Glucocorticoids are steroid hormones that have potent anti-inflammatory actions. Endogenous glucocorticoid action is modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyses the interconversion of active glucocorticoids (cortisol, corticosterone) and intrinsically inert forms (cortisone, 11-dehydrocorticosterone). There are 2 isozymes; 11β-HSD type 1 regenerates active glucocorticoids in vivo whereas 11β-HSD type 2 inactivates glucocorticoids. Although 11β-HSD1 is highly expressed in the lung, its role there has been little explored. In this study, the expression and localization of 11β-HSD1 mRNA in lung was confirmed by in situ hybridization. Immunohistochemical staining of mouse lung localized 11β-HSD1 to the cytoplasm of fusiform cells in alveolar walls, in a multivesicular pattern characteristic of interstitial fibroblasts. A lung fibrosis model of inflammation was used to test the role and regulation of 11β-HSD1. The results suggest that levels of 11β-HSD1 mRNA and enzyme were not changed during bleomycin-induced lung inflammation. However, 11β-HSD1-deficient mice showed a more severe inflammatory response than congenic wild-type controls, with greater inflammatory cell infiltration into the lung, and increased levels of HO-1 and iNOS mRNA 14 days following bleomycin installation into lung. Picrosirius red staining of lung sections suggested more collagen deposition in 11β-HSD1-deficient mice than in wild-type controls during the course of the lung inflammatory response. Moreover, whereas naïve 11β-HSD1-deficient mice had significantly lower collagen content in lung (84% of WT levels, p<0.05). 28d after bleomycin there was no significant difference between genotypes (KO having 94% of WT levels, p=0.42) confirming more collagen production in 11β-HSD1-deficient mice following bleomycin. Fibroblasts are critical in the regulation of inflammatory responses and are essential in the model of bleomycin-induced lung injury. Lung fibroblasts may have a different transcriptional regulation of 11β-HSD1 compared to other tissues. In the majority of tissues, 11β-HSD1 can be transcribed from 2 promoters; the P1 promoter is the main promoter used in lung, with other tissues mainly using the P2 promoter. To address the relevance of the P1 promoter in lung and to identify the cell type using the P1 promoter, mouse lungs were collagenase-digested to isolate primary fibroblast and epithelial cells. Isolated lung fibroblasts highly expressed 11β-HSD1, predominantly from the P1 promoter. During passage, primary lung fibroblasts switched promoter usage from P1 to P2. In fibroblast primary culture, treatment with TGF-β for 72h markedly decreased 11β-HSD1 expression to 38% of untreated levels, an effect which was reversed by SB431542, a TGF-β receptor antagonist. Whilst TGF-β reduced levels of mRNA initiating at the P2 promoter, initiation from the P1 promoter was completely repressed. Treatment with TGF-β receptor antagonist increased levels of P1-initiated 11β-HSD1 mRNA by 6.6-fold compared to untreated cells. These data suggest that the switch in 11β-HSD1 promoter usage may be regulated by TGF-β during an inflammatory response. Furthermore, as the P1 and P2 promoters are differentially regulated (e.g. by C/EBPβ, a cytokine-responsive transcription factor), the promoter switch may place 11β-HSD1 under a different transcriptional regulation during inflammation. Taken together, these results suggest that 11β-HSD1 deficiency worsens lung inflammation and results in greater lung fibrosis. Therefore, amplification of intracellular glucocorticoids levels, by 11β-HSD1, may represent an important mechanism to limit the inflammatory response and shape fibroblast function, limiting subsequent collagen production and fibrosis.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

The human ovarian surface epithelium (hOSE) is a cell monolayer that covers the surface of the ovary. Natural events like incessant ovulation, associated reproductive hormone action prior to and post-ovulation, along with the ovulationassociated inflammation, that result in injury and repair of hOSE, are considered to have a role in the development of epithelial ovarian cancer (EOC). Progesterone is apoptotic and anti-inflammatory, whereas androgens appear cytoproliferative for hOSE. Local generation of these steroid hormones is subject to 3β-hydroxysteroid dehydrogenase (3β-HSD) activity. Moreover, action of these hormones is achieved through coupling to their cognate receptors, progesterone (PR) and androgen receptors (AR). The overall aim of this thesis is to elucidate in vitro the regulation of progesterone and androgen biosynthesis and downstream signalling during the injury and repair of primary hOSE cells that were collected from pre-menopausal women who underwent surgery for benign gynaecological disorders. Injury was mimicked by treatment of cells with several pro-inflammatory cytokines, whereas repair was mimicked with T-lymphocyte, ‘anti-inflammatory’ cytokines. Immunohistochemical studies showed immunodetectable 3β-HSD in the human ovarian cell surface of whole ovary and three-week cultured hOSE cells, establishing 3β-HSD expression in vivo and in vitro. Cross-reaction of the 3β-HSD antibody with both enzyme isoforms did not allow investigation of isoform expression pattern. However, mRNA transcriptional studies with isoform specific primers and probe sets for semi-quantitative (sq) and quantitative (q) PCR revealed expression of both isoforms in hOSE cells; 3β-HSD1 mRNA was expressed at higher levels relative to 3β-HSD2 mRNA in accordance with the preference of this isoform in peripheral non-steroidogenic tissues. Of the cytokines tested, only IL-1α and IL-4 affected 3β-HSD expression. IL- 1α suppressed 3β-HSD1 mRNA, whereas it up-regulated 3β-HSD2 mRNA as assessed with qPCR, without though affecting total 3β-HSD protein and activity levels as assessed with western immunoblotting and radiometric activity assays, respectively. IL-1α did not affect AR or PR mRNA levels, suggesting a balance in androgen and progesterone biosynthesis during post-ovulatory wounding. IL-4 massively induced 3β-HSD1 and 3β-HSD2 mRNA and total 3β-HSD protein and activity. It also attenuated AR mRNA and protein, without affecting PR mRNA. Collectively, these data demonstrate that IL-4 sustains progesterone rather than androgen signalling and this may be part of the anti-inflammatory steroid action that protects hOSE from genetic damage. IL-1α effects appear to be mediated by NF-κB signalling pathway. PI-3K and p38 MAPK appeared involved in IL-1α-induced 3β- HSD2. IL-4-induced 3β-HSDs required STAT-6 and PI-3K pathways and also p38 MAPK at the case of 3β-HSD2. IL-4-attenuated AR was reversed by a p38 MAPK inhibitor. These data suggest that steroid signalling by IL-1α and IL-4 involve multiple signalling pathways. In primary EOC, 3β-HSD1 and 3β-HSD2 transcripts were attenuated relative to hOSE cells, suggestive of an acquired feature of neoplastic transformation. However, both transcripts could be restored after IL-4 treatment, attesting a therapeutic advantage of this cytokine. In conclusion, we have shown that 3β-HSD is under inflammatory control during ovarian post-ovulatory wound healing of hOSE. IL-1α- and IL-4-mediated 3β-HSD1 and 3β-HSD2 are regulated by multiple signalling pathways. Also, IL-4 was identified as an anti-inflammatory agent in hOSE with putative therapeutic benefit in malignancy.

No description available.

Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T.

Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T.

This study sought to determine boundary conditions for robustness of the Tukey HSD statistic when the assumptions of homogeneity of variance were violated. Box's coefficient of variance variation, C^2 , was utilized to index the degree of variance heterogeneity. A Monte Carlo computer simulation technique was employed to generate data under controlled violation of the homogeneity of variance assumption. For each sample size and number of treatment groups condition, an analysis of variance F-test was computed, and Tukey's multiple comparison technique was calculated. When the two additional sample size cases were added to investigate the large sample sizes, the Tukey test was found to be conservative when C^2 was set at zero. The actual significance level fell below the lower limit of the 95 per cent confidence interval around the 0.05 nominal significance level.

Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T. / Science, Faculty of / Zoology, Department of / Graduate

Syfte: Syftet med denna studie är att undersöka förhållandet mellan aktiesplit och överavkastning och att fastställa om en enskild investerare kan uppnå en överavkastning genom att investera i aktier noterade på OMXSPI som har genomfört en aktiesplit. Genom en genomgå av tidigare forskning samt genomförande av en egen dataanalys kommer denna studie att undersöka huruvida aktier som har genomfört en aktiesplit genererar en överavkastning jämfört med aktier som inte har genomgått en split. Teoretisk referensram: Denna studie bygger på och utmanar antagandet av den effektiva marknadshypotesen som hävdar att det inte är möjligt för en enskild investerare att uppnå överavkastning. Signalhypotesen och handelsintervallshypotesen kommer också att beaktas i undersökningen. Metod: Denna studie är av kvantitativ karaktär och använder en deduktiv ansats. Undersökningsmodellen är baserad på 131 handelsdagar som är uppdelade i fem olika eventfönster. Prisdata har samlats in för hela händelseperioden, och därefter har data bearbetats matematiskt och analyserats statistiskt. Slutsats: Resultaten från studien antyder att aktier som genomgick en aktiesplit mellan 2010 och 2022 genererade en avkastning som var 10,89% högre än aktier som inte genomgick en aktiesplit. Resultaten av studien kan bekräftas med 99% säkerhet. / Purpose: The study examines the relationship between stock splits and abnormal return, in order to investigate whether an individual investor can generate excess returns by investing in stocks listed on OMXSPI that are scheduled to undergo a split. By reviewing previous research and conducting an independent data analysis, the study will investigate whether stocks that have undergone a split generate abnormal return compared to those that have not undergone a split. Theoretical perspectives: The study builds on and challenges the efficient market hypothesis assumption that it is not possible for an individual investor to generate excess returns. The signaling hypothesis and the trading range hypothesis will also be considered. Method: The study is of a quantitative nature with a deductive approach. The research model is based on 131 trading days divided into five different events. Price data is collected for the entire event period and is mathematically calculated and analyzed statistically. Conclusions: The study's results indicate that stocks that undergo a stock split between 2010-2022 generate a 10.89% higher return than stocks that do not undergo a stock split. The results can be confirmed with a 99% level of certainty.

<p>Hydrodesulfurization is an important part of the hydrotreating process. More stringent regulations on the quality of fuels bring new requirements to the catalytic processes. The removal of sulfur has become a key issue in the oil refining and this work aims to address several aspects of the process.</p><p>Kinetic studies of the hydrodesulfurization reaction over conventional (molybdenum-based) and new (Pt/Y-zeolite) catalysts are reported. The hydrodesulfurization of both the real oil (light gas oil from Statoil Mongstad refinery) and model compounds (thiophene and dibenzothiophene) over a NiMo/γ-Al₂O₃ catalyst were studied. In a high-pressure study of the light gas oil, substituted alkyl-DBTs were found to be the most difficult to desulfurize and the order of reactivity was found to be DBT > 4-MDBT > 4,6-DMDBT. Steric hindrance together with electronic effects were identified as possible reasons for this behavior. The difference in reactivities of the individual compounds was found to decrease with the increasing reaction temperature. A gas chromatograph equipped with the atomic emission detector (GC-AED) was used for the analysis of the individual components of the oil.</p><p>The initial deactivation and the steady-state kinetics were studied during the HDS of thiophene at atmospheric pressure. Unpromoted Mo/γ-Al₂O₃, CoMo/γ-Al₂O₃, NiMo/γ-Al₂O₃, and phosphorus modified NiMo/γ-Al₂O₃ were used for the deactivation study, while NiMo/γ-Al₂O₃,CoMo/γ-Al₂O₃, and Pt/Y-zeolite (with three different pretreatments) were used for the steadystate study. Several experiments related to the deactivation of Mo/γ-Al₂O₃ and NiMo/γ-Al₂O₃catalysts prepared with the chelating agent (NTA) were also performed and NTA was found to have no significant effect on the activity of the catalysts.</p><p>In the deactivation study, a fast initial decrease in the activity was observed on all the catalysts. However, nickel promoted catalysts were found to be more resistant to deactivation than unpromoted ones. The presence of phosphorus slightly increased the activity of the catalyst towards the thiophene HDS, but had no effect on the deactivation behavior. Several methods to regenerate the catalyst were investigated. During the resulfiding experiments, a difference between Mo/γ-Al₂O₃ and NiMo/γ-Al₂O₃ was observed. Deactivation of the Mo catalyst was more severe with increasing temperature, while for the NiMo catalyst the opposite behavior was observed. Carbon deposition on catalysts followed the similar trend: More carbon was observed on the Mo catalyst at higher temperatures, while the opposite is true for NiMo. The restoration of the activity of NiMo was complete, while the reactivation of the Mo catalyst was only partial. The results from the reactivation experiments with pure H₂ and inert gas (helium) suggest that several mechanisms of the restoration of activity exist: Resulfiding of the desulfided active sites, hydrogenation and removal of the deposited carbonaceous species, and the desorption of the reactants and products from the active sites of the catalyst. Based on the observed results, the higher hydrogenation activity of nickel is assumed to be the reason for the behavior. Hydrogenation causes the faster removal of the deposited carbonaceous species and this leads to the conclusion that the desulfiding of the active sites and the adsorption of the reaction species is significantly less pronounced on the NiMo/γ-Al₂O₃catalyst.</p><p>Characterization studies show differences between standard and NTA-based catalysts. The higher amount of carbon on the NTA catalysts is attributed to the presence of the carboncontaining precursor - NTA. The changes in the surface area and the pore volume were observed only during the sulfiding process. In the case of standard catalysts the surface area and the pore volume decreased, while for the NTA-based catalysts the opposite is true. No change in the surface area and the pore volume with the increasing time on stream indicates that the deactivation is not due to structural changes of the catalyst. The amount of sulfur was found to be constant during the time on stream for all the catalysts.</p><p>In the steady-state study of the HDS of thiophene, CoMo and NiMo catalysts were found to be equally active. The activity of the Pt/Y-zeolite catalyst was found to be comparable to conventional catalysts when based on the amount of active material, but a fast deactivation was observed. The product selectivities during the HDS of thiophene were found to be the same for all standard catalysts, but slightly different for the Pt/Y-zeolite catalyst. This was attributed to a higher hydrogenation activity of the Pt/Y-zeolite catalyst. </p><p>The inhibition effect of other sulfur compounds and aromatics on the high-pressure hydrodesulfurization of dibenzothiophene (DBT), the so-called “matrix effect” was studied. Thiophene and DMDS have the same inhibiting effect on the total conversion of DBT, but differences exist in the effect on the selectivities of the products at low concentrations. The results indicate that the inhibiting effect of H₂S on the direct desulfurization route is stronger than the effect of thiophene on the hydrogenation pathway. In the study of aromatics, both toluene and naphthalene affect the total conversion of DBT. Naphthalene was found to be a much stronger inhibitor and inhibits mainly the direct desulfurization pathway, while the hydrogenation route is more affected by the presence of toluene.</p>