The enzyme soluble epoxide hydrolase (sEH) plays a major role in the pathogenesis and pathophysiology of neurodegenerative diseases like depression by catalyzing the hydrolysis of epoxyeicosatrienoic acids (EETs) into dihydroxyicosatrienoicacids (DHETs), its less biologically active form, influencing the anti-inflammatory system and promoting inflammation. Therefore, inhibiting sEH leads to increased levels of EETs, reducing inflammation, especially in the brain and can help mitigate neurodegenerative diseases. This study investigated sEH inhibition by a phenolic carotenoid compound, astaxanthin and its inhibitory mechanism of action. Enzyme inhibitory activity and kinetics demonstrated that astaxanthin had a half-maximal inhibitory concentration (IC50) of 26 ± 0.92 μM and is a mixed-non-competitive inhibitor of sEH. In silico ADME/tox analysis showed that astaxanthin is bioavailable, biostable, and non-toxic when taken orally. Molecular docking study demonstrated that astaxanthin binds to an allosteric site of sEH and formed a contact and clashing-only interaction with the ASP333 residue of the hydrolase pocket of sEH. In this study, we highlight the potential therapeutic application of astaxanthin as a natural sEH inhibitor in the treatment of inflammation-related diseases, particularly neurodegenerative diseases.

Over the course of more than ten years, there has been a significant increase in the approach employed to inhibit the function of soluble epoxide hydrolase (sEH). The phenomenon of upregulating soluble epoxide hydrolase (sEH) has been found to result in a decrease in the ratio of epoxyeicosatrienoic acids (EETs) to dihydroeicosatrienoic acids (DHETs) in the body. This has garnered significant attention due to the diverse biological functions attributed to EETs, including the regulation of vasodilation, neuroprotection, increased fibrinolysis, calcium ion influx, and anti-inflammatory effects. Consequently, there has been a growing interest in developing and discovering sEH inhibitors through chemical syntheses and natural extracts, with the aim of increasing the availability of these anti-inflammatory molecules by reducing their hydrolysis. A comprehensive examination of this project was conducted to explore the inhibitory effects of YMSV, a tetrapeptide derived from the castor bean (Ricinus communis), on sEH, as well as to elucidate its underlying mechanism of action. YMSV was determined to function as a mixed-competitive inhibitor of soluble epoxide hydrolase (sEH), and the interaction between the peptide and the protein resulted in the disruption of the secondary structural composition of sEH. Furthermore, the hydrogen bond interactions between YMSV and the Asp 333 residue in the active region of soluble epoxide hydrolase (sEH) were demonstrated using molecular docking investigations. However, quantitative structure-activity relationship (QSAR) research revealed that nonpolar, hydrophobic, and bulky amino acids are favored at the N- and C- terminals of peptides for sEH inhibition. The results of this study indicate that peptides obtained from dietary sources possess unique characteristics as inhibitors of soluble epoxide hydrolase (sEH), displaying significant potency. Consequently, these peptides have promise for further development as therapeutic medicines targeting inflammation and depression in the future.

The beginnings of metallurgical activity have intrigued scholars for decades. In this dissertation, I explore early metallurgical activity on the Iranian Plateau represented by the evidence at Tal-i Iblis in southern Iran, and Seh Gabi and Godin Tepe in central northern Iran. Together, these sites offer a diachronic view of metal production on the Plateau as well as a view of metallurgical activities practiced at different scales of production. The metallurgical materials from Tal-i Iblis are firmly dated to the late 6th to early 5th millennia BCE, and this corpus includes hundreds of crucible fragments excavated from multiple trash dumps. Seh Gabi and Godin Tepe offer a smaller range of production materials from the 4th through 2nd millennia BCE, but they also include a large collection of finished metal objects. These later materials differ in style and process from the Iblis debris.Thorough examination of these artifacts, combined with comparison to a series of carefully controlled casting experiments, has returned numerous significant results. The metallurgy of the Iranian Plateau does not fit the standard model of early metallurgical development. The Iblis crucibles do not reflect an early "experimental" stage in copper production. Rather, these artifacts represent a carefully controlled, production process with a narrow range of variability in both temperature and reducing atmosphere. Further, there is clear evidence for the preference of arsenical-copper alloys at Tal-i Iblis. These ancient craftspeople sought high-quality ores from a source (the Talmessi copper deposit) over 500 km from their production facility.Metallurgical production on the Iranian Plateau is also characterized by the long-term use of crucibles as the primary reaction vessel well into the 2nd millennium BCE. There are some production centers on the Iranian Plateau that see the use of furnaces during the 3rd millennium, but crucible use persists at many sites. At Godin Tepe--a site with significant evidence for contact with the Mesopotamian lowlands--variability in crucible form increases in later periods to include an Egyptian-style crucible during the 2nd millennium BCE. The presence of this crucible suggests that there was contact with foreign metallurgical processes, but the preference for small, portable reaction vessels persisted.

Ce travail a pour objectif de développer et d'appliquer une méthode originale permettant de simuler l'écoulement dans un milieu poreux fracturé. Cette méthode repose sur une approche multicouches double continuum permettant de séparer le comportement des différents aquifères présents sur un site. La résolution des écoulements, basée sur la méthode des Eléments Finis de Crouzeix-Raviart, est associée à une méthode inverse (minimisation de type Quasi-Newton combinée à la méthode de l'état adjoint) et à une paramétrisation multi-échelle.La méthode est appliquée dans un premier temps sur l'aquifère fracturé du site expérimental de Poitiers. Les résultats montrent une bonne restitution du comportement de l'aquifère et aboutissent à des champs de transmissivité plus réguliers par rapport à ceux de l'approche simple continuum. L'application finale est réalisée sur le site de Cadarache (taille plus importante et données d'entrée moins denses). Le calage des deux aquifères présents sur le site est satisfaisant et montre que ceux-ci se comportent globalement de façon indépendante. Ce calage pourra être amélioré localement grâce à données de recharge plus fines.

Ce travail a pour objectif de développer et d’appliquer une méthode originale permettant de simuler l’écoulement dans un milieu poreux fracturé. Cette méthode repose sur une approche multicouches double continuum permettant de séparer le comportement des différents aquifères présents sur un site. La résolution des écoulements, basée sur la méthode des Eléments Finis de Crouzeix-Raviart, est associée à une méthode inverse (minimisation de type Quasi-Newton combinée à la méthode de l’état adjoint) et à une paramétrisation multi-échelle.La méthode est appliquée dans un premier temps sur l’aquifère fracturé du site expérimental de Poitiers. Les résultats montrent une bonne restitution du comportement de l’aquifère et aboutissent à des champs de transmissivité plus réguliers par rapport à ceux de l’approche simple continuum. L’application finale est réalisée sur le site de Cadarache (taille plus importante et données d’entrée moins denses). Le calage des deux aquifères présents sur le site est satisfaisant et montre que ceux-ci se comportent globalement de façon indépendante. Ce calage pourra être amélioré localement grâce à données de recharge plus fines. / The aim of this study is to develop and validate a new method for the simulation of flow in fractured porous media. This method is based on a multi-layered and dual continuum approach allowing to discriminate the behavior of different aquifers present on a site. The flow equations are solved using a Crouzeix-Raviart Finite Element method, in association with an inverse method (Quasi-Newton minimization combined with the adjoint state method) and a multi-scale parameterization.The method is first applied and validated on the fractured aquifer of the Hydrogeological Experimental Site of Poitiers. The results closely reproduce the flow behavior of the aquifer and lead to a transmissivity field much more homogeneous than the one obtained with a simple continuum approach. The final application is performed on the site of Cadarache (large scale problem with heterogeneously distributed input data). The model calibration of both aquifers is rather satisfactory and shows that their behavior is globally independent. It could locally be improved if more accurate groundwater recharge data is made available.