecological balance between tuna and dolphins.

The growing need for wastewater treatment and control of disposal of sludge, residues and waste of agricultural production (mainly of pigs) worries the society because of the major environmental impacts that the improper disposal may result. Because of this and targeting the possibility of power generation through an anaerobic digestion system, with the reuse of this waste, this study aims to quantify and qualify the generation of biogas from the anaerobic digestion in different substrates derived from an Company active in different segments (primary production, chicken and poultry slaughterhouses and dairy industry) of the countryside of Rio Grande do Sul. There were performed six experiments in the Bioreactor Laboratory of Univates University Center, by using reactors of one liter, which were filled with 600 mL of different substrates at various concentrations of each substrate and in bench scale, and after filled, the reactors were kept in greenhouse under temperature control at 35°C. Performed through batch processes, the biogas generated in each experiment was quantified by using a device developed by the laboratory itself. The methane present in this biogas was quantified by a specific sensor called Advanced Gasmetter, of the company PRONOVA AnalysetechnichGmbH&Co. Different results were obtained for each mixture of substrates; the largest amount of biogas was 13.282,72 mL, observed in sample 1 of the VI experiment, which also showed the greatest concentration of methane, that was 8.897,72 mL. It was possible to verify that the cellulosic casing and the float sludge are great increment for increasing the production of biogas and consequently methane in the digestion process. The quantification of substrates also presented an satisfactory volume for possible construction of a digester in full scale aiming the energy generation. / A crescente necessidade pelo tratamento de efluentes e controle da destinação de lodo, resíduos e dejetos da produção agrícola (principalmente de suínos), preocupa a sociedade em razão dos grandes impactos ambientais que a inadequada destinação pode acarretar. Em razão disso e visando a possibilidade de geração de energia através de um sistema de biodigestão anaeróbia, com o aproveitamento desses resíduos, que este estudo visa quantificar e qualificar a geração de biogás proveniente da biodigestão anaeróbia em diferentes substratos provenientes de uma empresa atuante em diferentes segmentos (produção primária, abatedouros de aves e suínos e indústria de laticínios) no interior do Rio Grande do Sul. Foram realizados seis experimentos junto ao Laboratório de Biorreatores do Centro Universitário Univates, utilizando reatores de um litro, os quais foram preenchidos com 600 mL de diferentes substratos, em diversas concentrações de cada substrato e em escala de bancada, sendo que após preenchidos, os reatores eram mantidos em estufa sob controle de temperatura a 35ºC. Realizado por meio de processos por batelada, o biogás gerado em cada experimento foi quantificado utilizando um aparelho desenvolvido pelo próprio laboratório. O metano presente nesse biogás foi quantificado através de um sensor específico denominado Advanced Gasmetter, da empresa PRONOVA Analysetechnich GmbH & Co. Foram obtidos diferentes resultados para cada mistura de substratos, sendo que a maior quantidade de biogás foi de 13.282,72 mL, verificada na amostra 1 do experimento VI, a qual também apresentou a maior concentração de metano que foi de 8.897,72 mL. Foi possível verificar que a tripa celulósica e o lodo flotado são ótimos incrementos para aumentar a produção de biogás e consequentemente metano no processo de biodigestão. A quantificação dos substratos também apresentou um volume satisfatório para possível construção de um biodigestor em escala real visando a geração de energia.

Cette thèse s’inscrit dans le cadre de la recherche d’agonistes et d’antagonistes de récepteurs de chimiokines d’intérêt thérapeutique chez des champignons et des levures pathogènes pour l’homme ou l’animal. <p><p>Un screening préliminaire réalisé sur 88 souches de microorganismes a permis de sélectionner trois extraits de champignons présentant une activité compétitrice.<p><p>Des champignons Aspergillus ochraceus et Microsporum cookei, nous avons isolé une substance possédant une activité compétitrice sur le récepteur CCR5. Des chromatographies d’exclusion effectuées sur les lyophilisats des milieux conditionnés (CO.4) ont conduit à l’isolement d’une fraction active dont les constituants ont une masse moléculaire comprise entre 30 et 80 kDa. L’étude de ces substances n’a pas été poursuivie plus en détail.<p> <p>Par contre, de l’extrait dichlorométhane (CO.1) du champignon Trichoderma virens, nous avons isolé la gliotoxine [102] qui possède une activité antagoniste sur les récepteurs CCR2b et CCR5. Différents essais de culture de Trichoderma virens et d’Aspergillus fumigatus, connus pour synthétiser cette toxine, ont été entrepris en vue d’améliorer la quantité de gliotoxine produite. Malheureusement, ceux-ci n’ont pas abouti.<p> <p>A partir des faibles quantités de gliotoxine isolées, nous avons synthétisé deux analogues, la déthiogliotoxine [133] et la déhydrogliotoxine [134]. La comparaison des résultats des tests de compétition de ceux-ci sur le récepteur CCR2b démontre l’importance du pont disulfure pour l’observation de cette activité.<p> <p>Nous avons ensuite synthétisé les épidithiopipérazinediones (ETP) reprises ci-dessous, afin d’évaluer l’importance de cet élément structural pour l’activité compétitrice vis-à-vis des récepteurs CCR2b et CCR5.<p><p> \ / Doctorat en sciences, Spécialisation chimie / info:eu-repo/semantics/nonPublished

Det här projektet har under våren 2021 utförts som ett examensarbete på uppdrag av ETP Transmission AB. Företaget är beläget i Linköping och producerar hydrauliska axel-/navförband till flera olika marknader och användningsområden. Enkelheten att montera och applicera samt deras höga kvalitet är något som utmärker produkterna.  Syftet var att undersöka och utarbeta förbättringsförslag för företagets omställningsprocesser, framför allt vid lågvolymstillverkning. Målet var att försöka reducera ställtiden med 25–50%. För att uppnå det användes metoden Single Minute Exchange of Die (SMED) som är ett verktyg för att reducera ställtider. Valet av SMED gjordes efter en litteraturstudie där metoden visat goda resultat i liknande projekt. Nuläget analyserades med videoupptagning, spaghettidiagram och intervjuer med anställda. Det filmade materialet bearbetades i programvaran AviX, där omställningsarbetet kunde brytas ner i operationer och sorteras som inre eller yttre ställ. De största orsakerna till de nuvarande ställtiderna var verktygsbyten inklusive kalibrering samt programskrivning för nya produkter under omställningsprocessen. Med kunskap från teorin och framtagandet av nulägesanalysen utarbetades förbättringsförslag. De olika förslagens styrkor och svagheter analyseras samt vilken trolig effekt de skulle ha vid ett implementerande. För att tydligare illustrera förbättringsförslagens förväntade effekt samt belysa den arbetsinsats som krävs för att implementera dem, gjordes en PICK-analys. Resultatet visade att den enskilt bästa lösningen var att fokusera på samkörning av produkter med liknande verktygsuppsättning. Den teoretiska förbättringen för ETP Transmission AB:s mest sålda produkt var en ställtidsreducering med ca 30%. Ett ännu bättre teoretiskt resultat erhölls då förbättringsförslagen kombinerades. För produktgruppen Express gav en sådan kombinationslösning en teoretisk reducering på ca 47%.  Slutligen belyser rapporten vikten av att jobba med Lean och mäta mer i produktionen. / This bachelor thesis has been made during the spring of 2021 on behalf of ETP Transmission AB. The company is located in Linköping, Sweden and produces hydraulic hub-/shaft connectors for several different markets and applications. What defines their products is the high quality along with the quick and simple assembly/disassembly. The purpose was to examine and develop improvements for the company’s changeovers, especially for the low volume manufacturing. The aim was to reduce the changeover times with 25-50%. To achieve this the method SMED (Single Minute Exchange of Die) was used which is a Lean tool to help reduce changeover times. The choice of using SMED was made after conducting a literature study where it was shown to have great results in similar projects.  The current state was analysed using video, spaghetti charts and interviews with the employees. The software AviX was used to break down the changeovers into internal and external operations. Tool changes and programming of the machines during the changeover were found to be greatest time consumers.  By using the theory and analysing the current state, different improvement suggestions were developed. The strengths and weaknesses of the improvements were evaluated and visualized with the use of a PICK-chart. What was found to be the greatest improvement was to group similar products which use the same machine tools. A theoretical changeover time reduction for one of ETP Transmission AB most sold product group was estimated to be approx. 30%. If all the suggested improvements were to be implemented, it would theoretically reduce the changeover time by approx. 47%.  Lastly, the report highlights the importance of working with Lean and to measure more of the production.

The subject of this thesis is to describe the approach of the state and the non-profit sector to education of Romani children in Eastern Slovakia. The theoretical part is focused on the approach of state, from pre-school through elementary school. The second chapter is devoted to the concept of social disadvantages and definitions of children coming from this type of environment. It clarifies known concepts such as zero class, preparatory class, teacher assistant and a full-day educational system, related to primary education and pupils from socially disadvantaged environment. The practical part is specifically dedicated to a single non-profit organization working in eastern Slovakia, ETP Slovakia - Center for Sustainable Development, with a description of the organization and their projects. Qualitative research was conducted using semi-structured interviews. The aim of this thesis is to describe the activities of five staff members of the NGO ETP Slovakia, their preferred styles of work with children and to find out if they themselves see the benefits of non-profit organizations within the village Velka Ida. This thesis should be helpful for workers in the field of education of Roma and socially disadvantaged children, helping them to become familiar with the concepts and principles associated...