Structure-function relationships of the alpha1b-adrenergic receptor.

The alpha1b-adrenergic receptor (AR) is a member of the large superfamily of seven transmembrane domain (TMD) G protein-coupled receptors (GPCR). Combining site-directed mutagenesis of the alpha1b-AR with computational simulations of receptor dynamics, we have explored the conformational changes underlying the process of receptor activation, i.e. the transition between the inactive and active states. Our findings suggest that the structural constraint stabilizing the alpha1b-AR in the inactive form is a network of H-bonding interactions amongst conserved residues forming a polar pocket and R143 of the DRY sequence at the end of TMDIII. We have recently reported that point mutations of D142, of the DRY sequence and of A293 in the distal portion of the third intracellular loop resulted in ligand-independent (constitutive) activation of the alpha1b-AR. These constitutively activating mutations could induce perturbations resulting in the shift of R143 out of the polar pocket. The main role of R143 may be to mediate receptor activation by triggering the exposure of several basic amino acids of the intracellular loops towards the G protein. Our investigation has been extended also to the biochemical events involved in the desensitization process of alpha1b-AR. Our results indicate that immediately following agonist-induced activation, the alpha1b-AR can undergo rapid agonist-induced phosphorylation and desensitization. Different members of the G protein coupled receptor kinase family can play a role in agonist-induced regulation of the alpha1b-AR. In addition, constitutively active alpha1b-AR mutants display different phosphorylation and internalization features. The future goal is to further elucidate the molecular mechanism underlying the complex equilibrium between activation and inactivation of the alpha1b-AR and its regulation by pharmacological substances. These findings can help to elucidate the mechanism of action of various agents displaying properties of agonists or inverse agonists at the adrenergic system.

Covariation between colony social structure and immune defences of workers in the ant Formica selysi

Several ant species vary in the number of queens per colony, yet the causes and consequences of this variation remain poorly understood. In previous experiments, we found that Formica selysi workers originating from multiple-queen (=polygyne) colonies had a lower resistance to a fungal pathogen than workers originating from single-queen (=monogyne) colonies. In contrast, group diversity improved disease resistance in experimental colonies. This discrepancy between field and experimental colonies suggested that variation in social structure in the field had antagonistic effects on worker resistance, possibly through a down-regulation of the immune system balancing the positive effect of genetic diversity. Here, we examined if workers originating from field colonies with alternative social structure differed in three major components of their immune system. We found that workers from polygyne colonies had a lower bacterial growth inhibitory activity than workers from monogyne colonies. In contrast, workers from the two types of colonies did not differ significantly in bacterial cell wall lytic activity and prophenoloxidase activity. Overall, the presence of multiple queens in a colony correlated with a slight reduction in one inducible component of the immune system of individual workers. This reduced level of immune defence might explain the lower resistance of workers originating from polygyne colonies despite the positive effect of genetic diversity. More generally, these results indicate that social changes at the group level can modulate individual immune defences.

Superficial and deep changes of cellular mechanical properties following cytoskeleton disassembly.

The cytoskeleton, composed of actin filaments, intermediate filaments, and microtubules, is a highly dynamic supramolecular network actively involved in many essential biological mechanisms such as cellular structure, transport, movements, differentiation, and signaling. As a first step to characterize the biophysical changes associated with cytoskeleton functions, we have developed finite elements models of the organization of the cell that has allowed us to interpret atomic force microscopy (AFM) data at a higher resolution than that in previous work. Thus, by assuming that living cells behave mechanically as multilayered structures, we have been able to identify superficial and deep effects that could be related to actin and microtubule disassembly, respectively. In Cos-7 cells, actin destabilization with Cytochalasin D induced a decrease of the visco-elasticity close to the membrane surface, while destabilizing microtubules with Nocodazole produced a stiffness decrease only in deeper parts of the cell. In both cases, these effects were reversible. Cell softening was measurable with AFM at concentrations of the destabilizing agents that did not induce detectable effects on the cytoskeleton network when viewing the cells with fluorescent confocal microscopy. All experimental results could be simulated by our models. This technology opens the door to the study of the biophysical properties of signaling domains extending from the cell surface to deeper parts of the cell.

Rights jurisprudence and the charter : evaluating the changing structure of Canadian federalism /

Abstract . Rights jiirisprudence in Canada dates back as far as Confederation in 1867. Between this date and 1982, the organizing principle of Confederation - federalism - has kept this jurisprudence solely within the supremacy of Parliament, subject to its confines and division of powers. After 1982, however, a new constitutional organizing principle was introduced, when Prime Minister Pierre Trudeau introduced the patriation initiative, touted as the "people's package". Individual rights and freedoms were now guaranteed by the Constitution. Citizens of Canada now had a direct link to the Constitution via the Charter and there were now two significantly different organizing principles within the constitutional order widch created an unstable coexistence. This instability has led to a clash between judicially enforced Charter rights and federalism. The Charter has since had both a nationalizing and centralizing effect on Canadian federalism. This thesis explores the relationship between rights and federalism in Canada fix)m Confederation to present day by comparing the jurisprudence of pre and post Charter Canada. An analysis of Supreme Court's (and its predecessor's, the JCPC) decisions shows the profound effect the Charter has had on Canadian federalism. The result has been an undermining of federalism in Canada, with Parliamentary Supremacy replaced by Constitutional supremacy, and ultimately. Judicial Supremacy. Moreover, rights discourse has largely replaced federalism discourse. Canadians have become very attached to their Charter, and are unwilling to allow any changes to the constitution that may affect their rights as political elites discovered the hard way after the collapse of the Meech and Charlottetown Accords. If federalism is to remain a relevant and viable organizing principle in the Constitution, then governments, especially at the provincial level, must find new and iimovative ways to assert their importance within the federation.

Evolution of an Archean greenstone belt in the Stormy Lake - Kawashegamuk Lake area (stratigraphy, structure and geochemistry) - Western Wabigoon Subprovince, Northwest Ontario /

330 km 2 of the easter-n part of the Archean Manitou Lakes - Stormy Lake metavolcanic - metasedimentary belt have been mapped and sampled. A large number of rocks ~.vere analyzed for the major and trace constituents including the rare-earth elements (REE). The Stormy Lake - Kawashegamuk Lake area may be subdivided into four major lithological groups of supracrustal rocks 1) A north-facing mafic assemblage, consisting of pillowed tholeiitic basalts and gabbro sills characterized by flat REE profiles, is exposed in the south part of the map area and belongs to a 8000 m thick homoclinal assemblage outside the map area. Felsic pyroclastic rocks believed to have been issued from a large central vent conformably overlie the tholeiites. 2) A dominantly epiclastic group facing to the north consists of terrestrial deposits interpreted to be an alluvial fan deposit ; a submarine facies is represented by turbiditic sediments. 3) The northeastern part of the study area consists of volcanic rocks belonging to two mafic - felsic cycles facing to the southuest ; andesitic flows with fractionated REE patterns make up a large part of the upper cycle, whereas the lower cycle has a stronger chemical polarity being represented by tholeiitic flows, with flat REE, which a r e succeeded by dacitic and rhyolitic pyroclasti cs. iii 4) A thick monotonous succession of tholeiitic pillmled basalt f lows and gabbro sills with flat REE represent the youngest supracrustal rocks. TIle entire belt underwent folding, faulting and granitic plutonism during a tectono-thermal event around 2700 Ma ago. Rocks exposed in the map area were subjected to regional greenschist facies metamorphism, but higher metamorphic grades are present near late granitic intrusions. Geochemical studies have been useful in 1) distinguishing the various rock units ; 2) relating volcanic and intrusive rocks 3) studying the significance of chemical changes due to post magmatic processes 4) determining the petrogenesis of the major volcanic rock types. In doing so, two major volcanic suites have been recognized : a) a tholeiitic suite, mostly represented by mafic rocks, was derived from partial melting of upper mantle material depleted in Ti, K and the light REE ; b) a calc-alkalic suite which evolved from partial melting of amphibolite in the lower crust. The more differentiated magma types have been produced by a multistage process involving partial melting and fractional crystallization to yield a continuum of compos i t i ons ranging from basaltic andesite to rhyolite. A model for the development of the eastern part of the Manitou Lakes - Stormy Lake belt has been proposed.

The crystal and molecular structure of 18-Crown-6 HgC12 and 18-Crown-6 Cdc12

Hg(18-Crown-6)C12 and Cd(18-Crown-6)C12 are isostructura1, space group Cl~ Z = 2. For the mercury compound, a = 10.444(2) A° , b = 11. 468(1) A° , c = 7.754(1) A° , a = 90.06(1)°, B = 82.20(1)°, Y = 90.07(1)°, Dobs = 1.87, Dca1c = 1.93, V = 920.05 13, R = 4.66%. For the cadmium compound, 000 a = 10.374(1) A, b = 11.419(2) A, c = 7.729(1) A, a = 89.95(1)°, B = 81.86(2)°, Y = 89.99(1)°, Dobs = 1.61, Dcalc = 1.64, V = 906.4613, R = 3.95%. The mercury and cadmium ions exhibit hexagonal bipyramidal coordination, with the metal ion located on a centre of symmetry in the plane of the oxygen atoms. The main differences between the two structures are an increase in the metal-oxygen distance and a reduction in the metalchloride distance when the central ion changes from Cd2+ to Hg2+. These differences may be explained in terms of the differences in hardness or softness of the metal ions and the donor atoms.

The effectiveness of explicit strategy instruction on the top level structure of a text

Thesis (M.Ed.)-- Brock University, 1995.

The relationship between stem-form, stand-closure and site -conditions : the influence of environmental conditions on tree allometry and forest structure in west-central Alberta

Changes in the configuration of a tree stern result insignificant differences in its total volume and in the proportion of that volume that is merchantable timber. Tree allometry, as represented by stem-fo~, is the result of the vertical force of gravity and the horizontal force of wind. The effect of wind force is demonstrated in the relationship between stem-form, standclosure and site-conditions. An increase in wind force on the individual tree due to a decrease in stand density should produce a more tapered tree. The density of the stand is determined by the conditions that the trees are growing under. The ability of the tree to respond to increased wind force may also be a function of these conditions . This stem-form/stand-closure/site-conditions relationship was examined using a pre-existing database from westcentral Alberta. This database consisted of environmental, vegetation, soils and timber data covering a wide range of sites. There were 653 sample trees with 82 variables that formed the basis of the analysis. There were eight tree species consisting of Pinus contorta, Picea mariana, Picea engelmannii x glauca, Abies lasiocarpa, Larix laricina, Populus tremuloides, Betula papyrifera and Populus balsamifera plus a comprehensive all-species data set. As the actual conformation of the stern is very individual, stem-fo~was represented by the diameter at breast height to total height r~tio. The four stand-closure variables, crown closure, total basal area, total volume and total number of stems were reduced to total basal area and total number of stems utilizing a bivariate correlation matrix by species. Site-conditions were subdivided into macro, meso and micro variables and reduced in number 3 using cross-tabulations, bivariate correlation and principal components analysis as screening tools. The stem-fo~/stand-closure relationship was examined using bivariate correlation coefficients for stem-fo~ with total number of stems and stem-fo~ with total basal area. The stem-fo~/site-conditions and the stand-closure/site- conditions relationships were examined using multiple correlation coefficients. The stem-form/stand-closure/site-conditions relationship was examined using multiple correlation coefficients in separate analyses for both total number of stems and total basal area. An increase in stand-closure produced a decrease in stem-form for both total number of stems and total basal area for most species. There was a significant relationship between stem-form and site-conditions and between stand-closure and site-conditions for both total number of stems and total basal area for most species. There was a significant relationship between the stemform and site-conditions, including the stand-closure, for most species; total number of stems was involved independently of the site-conditions in the prediction of stem-form and total basal area was not. Larix laricina and Betula papyrifera were the exceptions to the trends observed with most species. The influence of both stand-closure (total number of stems in particular) and site-conditions (elevation in particular) suggest that forest management practices should include these- ecological parameters in determining appropriate restocking levels.

The Structural and Functional Changes of Blood Vessels during Aging

The vascular adventitia is recognized as a dynamic mediator of vascular structure and function, yet its role in aging is not understood. The purpose of this thesis was to examine the age-related changes of the vascular adventitia and determine the underlying mediators responsible. Male Sprague-Dawley rats were aged to 15, 30, 50 and 80 weeks before being anesthetised and euthanized by exsanguination. Thoracic aortas, mesenteric and pudental arteries were isolated, formalin fixed, and embedded in paraffin then sectioned at 5μm. Vessels were examined by microscopy and protein expression was determined by indirect immunofluorescence. The thickness of the adventitia increased dramatically with age. Immunofluorescence revealed a robust expression of endothelin system proteins in the adventitia. Additionally, extracellular matrix proteins collagen and fibronectin, and the proliferation marker Ki67 showed strong adventitial origin. The changes observed in the vascular adventitia with aging clearly demonstrate an important role in the process of vascular aging.

Left ventricular structure in children with developmental coordination disorder

Developmental coordination disorder (p-DCD) is a neuro-developmental disorder featuring impairment in developing motor coordination. This study examined left ventricular mass (LVM) in children with p-DCD (n=63) and controls (n=63). LVM was measured using echocardiography. Body composition was determined using BOD POD and peak oxygen uptake (peak V02) was measured by a progressive exercise test. Height, weight and blood pressure were also measured. LVM was not significantly elevated in p-DCD compared to controls. Peak V02 was lower and SBP, BMI, HR, and BF(%) were significantly higher in p-DCD. They also demonstrated elevated stroke volume (SV), cardiac output (CO), end-diastolic volume, and ventricular diameter in diastole. In regression analyses, p-DCD was a significant predictor of SV and CO after accounting for height, FFM, V02FFM, and sex. These differences in children with p-DCD indicate obesity related changes in the left ventricle and may represent early stages of developing hypertrophy of the left ventricle.

The structural and functional changes of blood vessels during aging

The vascular adventitia is recognized as a dynamic mediator of vascular structure and function, yet its role in aging is not understood. The purpose of this thesis was to examine the age-related changes of the vascular adventitia and determine the underlying mediators responsible. Male Sprague-Dawley rats were aged to 15,30,50 and 80 weeks before being anesthetised and euthanized by exsanguination. Thoracic aortas, mesenteric and pudental arteries were isolated, formalin fixed, and embedded in paraffin then sectioned at 51lm. Vessels were examined by microscopy and protein expression was determined by indirect immunofluorescence. The thickness of the adventitia increased dramatically with age. Immunofluorescence revealed a robust expression of endothelin system proteins in the adventitia. Additionally, extracellular matrix proteins collagen and fibronectin, and the proliferation marker Ki67 showed strong adventitial origin. The changes observed in the vascular adventitia with aging clearly demonstrate an important role in the process of vascular aging.

Some Implications of the Zero Lower Bound on Interest Rates for the Term Structure and Monetary Policy

In an economy where cash can be stored costlessly (in nominal terms), the nominal interest rate is bounded below by zero. This paper derives the implications of this nonnegativity constraint for the term structure and shows that it induces a nonlinear and convex relation between short- and long-term interest rates. As a result, the long-term rate responds asymmetrically to changes in the short-term rate, and by less than predicted by a benchmark linear model. In particular, a decrease in the short-term rate leads to a decrease in the long-term rate that is smaller in magnitude than the increase in the long-term rate associated with an increase in the short-term rate of the same size. Up to the extent that monetary policy acts by affecting long-term rates through the term structure, its power is considerably reduced at low interest rates. The empirical predictions of the model are examined using data from Japan.

Political Influence, Economic Interests and Endogenous Tax Structure in a Computable Equilibrium Framework: with Applicatioon to the United States, 1973 and 1983

A full understanding of public affairs requires the ability to distinguish between the policies that voters would like the government to adopt, and the influence that different voters or group of voters actually exert in the democratic process. We consider the properties of a computable equilibrium model of a competitive political economy in which the economic interests of groups of voters and their effective influence on equilibrium policy outcomes can be explicitly distinguished and computed. The model incorporates an amended version of the GEMTAP tax model, and is calibrated to data for the United States for 1973 and 1983. Emphasis is placed on how the aggregation of GEMTAP households into groups within which economic and political behaviour is assumed homogeneous affects the numerical representation of interests and influence for representative members of each group. Experiments with the model suggest that the changes in both interests and influence are important parts of the story behind the evolution of U.S. tax policy in the decade after 1973.

Structure et dynamique des communautés multi-espèces : le rôle de l’espace

Cette thèse porte sur le rôle de l’espace dans l’organisation et dans la dynamique des communautés écologiques multi-espèces. Deux carences peuvent être identifiées dans les études théoriques actuelles portant sur la dimension spatiale des communautés écologiques : l’insuffisance de modèles multi-espèces représentant la dimension spatiale explicitement, et le manque d’attention portée aux interactions positives, tel le mutualisme, en dépit de la reconnaissance de leur ubiquité dans les systèmes écologiques. Cette thèse explore cette problématique propre à l’écologie des communautés, en utilisant une approche théorique s’inspirant de la théorie des systèmes complexes et de la mécanique statistique. Selon cette approche, les communautés d’espèces sont considérées comme des systèmes complexes dont les propriétés globales émergent des interactions locales entre les organismes qui les composent, et des interactions locales entre ces organismes et leur environnement. Le premier objectif de cette thèse est de développer un modèle de métacommunauté multi-espèces, explicitement spatial, orienté à l’échelle des individus et basé sur un réseau d’interactions interspécifiques générales comprenant à la fois des interactions d’exploitation, de compétition et de mutualisme. Dans ce modèle, les communautés locales sont formées par un processus d’assemblage des espèces à partir d’un réservoir régional. La croissance des populations est restreinte par une capacité limite et leur dynamique évolue suivant des mécanismes simples de reproduction et de dispersion des individus. Ces mécanismes sont dépendants des conditions biotiques et abiotiques des communautés locales et leur effet varie en fonction des espèces, du temps et de l’espace. Dans un deuxième temps, cette thèse a pour objectif de déterminer l’impact d’une connectivité spatiale croissante sur la dynamique spatiotemporelle et sur les propriétés structurelles et fonctionnelles de cette métacommunauté. Plus précisément, nous évaluons différentes propriétés des communautés en fonction du niveau de dispersion des espèces : i) la similarité dans la composition des communautés locales et ses patrons de corrélations spatiales; ii) la biodiversité locale et régionale, et la distribution locale de l’abondance des espèces; iii) la biomasse, la productivité et la stabilité dynamique aux échelles locale et régionale; et iv) la structure locale des interactions entre les espèces. Ces propriétés sont examinées selon deux schémas spatiaux. D’abord nous employons un environnement homogène et ensuite nous employons un environnement hétérogène où la capacité limite des communautés locales évoluent suivant un gradient. De façon générale, nos résultats révèlent que les communautés écologiques spatialement distribuées sont extrêmement sensibles aux modes et aux niveaux de dispersion des organismes. Leur dynamique spatiotemporelle et leurs propriétés structurelles et fonctionnelles peuvent subir des changements profonds sous forme de transitions significatives suivant une faible variation du niveau de dispersion. Ces changements apparaissent aussi par l’émergence de patrons spatiotemporels dans la distribution spatiale des populations qui sont typiques des transitions de phases observées généralement dans les systèmes physiques. La dynamique de la métacommunauté présente deux régimes. Dans le premier régime, correspondant aux niveaux faibles de dispersion des espèces, la dynamique d’assemblage favorise l’émergence de communautés stables, peu diverses et formées d’espèces abondantes et fortement mutualistes. La métacommunauté possède une forte diversité régionale puisque les communautés locales sont faiblement connectées et que leur composition demeure ainsi distincte. Par ailleurs dans le second régime, correspondant aux niveaux élevés de dispersion, la diversité régionale diminue au profit d’une augmentation de la diversité locale. Les communautés locales sont plus productives mais leur stabilité dynamique est réduite suite à la migration importante d’individus. Ce régime est aussi caractérisé par des assemblages incluant une plus grande diversité d’interactions interspécifiques. Ces résultats suggèrent qu’une augmentation du niveau de dispersion des organismes permet de coupler les communautés locales entre elles ce qui accroît la coexistence locale et favorise la formation de communautés écologiques plus riches et plus complexes. Finalement, notre étude suggère que le mutualisme est fondamentale à l’organisation et au maintient des communautés écologiques. Les espèces mutualistes dominent dans les habitats caractérisés par une capacité limite restreinte et servent d’ingénieurs écologiques en facilitant l’établissement de compétiteurs, prédateurs et opportunistes qui bénéficient de leur présence.