No description available.

Common observations of reduced gonad size and spawning inhibition in wild and laboratory raised fish exposed to pulp mill effluents indicate that reproductive neuroendocrine signalling pathways may be upset. This thesis supported the neuroendocrine disruption of reproduction hypothesis by identifying potential disruptors and targets where these impacts may occur. A mechanistic study of the in vivo fathead minnow (FHM) spawning assay used by industry to assess effluent quality showed that ovulation, but not milt production, was impaired. This finding supported the hypothesis that the neuroendocrine cascade that triggers ovulation may be disrupted. I hypothesized that neuroactive constituents previously described in effluents were originating in wood feedstocks and neuroactive extracts of hardwood and conifer feedstocks were identified. Phytochemicals associated with effluents were neuroactive. Structurally similar phenolic phytochemicals showed monoamine oxidase (MAO) inhibition, and resin acid diterpenes displayed glutamic acid decarboxylase (GAD) inhibition. Inhibitors of these enzymes may have impacts on the control of reproduction since MAO metabolizes dopamine, an inhibitor of the neuroendocrine reproductive axis, while GAD synthesizes -aminobutyric acid (GABA), a stimulator of this axis. Bioassay-guided fractionations of effluents and wood feedstocks identified that medium polar extracts of primary- and secondary-treated effluents and balsam fir feedstock contained high GAD inhibitory activity. This activity was associated with chemically complex fractions rather than single active principles. Advanced metabolomic comparison of medium polar extracts of feedstock and treated effluent identified 15 common plant metabolites, demonstrating that phytochemicals entering the mill in wood are surviving pulp production and effluent treatment processes and may be responsible for observed GAD inhibition. Discriminant metabolomics analysis identified 4-acetylpyridine, a novel compound to be described in effluents, as well as two other tentatively identified compounds, as chemical markers of GAD inhibitory effluent fractions. Five tentatively identified chemical markers and (+)-lariciresinol were found in inhibitory balsam fir feedstock fractions. Neuroendocrine pathways that control reproduction in fish, such as dopamine and GABA pathways, are also important drug targets for the treatment of neurological disorders in mammals; therefore these results also have implications for the development of natural health products from phytochemicals and tree extracts common to Canadian forests. By using an interdisciplinary approach (phytochemistry, neuroendocrinology, ecotoxicology), I was able to explore the various implications of my research on the fields of natural health products chemistry and aquatic toxicology.

The mesocorticolimbic system is involved in fundamental processes that drive motivational behaviors essential for survival (feeding, reproduction and sexual behavior, etc.), as well as neurochemical activity involved in mood regulation. Stressful life events are an important cause of dysregulated psychological functioning, which in some leads to a pathophysiology of mood disorders. A source of such disorder could be, among other underlying factors, an impairment of synaptic plasticity induced by alterations in the levels of neurotrophins and/or aberrant glucocorticoid responses. The role of the brain derived neurotrophic factor (BDNF) and its high affinity receptor tyrosine-related kinase B (TrkB) in the mesocorticolimbic reward circuitry has been largely studied in adulthood, yet a possible role of this system in mediating memory and emotional responses induced by stress during the juvenile, adolescence period has not been elucidated. The proposed set of thesis studies are designed to investigate the roles of BDNF and TrkB signaling, via the selective and non-competitive TrkB antagonist, ANA-12 (N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl] benzo[b]thiophene-2-carboxamide), in the expression of stress-induced changes in the brain stress circuitry (including the medial prefrontal cortex (mPFC), hypothalamic-pituitary-adrenal (HPA) axis, and hippocampus) and reward signaling systems of the brain (including the nucleus accumbens (NAc) and ventral tegmental area (VTA)). In addition, experiments aim to determine behavioral changes following stress exposure in male and female Wistar rats. Finally, the possible interplay between BDNF, dopamine, glutamate and orexins in response to repeated stress is examined. Articles 1 and 2, aimed to assess the biochemical and behavioral effects of direct ANA-12 infusion (0.25 µg/ 0.5µl) into the nucleus accumbens shell during exposure to a 10-day heterotypic stress paradigm in male rats. Specifically, Article 1 demonstrated a key role for BDNF/TrkB signaling to regulate stress-induced effects. Notably, the impact of ANA-12 to attenuate anxiety-like behavior in repeatedly stressed rats while increasing anxiety behavior in non-stress rats suggest an interesting behavioral and neurochemical state-dependent process induced by TrkB receptor signaling. Article 2 supports the key role for BDNF secretion in basal and stress-induced behaviors in rats suggesting an influence of TrkB in sociability, motivation and passive avoidance. Furthermore, this role of TrkB extended to increased expression of orexin A in the Perifornical area (PfA) and a decrease in the ventral CA1 of the hippocampus, and in stress-induced elevations in orexinergic projections to the VTA, of which reductions were observed in non-stress groups treated with ANA-12. Article 3 demonstrated gender-specific behavioral and biochemical responses in different developmental periods and the impact of TrkB activation, dependent on stress exposure, to affect the regulation of TrkB receptor isoforms (full length and truncated TrkB, TrkB.FL and TrkB.T1, respectively) in adulthood. Results revealed increased CORT responses in adolescent females relative to males and attenuated CORT secretions in both genders by TrkB inhibition. Elevated activity levels in young adult females and increased passive coping behavior in the forced swim in stress-naïve females were also noted, in addition to novel observations on brain region and sex differences in TrkB receptor isoforms. Taken together, thesis findings derived from applications of ANA-12, shall foster knowledge on the contribution of BDNF in regulation of mood upon stress exposure at times when the brain is undergoing important maturation and remodelling, as well as on the relationship of stress exposure during adolescence and lasting brain and behavioral disorders in adulthood.

Une grande diversité dans la réponse adaptative au stress est observée entre les individus favorisant une sensibilité variable face aux stresseurs et pouvant conduire à une vulnérabilité à développer divers troubles et pathologies. Cette diversité est sous tendue par les caractéristiques propres de chaque individu, déterminées par le patrimoine génétique en interaction avec les facteurs environnementaux. Des études génétiques menées au laboratoire ont permis de placer le gène de la Cbg comme un candidat important influençant les réponses de stress. L’équipe a alors développé un modèle de souris déficiente pour le gène Cbg (k.o. total). La CBG est une glycoprotéine plasmatique responsable de la biodisponibilité et du transport jusqu’à leur cible des glucocorticoïdes, produits finaux de l’axe corticotrope. A l’aide de ce modèle original, l’objectif de mon travail de thèse a été d’étudier les conséquences fonctionnelles de la déficience en CBG sur les réponses de stress. Nous avons ainsi analysé l’activité et la réactivité de l’axe corticotrope ainsi que les comportements émotionnels des mâles et des femelles k.o. Cbg dans des conditions de repos, de stress aigu et dans un contexte mimant l’effet d’un style de vie occidentale (modélisé par une alimentation enrichie en gras, associée à un stress chronique). Nous présentons ainsi un modèle murin unique d’hypo-réponse des glucocorticoïdes au stress associé à une réponse comportementale adaptative ralentie au niveau émotionnel et cognitif. L’ensemble de ces travaux contribue à placer la CBG et son gène comme acteur majeur de la variabilité individuelle des réponses de stress. / A great diversity in the adaptive response to stress is observed between individuals favoring a variable sensitivity to face stressors and leading to a vulnerability to develop various disorders and diseases. This diversity is due to the characteristics of each individual, as determined by the genetic background in interaction with environmental factors. Genetic studies conducted in the laboratory demonstrated that the Cbg gene is an important candidate influencing stress responses. The team then developed a mouse model deficient for the gene Cbg (total k.o.). CBG is a plasma glycoprotein responsible for the bioavailability and the transport of glucocorticoids, the final products of the HPA axis, to their target.Using this original model, the objective of my thesis was to study the functional consequences of CBG deficiency on responses to stress exposure. We have analyzed the activity and reactivity of the HPA axis and the emotional behaviors of males and females k.o. Cbg in resting conditions, acute stress and in a context that mimics the effect of a Western life style (modeled by a high fat diet, associated with chronic stress). We present an unique mouse model of glucocorticoid hyposignaling in response to stress associated with behavioral responses slowed down at the emotional and cognitive levels. Overall, this work contributes to place CBG and its gene as major actor of individual variability to stress.

The aim of this thesis "Regional analysis of the impacts of the projects of the Operational Programme Prague Adaptability (focused on the priority axis 3 Modernization of initial education)" is to find some allocation, aiming and impacts of approved funds of the priority axis 3 Modernization of initial education from the Operational Programme Prague Adaptability, using financial, quantitative and qualitative analysis. The thesis is divided into a theoretical and a practical part. In the theoretical apart there is analysed the structure of EU funds as well as the implementation of the Operational Programme Prague Adaptability. The practical part covers the financial allocation, the structure of the recipients, the location of the realization of the approved projects and their focus. It makes use of the methods of quantitative and qualitative analyses. The financial and quantitative analyses are defined according to various criteria (e.g. priority axis, recipients, calls etc.). The qualitative analysis guarantees the focus of the completed projects, the impacts and their importance for the surroundings. The expert method is used a semi-structured interview with some experts, a questionnaire survey and the method of cartograms. At the end there are summarized the findings from the individual parts of the thesis.

This dissertation details the design of a fish processing and distribution building in the Fishery Port of Maputo. The ‘port’ is explored as a threshold between a city and the ocean and the perceived spatial permanence of city form is brought into dialogue with the constantly changing forces of the harbour across this threshold. The cyclic fluidity of civic life mediates this dialogue to achieve an architecture conscious and manifest of the temporal. / Dissertation (MArch(Prof))--University of Pretoria, 2012. / Architecture / unrestricted

This dissertation contributes to our understanding of the use of the Li-isotopic composition of seawater as a tracer of the earth system with a focus on the role of low-temperature hydrothermal systems within the lava section of the ocean crust. Experiments were conducted to study the exchange coefficient (D(Li/Ca)) and isotopic fractionation factor (α; 1000ln(α)=Δ) for lithium between inorganic calcite and an aqueous solution as a function of solution chemistry. These experiments show that, under the conditions used, D(Li/Ca) negatively correlates with solution H+/Ca2+ ratio (and the solution pH) and Δ positively correlates with solution pH. The change in D(Li/Ca) with solution chemistry is interpreted as indicating that Li is incorporated into calcite as LiHCO3, and hence depends on solution H+/Ca2+. A series of diffusion experiments were performed to test whether changes in pH led to changes in the aqueous Li speciation that would lead to changes in the relative diffusivity of the two Li-isotopes, but no such changes were observed. It is proposed that the change in Δ with changing solution pH may either reflect a kinetic or equilibrium isotope fractionation associated with changing solution chemistry. These results have important implications for interpreting the Li content of calcite that has undergone any diagenetic modification. The Li-content and isotopic composition of rocks altered by low-temperature, off-axis hydrothermal systems in the upper oceanic crust were studied to better understand the role of these systems in controlling the Li-isotopic composition of seawater. Results of a detailed study of DSDP Holes 417A, 417D and 418A from 119 Myr Western North Atlantic Ocean basin show that the Li content of the lavas decreases with depth in the upper ~30 m below sediments while the Li-isotopic composition increases from a low value and then does not show systematic variation in deeper sections. No evidence was found to support a role for a change in mineralogy of alteration products to explain the observed variation in Li composition of lavas. There is also no evidence for the modification of the composition of hydrothermal fluid due to a mixture with sediment pore-fluid. Simple one-dimensional fluid flow and fluid-rock reaction models also cannot explain the observed variation. Instead, a model of free-circulation of seawater through the upper few tens of meters of the lavas, and leakage of modified fluid into the deeper portion of the lava pile seems to explain the observed variations best. To investigate the role of low-temperature off-axis hydrothermal systems on the Li content and isotopic composition of seawater from the Cretaceous to modern era, five DSDP/ODP holes with crustal age spanning from 13.6 to 95 Myr were studied in combination with results from previous studies. Results suggest that the average amount of Li added to the upper oceanic crust decreases, while its average Li-isotopic composition increases, from the Cretaceous to the modern. The simplest explanation for these variations may be a decrease in Li concentration and an increase in Li-isotopic composition, of seawater over this time interval. / Graduate

<p>In this study, structural specificity of flavonoids was investigated toselectively inhibit starch digestive enzymes to stimulate the ileal-brake by triggering glucagon-like peptide-1 (GLP-1) through distal small intestine starch digestion which can regulate food intake and appetite. The double bond between C2 and C3 on flavonoid’s chemical structure plays a critical role to inhibit human pancreatic α-amylase, leading to π-staking interaction. Meanwhile, the hydroxyl group at C3 on the backbone benzopyran ring is intimately related to inhibition of the mucosal α-glucosidases. This selective inhibition is likely the result of fundamental differences in the protein structures of α-amylase and α-glucosidases, as they belong to different glycosyl hydrolase Families 13 and 31 (GH13 and GH31). α-Amylase has the catalytic active siteslocated in wide and shallow grooves on the protein structure, while α-glucosidases possess the narrow and deep catalytic pocket. In an acute study done on mice, luteolin, which had thehigher degree of selectivity toward α-amylase, showed a slow and sustained postprandial glycemic response with a reduced blood glucose peak and extended high glucose profile, compared to 3’,4’-dihydroxylflavonol as the selective α-glucosidases specific inhibitor. Quercetin was inhibitory of both α-amylase and α-glucosidases.Glycemic profiles in mice confirmed in vitro analysis of the inhibitory selectivity of the flavonoids tested. Additionally, the extended glycemic response with luteolin was accompaniedthe higher secretion of GLP-1 at extended postprandial times by delivering more starch portion into the distal small intestine where the ileal-brake and gut-brain axis activation takes place. Overall, selective inhibition of α-amylase by flavonoids potentially could be considered as a key approach to control glucose release from starch with slow and extended, but still complete, digestion for improved glycemic response and minimized adverse side effects that result from severely restricting or even shutting down starch digestion by pharmaceutical grade inhibitors.<br></p>

Chronic stress exposure is hypothesized to increase the risk for developing a mental or physical disease, which can be summarized as an overall increased vulnerability to adverse health conditions. This thesis shows one potential pathway of stress exposure entering the body via activation of the hypothalamus pituitary adrenal (HPA) axis and the interaction between HPA axis and immune activation. Chronic stress caused by work overload or the experience of stressful life events was associated with altered levels of cortisol, the main effector hormone of the HPA axis. Further, chronic stress was shown to effect the distribution of neutrophils, a leukocyte subtype known for its defence properties as well as for its side effects of tissue damage. Additional analyses support a theory that HPA axis and immune cells work in synergy to adapt the organism to chronic stress exposure and therefore represent one pathway how stress can cause altered immune defence toward an increased vulnerability to disease.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23335号 / 生博第453号 / 新制||生||60(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 野田 岳志, 教授 杉田 昌彦, 教授 千坂 修 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM