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Les propriétés fonctionnelles de la protéine membranaire SLC5A8 et son rôle physiologique ont été étudiées in vitro et in vivo en utilisant des souris slc5a8-/-. In vitro, des mesures d’accumulation de métabolites par LC-MS sur des cellules HEK transfectées par SLC5A8 ont permis d’étudier ses capacités de transport de monocarboxylates sodium-dépendant (pyruvate mais aussi corps cétoniques). L’étude par analyse métabolomique a permis de montrer que l’uptake de pyruvate médié par SLC5A8 avait pour conséquences, outre l’alimentation énergétique du cycle de Krebs, un effet inhibiteur d’une enzyme glycolytique (GAPDH). Son dérivé halogéné (bromopyruvate), agent anti-tumoral ciblant la GAPDH, génère la même accumulation du substrat de la GAPDH. Nos résultats indiquent que le rôle proposé dans la littérature de suppresseur tumeur de SLC5A8 soit associé à un effet anti-Warburg. In vivo, les souris slc5a8-/- âgées présentaient un œdème intramyélinique diffus sans démyélinisation témoignant de désordres hydro-ioniques dans l’espace périaxonal par carence énergétique. Si l’expression tubulaire rénale de SLC5A8 a été confirmée, l’expression neuronale ne l’a pas été faisant envisager une origine rénale à la leucoencéphalopathie décrite. Les souris slc5a8-/- présentaient une fuite urinaire massive de corps cétoniques à l’origine d’une insuffisance cérébrale en β-hydroxybutyrate. Ce carburant est essentiel pour le cerveau, notamment en cas de dysfonction du métabolisme glucidique, comme l’insulinorésistance démontrée en deuxième partie de vie des souris slc5a8-/-. Cette étude illustre le rôle majeur des corps cétoniques en neuroénergétique. / The functional properties of the SLC5A8 membrane protein and its physiological role have been studied in vitro and in vivo using slc5a8-/- mice. In vitro, analysis of metabolite uptake by LC-MS with slc5a8 transfected HEK cells to study sodium-dependent transport of monocarboxylates, in particular pyruvate but also ketone bodies. Using a metabolomic approach, we showed that SLC5A8-mediated pyruvate uptake fuels the Krebs cycle and has an inhibitory effect on the glycolytic enzyme, GAPDH. Bromopyruvate, the halogen derivative of pyruvate, is a known antitumour agent targeting GAPDH and has a similar effect. We propose that the tumour suppressor function reported for SLC5A8 in the literature is associated with an "anti-Warburg" effect. In vivo, aged slc5a8-/- mice showed diffuse intramyelinic oedema without demyelination. This indicated a hydro-ionic disorder in the periaxonal space due to chronic energy deficiency. While expression of SLC5A8 was confirmed in renal tubular cells, the expression of the protein was not detected in brain suggesting a renal origin of the described leukoencephalopathy. Slc5a8-/- mice showed strong urinary loss of ketone bodies leading to cerebral insufficiency of β-hydroxybutyrate. This ketone is an essential energy source for the brain, in particular when carbohydrate metabolism is dysfunctionning, like in the case of insulin resistance that was found in aged slc5a8-/- mice. This study highlights the major role of ketone bodies in neuroenergetics.

There has been a great interest in preparing polymeric reflective surfaces in the last few years. The application of supercritical fluid technology in this area is beginning to receive a great deal of attention. Poly ether ether ketone (PEEK) is well known for its excellent thermal, chemical, mechanical and electrical properties. These properties make it ideal for use in aerospace, electrical, fluid handling and coating industries. Supercritical infusion of a silver-containing additive (1,5-cyclooctadiene- 1,1,1,5,5,5-hexafluoroacetylacetonato)silver(I) into a PEEK film was achieved with moderately high density CO2 at various temperatures, pressures, and times. During the infusion process: 1) polymer sample was exposed to both supercritical CO2 and the additive under pressure for a brief time, 2) depressurization of the system caused the CO2 to rapidly diffuse out of the polymer; while the remaining additive in the polymer desorbed at a much slower rate governed by its diffusivity in the CO2-free polymer. Following this process the infused film was heated for a short time period to thermally reduce the infused metal and to form a reflective surface. In this research the effect of different additive concentrations, infusion conditions (e.g. temperature, pressure, time), and curing conditions (e.g. air flow rate, temperature, time) on the nature of the PEEK surface will be presented. / Master of Science

The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders.

No description available.

Ce travail de thèse présente de nouvelles réactions catalysées au cobalt de couplages croisés entre un arylzincique et divers électrophiles. Après une introduction générale sur la catalyse au cobalt et les arylzinciques, le premier chapitre est consacré à la formation de biaryles cétones. La réaction entre un arylzincique et le chloroformiate d’éthyle en présence du bromure de cobalt et du ligand bipyridine conduit à la formation de biaryles cétones symétriques avec de très bons rendements dans des conditions simples. Il a été démontré que ce chloroformiate d’éthyle se décompose en monoxyde de carbone au cours de la réaction. Les premiers essais pour étendre cette méthode à la synthèse de biaryles asymétriques sont également décrits à partir d’arylzinciques et de diverses molécules carbonylées. Le deuxième chapitre est quant à lui porté sur le couplage de Negishi entre un arylzincique et un bromure d’aryle ou unchlorure d’hétéroaryle. L’avantage de cette méthode est que le cobalt présent pour former l’arylzincique sert également à former le biaryle, il n’y a donc pas ajout d’un autre catalyseur dans la seconde étape de la réaction. Les premiers résultats obtenus pour la formation de biaryles sont encourageants mais ont besoin d’être approfondis. Une méthode similaire a été utilisée pour la synthèse de nouvelles molécules à fluorescence retardée pour obtenir des diodes électro luminescentes organiques de troisième génération. Le troisième chapitre décrit la réaction catalysée au cobalt entre un arylzincique et des sources électrophiles de soufre, les sels de Bunte. Cependant, ces sulfures d’aryles s’oxydent facilement dans le milieu réactionnel et donnent des sulfoxydes et des sulfones, ce qui limite l’utilisation de cette méthode. Enfin, le dernier chapitre est consacré à des travaux préliminaires sur la trifluorométhylation d’aryl zinciques à partir de sources électrophiles ou nucléophiles trifluorométhylées. / This thesis presents new cobaltcatalyzed cross-coupling reactions between arylzinc derivatives and various electrophilic reagents. After a general introduction on cobalt-catalysis and arylzinc compounds, the first chapter is dealing with the formation of diaryl ketones. Reaction between arylzinc bromides and ethyl chloroformate in presence of cobalt bromide and bipyridine ligand leads to the formation of symmetrical diaryl ketones with very good yields under simple conditions. It has been shown that ethyl chloroformate decomposes into carbon monoxide during the reaction. First attempts to extend this method to the synthesis of unsymetrical diaryl ketones are also described from arylzinc bromides and various carbonyl containing substrates. As for the second chapter, it is focused on the Negishi coupling between arylzinc bromides and an aryl bromide or an heteroaryl chloride. The advantage of this method is that the cobalt used to form the arylzinc bromide also serves to form the biaryl, hence there is no addition of another catalyst in the second step of the reaction. Results about the formation of biaryls are promising, but this reaction needs to be thorough. A similar methodology was used for the synthesis of new delayed fluorescence molecules to obtain highly efficient organic light emitting diodes. The third chapter describes the cobalt-catalyzed reaction between an arylzinc bromide and an electrophilic source of sulfur, a Bunte salt. However, these aryl sulfides can be easily oxidized in the reaction mixture and give sulfoxides and sulfones, which limit the use of this method. Finally, the last chapter is about preliminary works on the trifluoromethylation of arylzinc bromides from electrophilic or nucleophilic trifluoromethyl sources.

High molecular weight poly(phenylene sulfide sulfone) (PPSS) homo- and statistical copolymers have been reproducably synthesized using a known, but complex procedure utilizing 4,4'-dichlorodiphenyl sulfone (DCDPS), sodium hydrosulfide, sodium hydroxide, sodium acetate, and deionized water, in NMP at elevated reaction temperatures and pressure. The effect of these variations, e.g., reaction temperatures and times, molar ratios of H2O-to-NaSH, NMP-to-H2O, etc. were investigated. Optimized conditions were defined, which produced Tg as high as 222°C, very high refractive index (1.70), and tough/solvent resistant films could be prepared by melt fabrication. A two-stage decomposition mechanism in air was demonstrated by dynamic thermal gravimetric analysis. The melt stability of PPSS was improved by incorporating thermally stable endgroups, such as diphenyl sulfone, 4-chlorophenylphenyl sulfone, and t-butylphenoxide. The chemical structures of the endgroups were confirmed by 13C and 1H NMR spectra. Compared with mercaptide endcapped PPSS, the new systems showed higher initial degradation temperatures (2% and 5% weight loss), higher char yield at 650°C in air and a more stable melt viscosity at 300°C. A greatly simplified synthesis of both homo and copolymers has been successfully developed using the new A-A or A-B type thiol-functional monomers, such as bis-(4-mercaptophenyl) sulfone, 4-chloro-4'-mercaptodiphenyl sulfone and 4-chloro-4'-mercapto benzophenone, instead of sodium hydrosulfide. A series of high molecular weight triphenyl phosphine oxide and/or diphenyl ketone containing PPSS copolymers were subsequently synthesized from the bis-(4-mercaptophenyl) sulfone by reaction with 4,4'-dichlorodiphenyl sulfone, bis-(4-fluorophenyl) phenyl phosphine oxide, and 4,4'-difluorobenzophenone in DMAc in the presence of K2CO3 at 160°C. The new phosphine oxide containing PPSS copolymers were completely amorphous, showed improved solubility in common organic solvents and exhibited very high char yields in air at 750°C. Surface (XPS) analysis results suggested that the phosphorus moieties in the polymer backbone can form phosphate-like layers on the polymer surface which protects the inner materials from further decomposition in air at high temperatures. The diphenyl ketone containing PPSS copolymers showed very high char yields at 750°C in a nitrogen atmosphere, compared to sulfide sulfone homopolymer and phosphine oxide containing copolymers, possibly because of higher bond energies. Semi-crystalline poly(phenylene sulfide ketone) homopolymers and sulfone containing copolymers with sulfone/ketone mole ratio (S : K) < 25 : 75 were synthesized by a novel base catalyzed self-polycondensation of 4-chloro-4'-mercaptodiphenyl sulfone and/or 4-chloro-4'-mercapto benzophenone in N-cyclohexyl-2-pyrrolidinone (CHP) at 290°C. Amorphous copolymers with S : K ratios > 25 : 75 were prepared in DMAc at 160°C. These materials exhibited an increase in glass transition temperature with increasing sulfone content. TGA and micro cone calorimetry analyses showed that the semi-crystalline materials with high ketone content had much higher char yields and significantly lower heat release rate and total heat release, compared to the poly(phenylene sulfide sulfone) and poly(pheylene sulfide) controls. / Ph. D.

This thesis focuses on ignition of diisopropyl ketone (DIPK), a new biofuel candidate that is produced by endophytic conversion. The ignition delay times behind reflected shockwaves were modeled in a high-pressure shock tube. The ignition delay times were compared to other biofuels and gasoline surrogates. Parametric studies of the ignition delay experiments were performed between 1-10 atm and 900 -1200K. An OH optical sensor was developed in conjunction for the ignition delay experiments. The OH optical sensor uses a microwave discharge lamp to generate light at 308 nm that will then be shined through the combustion reaction. Using Beer-Lambert law the concentration of OH can be obtained during ignition and oxidation of hydrocarbon fuels in a shock tube. DIPK ignition delay time experiments are planned in two shock tubes (located at UCF and UF) to provide ignition and OH time-histories data for model validation.

No description available.

A novel method for asymmetric synthesis of α-hydroxy ketone with excellent regio- and stereoselectivity has been established by the systematic investigation of asymmetric dihydroxylation of allenes. The efficiency of kinetic resolution of racemic allenes was also investigated by using the AD reaction on both 1,3-disubstituted and trisubstituted allenes. Steric effects, electronic effects and allene substitution are also discussed. Aziridines were formed by copper-catalyzed intramolecular nitrene addition to alkenes. The carbamate group was used as the tether between the alkene and the nitrene. Subsequent nucleophilic attack of the aziridine was accomplished using RSH, R2NH, N3-,or ROH as the nucleophile. This addition was found to be regio- and stereoselective. This methodology has provided a new strategy for the stereoselective construction of three adjacent functional groups, in particular the 1,2 diamino-3-hydroxy unit. The rhodium-catalyzed intramolecular aziridination of allenic N-sulfonyloxy carbamates has been established. Efficient ring opening of these bicyclic compounds may provide synthetic utility in organic chemistry. The intramolecular aziridination of allenic sulfamate esters was tested on a single example to afford in situ a ring opened product.