Ce mémoire traite de la synthèse et des propriétés thermiques et mécaniques de polyesteramides statistiques et quasi-alternés obtenus à partir de l’ε-caprolactone et d'acides aminés naturels (β-alanine, glycine et α-alanine). Les polyesteramides statistiques ont été obtenus par ouverture de cycle et polycondensation simultanée des deux monomères par une méthode monotope, tandis que les polyesteramides quasi-alternés ont été élaborés par polyestérification d’un dimère à extrémités hydroxy et ester, préalablement synthétisé par réaction entre ε-caprolactone et ester d'acide aminé. La structure et la microstructure de ces polyesteramides ont été étudiées par spectroscopiques IRTF et RMN 1D et 2D. Les polyesteramides obtenus en deux étapes présentent, comme attendu, une forte tendance à l'alternance, alors que ceux obtenus par synthèse monotope sont complètement statistiques. L’étude des propriétés thermiques par DSC et ATG montre que ces polyesteramides sont semi-cristallins et qu'ils présentent une meilleure stabilité thermique que celle de la poly(ε-caprolactone). Les polyesteramides statistiques contenant des fractions croissantes en β-alanine et supérieures ou égales à 50 mol-% présentent des valeurs de module d’Young et de contrainte à la rupture en traction croissantes et plus élevées que celles de la poly(ε-caprolactone). Les polyesteramides quasi-alternés présentent une cristallinité et des propriétés mécaniques nettement supérieure à celles de leurs homologues statistiques. / This thesis reports the synthesis and thermal and mechanical properties of random or quasi-alternating polyesteramides obtained from ε-caprolactone and natural aminoacids (β-alanine, glycine and α-alanine). The random polyesteramides were obtained by one-pot simultaneous ring-opening and polycondensation of the two monomers, while the alternating ones were prepared by polyesterification of hydroxy- and ester-terminated dimers, previously synthesized by reaction between ε-caprolactone and aminoacid esters. The structure and microstructure of these polyesteramides were studied by FTIR and 1D and 2D NMR spectroscopies. As expected, polyesteramides synthesized by the two-step method present a quasi-alternating structure, while those synthesized by the one-pot method are completely random. The study of their thermal properties by DSC and TGA shows that these polyesteramides are semi-crystalline and present a better thermal stability than poly(ε-caprolactone). For the random polyesteramides with β-alanine fractions greater than or equal to 50 mol-%, increasing β-alanine fractions leads to increasing Young's modulus and tensile strength, larger than those of poly(ε-caprolactone). The quasi-alternating polyesteramides exhibit thermal and mechanical properties well above than those of their random counterparts.

A series of novel alpha-aminoxy peptides have been recently developed, and showed a therapeutic potential for the treatment of CI- channel dysfunctional diseases. The present study aimed to investigate the pharmacokinetics of five structural related tx-aminoxy peptides (P1 to P5), and effect of structural modifications on their pharmacokinetic properties. / P1 showed significantly low intestinal permeability due to P-gp-mediated efflux. Structural modifications resulted in alterations of transport mechanisms from P-gp-mediation (P1, P2) to multidrug resistance-associated protein (MRP)-mediation (P3), MRP plus breast cancer resistance protein (BCRP)-mediation (P4) active transport, or even passive paracellular diffusion (P5) without any efflux transporters involved. Comparing with P1, the absorbable permeability in Caco-2 monolayer increased to about 7-fold (P3), 4-fold (P4) and 11-fold (P5), respectively, and the absorption through intestine in SPIP model significantly increased to about 36-fold (P2), 42-fold (P3), 55-fold (P4) and 102-fold (P5), respectively. P1 was unstable in the GI tract with 41% degradation in SGF within 1 h and 47% degradation in SIF within 3 h. The other four peptides were much more stable than P1 with degradation less than 6% under the same incubated conditions. For the hepatic metabolism, about 31% of P1 was metabolized by rat liver S9 within 30 min, while the metabolic stability was significantly improved to 3.3-fold (P3), 2.9-fold (P4) and 7.5-fold (P5), respectively with no metabolism for P2. Their metabolism was mainly via oxidation catalyzed by CYP enzymes to form hydroxylated metabolites. After i.v. administration (5 mg/kg), both P1 and P5 was eliminated rapidly. P1 mainly distributed to liver and lung, while P5 to kidney and intestine. P1 was cleared mainly through metabolism via oxidation followed by sulphation (∼80% of the dose), while P5 was mainly eliminated as an intact form (∼53% of the dose). Oral bioavailability of P1 was low (0.36%) due to instability in the GI tract and poor intestinal absorption mediated by P-gp efflux transport. Oral bioavailability of P5 was improved to about 3-fold comparing with P1 but still low mainly because of poor intestinal absorption through passive diffusion and some unknown factor(s). / The present studies demonstrated that our rationale for the structural modifications of the designed cc-aminoxy peptides is an effective way to improve their intestinal absorption, gastrointestinal and metabolic stability, and appropriate pharmacokinetic properties. Our findings also provide scientific evidence to support further development of better alpha-aminoxy peptide cadidates with high oral bioavailability and appropriate pharmacokinetic properties. / Three absorption models, including Caco-2 cell monolayer, Ussing chamber and in situ rat single-pass intestinal perfusion (SPIP) model, were used. The stability in gastrointestinal (GI) tract was determined using simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The hepatic metabolism was investigated in rat liver subcellular fractions and human liver microsome. P1 and P5 were selected for pharmacokinetic study in rats. / Ma, Bin. / Adviser: Ge Lin. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 199-215). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Estradiol (Compudose®, COM) implants are extensively used in beef cattle production systems to alter body composition and feed efficiency. Little information exists about the physiological mechanisms affected by COM treatment in growing, mature, and senescent female cattle. Moreover, no reports describe the level of blood estradiol resulting from COM treatment. The effect of COM on levels of plasma estradiol and blood metabolites and proteins, and relative content of glutamine synthetase (GS) and other amino acid nitrogen-metabolizing enzymes in liver tissue, was studied using three experimental models relevant to cow-calf production regimens: senescent cows (Trial 1), young mature (young) versus senescent (old) cows (Trial 2), and growing heifers (Trial 3). In Trial 1, plasma estradiol concentrations were 222 % more after 14 and 28 d in COM-implanted than sham implanted (Control) cows. COM treatment did not affect measured blood metabolites and enzymes, but increased hepatic GS protein expression by 350% after 14 d and 200% after 28 d of implantation. In contrast, protein expression of alanine transaminase, aspartate transaminase, glutamate dehydrogenase, and two glutamate transporters was not affected by COM. In Trial 2, plasma estradiol concentrations of COM implanted young and old cows were 48% higher than Control groups, whereas blood metabolites were not affected. COM implantation did not affect GS protein expression in young cows, but tended to increase GS expression in the old cows by 283% after 14 d and 41% after 28 d. GS mRNA content was increased about 38% in both young and old COM-treated cows. Hepatic content of beta-catenin and G protein-coupled receptor 30 (GPR30) content was not affected by COM treatment, indicating that estradiol-mediated GS expression was not regulated by beta-catenin- or GPR30-controlled pathways. In Trial 3, plasma estradiol levels in COM-treated heifers were 70% higher in COM heifers, concomitant with increased levels of total bilirubin and creatine kinase, and decreased creatinine. Correlation analysis of plasma estradiol levels and blood constituents only identified a positive correlation between plasma estradiol and potassium. Collectively, these data describe positive estradiol-mediated effects on hepatic metabolism and blood parameters in female cattle.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

No description available.

To differentiate pyogenic brain abscess from other brain diseases such as necrotic glioblastomas is very important for clinic treatment. Cytosolic animo acids, lactate, alanine, succinate and acetate have been recognized as potential abscess markers. LCModel is a well-known tool to analyze the MRS data, as it provides opportunity of quantitative of metabolite concentration. Using MRS with LCModel to identify and quantitate these metabolites would benefit more precisely noninvasive diagnosis and treatment of pyogenic brain abscess. However, to differentiate the MR spectra of strongly overlapping metabolites are not easy. In this study, we validate the accuracy of LCModel on detecting these overlapping metabolites. We use some GAVA-simulated resonance spectra as our input signals and figure out the performance of LCModel analysis in different conditions. Our goal is to find an optimal analysis method to help the clinic diagnosis of abscess patients. Our result shows that the determination of basis sets is very important since the analyzed result might be different due to the improper selection of basis sets.

Transcription elongation regulator 1 (TCERG1) has previously been demonstrated to be an inhibitor of the transactivation and growth arrest activities of CCAAT/Enhancer binding protein alpha (C/EBPα). Furthermore, TCERG1 had been demonstrated to become relocalized from nuclear speckles to the pericentromeric regions where C/EBPα resides when both proteins are co-expressed in the cell. This thesis demonstrates that the deletion of a unique, imperfect series of 38 glutamine-alanine (QA) repeats near the amino terminus of TCERG1 is able to abrogate the ability of TCERG1 to inhibit C/EBPα-mediated growth arrest, the physical interaction between TCERG1 and C/EBPα, and the relocalization of TCERG1 from nuclear speckles when C/EBPα is co-expressed in the cell. The deletion of the QA domain demonstrated that there was a threshold amount of QA repeats required in TCERG1 for the relocalization and growth arrest inhibitory activities between TCERG1 and C/EBPα. It was demonstrated that between 11 and 20 QA repeats were required in TCERG1 to produce the relocalization from nuclear speckles or to be able to inhibit C/EBPα-mediated growth arrest. The physical interaction of TCERG1 and C/EBPα as examined by co-immunoprecipitation was also found to be QA dependent, with a diminishing interaction observed as the number of QA repeats in TCERG1 were reduced. However, experiments examining the isolated QA domain indicated that it was insufficient to relocalize an mCherry fluorescent protein fusion to either the nucleus or to pericentromeric regions where C/EBPα is concentrated. This inability to produce relocalization suggests that the QA domain requires another domain or domains from TCERG1 to mediate the relocalization activity. When expressed with the WT TCERG1, ΔQA TCERG1 was able to act in a dominant negative manner, preventing the relocalization of the WT TCERG1 protein to pericentromeric domains. Interestingly, the transactivation inhibitory activities of TCERG1 on C/EBPα do not appear to require the QA domain, but rather are localized to the carboxy half of TCERG1, somewhere within amino acids 612-1098. The data obtained provides the first report of a role for this unique QA repeat domain.

No description available.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 154-168).

This thesis investigates the effects of alanine on rainbow trout’s glucose metabolism at the organismal and molecular levels. Rainbow trout is an important aquaculture species that belongs to the salmonid family. As a carnivorous fish, the requirement of protein/amino acids in trout’s diet is high. In contrast, rainbow trout are poor utilizers of carbohydrates. One prevalent hypothesis suggests that high levels of dietary amino acids could indeed contribute to the poor utilization of carbohydrates in this species. In mammals, there is evidence supporting the importance of alanine as a gluconeogenic precursor. However, a recent study found that alanine stimulates hepatic AMP-activated protein kinase (AMPK) to lower circulating glucose levels in mice. Alanine levels are high in all tissues in rainbow trout. The role of alanine in gluconeogenesis is less clear in trout and there is no evidence, to our knowledge, regarding its effects on glucose kinetics. Therefore, the main goal of the study was to investigate the impact of the continuous infusion of exogenous alanine for 4h on glucose fluxes and to identify potential mechanisms in tissues that could interpret the observed changes in glucose fluxes in vivo. Glucose turnover, appearance and disposal, Rt, Ra and Rd, respectively, were measured to determine the impact of alanine on glucose fluxes. The expression and/or activity of key genes in glucose transport, utilization and gluconeogenesis were assessed in liver and muscle. An additional goal was to assess whether alanine activates AMPK in trout. The levels of phosphorylated AMPK and other signaling proteins known to interact with the latter were quantified. Results show that alanine reduced plasma glucose levels and inhibited Ra and Rd glucose, consistent with previously observed effects of insulin in rainbow trout. The reduction in the expression of a paralogue of glut4, a key gene in glucose transport, and the activity of hexokinase (HK), a key enzyme in glucose utilization, in muscle can partially explain the observed reduction in Rd glucose. Together, these results suggest that glucose was not a preferred substrate under conditions of increased alanine availability and that alanine was probably oxidized to provide energy. Alanine failed to activate AMPK in trout, contrary to mammalian findings. However, it increased AKT (also known as protein kinase B) phosphorylation in muscle, similar to the effect of insulin in trout. In conclusion, my results suggest that alanine mediated at least some of the observed effects by stimulating insulin secretion given the similarities between the effects of exogenous alanine and insulin in rainbow trout as discussed above. Future studies are warranted to investigate the hypothesis that alanine is an insulin secretagogue in rainbow trout.