Le paludisme reste une des maladies infectieuses les plus importantes au monde. Récemment, le laboratoire de Dr E. Davioud-Charvet a conçu des 3-Benzyl-Ménadiones substituées (benzylMD) comme agents antipaludiques prometteurs. Les études sur le mode d'action ont mis en évidenceque ces molecules déstabilisent l'équilibre redox des érythrocytes infectés en agissant comme agent catalytique redox (redox-Cycler), une stratégie prometteur pour le développement de nouveaux agents antipaludiques. Le travail de thèse présenté a caractérisé l'activité in vitro et le mécanisme d'action de tête de série, la 3-[4-(trifluorométhyl)-Benzyl]-Ménadione 1c, ce qui représente une partie principale du développement des benzylMDs. Une deuxième partie explorait les relations structure-Activité de benzylMD dérivés. Dans l'ensemble, les résultats démontrent l'activité in vitro très prometteuse de la benzylMD 1 cet soutiennent l'amélioration de benzylMDs comme nouveaux candidats-Médicaments antipaludiques. / Malaria is still one of the most important infectious diseases worldwide. Previously, the laboratory of Dr. E. Davioud-Charvet presented the chemical design of very promising antimalarial agents, 3-[substituted-Benzyl]-Menadiones (benzylMD). Studies on the mode of action evidenced that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox-Cyclers - a promising strategy for the development of new antimalarial agents. The presented PhD work characterized the in vitro potency and the mechanism of action of the lead agent, the 3-[4-(trifluoromethyl)benzyl]-Menadione 1 c, which represents an essential part of the lead optimization stage of the benzylMD drug development process. A second part of this work focused on the structure-Activity relationships benzylMD derivatives. Overall, the presented findings demonstrate the promising in vitro potency of lead benzylMD 1c and highly support the further development of benzylMDs as antimalarial drug candidates.

Amplification of target DNA in vitro via polymerase chain reaction (PCR) is a widely used scientific technique in molecular biology. This method relies on repeated heating and cooling cycles of the DNA and enzyme mixture, resulting with the enzymatic replication of the DNA. A heat stable Taq DNA polymerase and a thermal cycler that enables repeated heating/cooling cycles are the two key components of the PCR. In this study we have produced a high activity Taq DNA polymerase and used this enzyme to validate and optimize two newly developed thermal cyclers- a conventional and a capillary thermal cycler. Taq DNA polymerase gene was amplified from Thermus aquaticus DNA, was cloned and overexpressed using Gateway&reg / recombination cloning technology. Highly active Taq DNA polymerase enzyme was purified from E.coli and its activity was tested by PCR, using different sources of DNA. Our results showed that the enzyme activity of the produced Taq DNA polymerase was not significantly different from the commercial available Taq DNA polymerase. To further characterize the purified enzyme, endonuclease and nicking activities were also tested to be absent. The fidelity of the purified Taq DNA polymerase was also tested and found to be the same as the commercially available Taq polymerases. In this study, in addition to the production of a Taq polymerase, optimization studies for two new thermal cyclers, a conventional and a capillary, was also carried out. The conventional thermal cycler was found to be as efficient as the commercially available thermal cyclers in the 95% confidence interval. The capillary thermal cycler was tested as a proof of concept and our results showed that it works less efficiently due to the insufficient insulation and capillary tubes being longer than the capillary tube holder.

Today, Mars is one of the most interesting and important destinations for humankind and copious methods have been proposed to accomplish these future missions. One of the more fascinating methods is the Earth-Mars cycler trajectory which is a trajectory that accomplishes repeat access to Earth and Mars with little to no fuel-burning maneuvers. This would allow fast travel to and from Mars, as well as grant the possibility of multiple missions using the same main vehicle. Insertion from Earth-orbit onto the cycler trajectory has not been thoroughly ex- plored and the only existing method so far is a Hohmann-esque transfer via direct burn. The use of manifolds from gravitational equilibrium points has not been con- sidered for low energy transfer to the cycler trajectory. This work is primarily focused on closing this gap and analyzing the feasibility of this maneuver. To accomplish this, a study of the cycler trajectory – and the S1L1-B class specif- ically – was completed. The required gravity assist maneuvers at each planet was analyzed through V∞ matching and the entire trajectory was generated over the re- quired inertial period. This method allowed for the generation of 2 cycler trajectories of the inbound and outbound classes, which combine to allow for a reduction in the amount of time the astronauts spend in space. The Earth-Sun L2 point is analyzed as a potential hub for the maneuver and a halo orbit about this libration point is optimized for low energy transfer from and Earth parking orbit. The associated invariant manifold is then optimized for launch date and distance to the first trajectory on the cycler in order to burn from a trajectory on the manifold to the cycler trajectory. iv The comparisons of this work lie in the required ∆V to perform each maneuver compared to a direct burn onto the cycler trajectory. These values are compared and the practicality of this maneuver is drawn from these comparisons. It was found that the total required ∆V for the manifold method is larger than a direct burn from Earth orbit. However, this considers the trajectory from Earth to the halo orbit and if this is removed from consideration the ∆V is significantly reduced. It was shown that the feasibility of this method relies heavily on the starting position of the cycler vehicle. If the vehicle begins in Earth-orbit, a direct burn is preferred, however, if the vehicle began in a halo orbit (say it was assembled there) the manifold maneuver is largely preferable.

Adaptation to chronic hypoxia provides myocardial protection against ischemia - reperfusion injury (IR). Cardioprotective effect of adaptation depends on the degree and duration of hypoxic exposure and daily regime of adaptation. Certain protective regimes of adaptations to hypoxia have been reported to activate proapoptotic signaling pathways and bioactive sphingolipids were recently shown to play important role in the regulation of apoptosis in the heart. We aimed to determine the mRNA level of selected genes related to apoptotic pathways and to sphingolipid metabolism in two models of hypoxic adaptation, continous normobaric hypoxia (CNH 10% O2) with different exposures (4h, 48h, 120h, 21days) and intermitent hypobaric hypoxia (IHH 7000 m, 8h/day). Both ventricles, LV and RV, were analysed after adaptation to CNH and only LV was analysed after IHH adaptation. Our results show that both types of adaptation increased mRNA of proapoptotic genes, CNH mainly in RV and IHH in LV. Furthermore, increased expressions of proapoptotic genes were accompanied by the increase of expression of enzymes producing predominantly protective kinds of sphingolipids. The exact role of apoptosis and sphingolipid signaling molecules in endogenous myocardial protection requires further research. Key words: Apoptosis,...

In this research, the focus was on the development of a Battery Cycler system with the primary objective of accurately predicting both the State of Charge (SoC) and State of Health (SoH) for batteries. Machine learning techniques, specifically MLP Regression, K-Nearest Neighbor, and Decision Tree Regression, were harnessed for a comprehensive analysis. The data collection and processing phase spanned 44 days. The findings underscore the potential of employing relatively uncomplicated machine learning models for the prediction of SoC and SoH. Particularly noteworthy was the strong performance of K-Nearest Neighbor, especially after deliberate optimization efforts were applied. Despite the simplicity of these techniques, the results suggest significant promise for battery management and health assessment. Nevertheless, challenges linked to temperature fluctuations and current noise were identified as factors impacting predictive performance. Mitigating these challenges is imperative to enhance the robustness and precision of predictive models in future iterations. The implications of this work extend to broader applications in battery management systems, offering insights into potential avenues for optimizing battery usage, extending longevity, and enhancing overall performance. Leveraging machine learning methodologies in a straightforward manner, this research is anticipated to contribute to advancements in battery health monitoring and management, setting the stage for more intricate models in subsequent studies. / I denna forskning har vi tagit oss an utvecklingen av ett battericykelsystem med målet att noggrant förutsäga både laddningstillstånd (SoC) och hälsotillstånd (SoH) för batterier. Genom att utnyttja maskininlärningstekniker utförde vi en omfattande analys med hjälp av MLP-regression, K-Nearest Neighbor och Decision Tree regression. Över en tidsperiod av 44 dagar samlades batteridata in och bearbetades noggrant. Resultatet understryker möjligheten att använda relativt okomplicerade maskininlärningsmodeller för att förutsäga både laddningstillstånd och hälsotillstånd. Särskilt K-Nearest Neighbor framstår som en lovande kandidat med tanke på förutsägbarhetsnoggrannheten den visat, särskilt efter medvetna ansträngningar för optimering. Trots teknikernas enkelhet antyder våra resultat en betydande potential för batterihantering och hälsobedömning. Emellertid har utmaningar som temperaturvariationer och strömbuller identifierats som faktorer som påverkar förutsägelseprestanda. Att bemöta dessa utmaningar är avgörande för att öka robustheten och precisionen i våra förutsägelsemodeller i framtida utföranden.. Denna forsknings arbetsresultat sträcker sig till bredare användningsområden inom batterihanteringssystem och erbjuder insikter i möjliga riktningar för att optimera batterianvändning, livslängd och övergripande prestanda. Genom att utnyttja maskininlärningsmetoder förutser vi att denna forskning kommer att bidra till framsteg inom övervakning och hantering av batterihälsa, och lägga grunden för mer sofistikerade modeller i framtiden.

Dendritische Zellen (DZ) sind essentiell für die Aktivierung von Immunantworten. Drei Flt3-abhängige DZ Populationen aus dem Blut bestehend aus konventionellen (kDZ) BDCA1+ DZs und BDCA3+ DZs und plasmazytoide DZs wurden bereits beschrieben. Hier wurden zum ersten Mal sich aus Monozyten entwickelnde DZ (moDZ), genauer BDCA1+CD14+ pro-inflammatorische DZ (pro-iDZ) aus periphärem Blut unter homöostatischen Bedingungen identifiziert. Isolierte pro-iDZ sekretierten spontan große Mengen an pro-inflammatorischen Zytokinen, die kDZ reifen ließen und T Zell Proliferation unterstützten. Sie waren BDCA1+CD14- DZ und CD14+CD16- Monozyten in der TH17 Zell Induktion überlegen. Pro-iDZ ähnliche BDCA1+CD14+ Zellen konnten durch imaging cycler microscopy in Geweben von Patienten die an Psoriasis, Dermatomyositis oder entzündetem Halonävus erkrankt waren identifiziert werden. Ihr Fehlen in gesunder Haut deutete eine Rekrutierung von pro-iDZs in entzündetes Gewebe an. Eine Verwandtschaftsanalyse von pro-iDZ zwischen Monozyten, kDZ des Blutes und in vitro generierten moDZ auf genomweiter Ebene wies auf einen monozytären Ursprung hin. Anylse mittels funktioneller Annotation auf differentiell exprimierten Genen zwischen pro-iDZ und Monozyten zeigte eine DZ spezifische Gensignatur auf. Diese Gene waren insgesamt in der gleichen Weise wie in kDZ und moDZ reguliert, das eine Entwicklung von Monozyten nach DZ nahelegte. Dieses Entwicklungskonzept wurde insofern unterstützt, indem unter entzündlichen Bedingungen kultivierte CD14+CD16- Monozyten BDCA1 Expression und DZ Funktion erlangten. Da pro-iDZ sehr ähnlich zu BDCA1+CD14+ Zellen aus entzündeter Haut waren und beide große Konvergenz mit zuvor beschriebenen BDCA1+CD14+ inflammatorischen DZ (infDZ) aus entzündeten Geweben aufwiesen, können pro-iDZ als direkte infDZ Vorläufer angesehen werden. Dadurch und wegen ihrer monozytären Herkunft können pro-iDZ als Beweis für die humane Differenzierung von Monozyten nach DZ in vivo betrachtet werden. / Dendritic cells (DCs) are critical for the activation of immune responses. Three Flt3-dependent blood DC populations including conventional BDCA1+ DCs and BDCA3+ DCs (cDCs) and plasmacytoid DCs were described previously. This work identifies for the first time human peripheral blood monocyte derived BDCA1+CD14+ pro-inflammatory DCs (pro-iDCs) during steady state. Isolated pro-iDCs spontaneously secreted high amounts of pro-inflammatory cytokines, which matured cDCs and promoted T cell proliferation. They were superior in priming TH17 cells when compared to BDCA1+CD14- DCs and CD14+CD16- monocytes. BDCA1+CD14+ cells resembling blood pro-iDCs as identified by imaging cycler microscopy were found in samples from patients suffering from psoriasis, dermatomyositosis and inflamed halo nevus. Their absence in healthy donor’s skin indicated a recruitment of pro-iDCs to sites of inflammation. Analysis of the developmental relationship of pro-iDCs between monocytes, blood cDCs and in vitro generated monocyte derived DCs (moDCs) on whole genome level strongly suggested a monocytic origin. Functional annotation analysis of differentially regulated genes between monocytes and pro-iDCs revealed a DC specific gene signature. In addition, these genes were overall regulated in the same way in blood cDCs and moDCs, indicating an ongoing development of pro-iDCs from monocytes towards DCs. This developmental concept was supported as CD14+CD16- monocytes cultured under inflammatory conditions gained BDCA1 expression and DC function. Since pro-iDCs were highly similar to BDCA1+CD14+ cells found in inflamed skin and as both showed a marked convergence with BDCA1+CD14+ inflammatory DCs (infDCs) present in inflamed tissues described previously, pro-iDCs can be regarded as immediate precursors of infDCs. Thus, in respect of a monocytic origin and a presumably inflammatory DC fate, pro-iDCs may constitute a missing link to prove human moDC differentiation in vivo.